Atlas of Genetics and - Revues et Congrèsdocuments.irevues.inist.fr/bitstream/handle/2042/45787/... · 2019. 12. 6. · Richard Gatti (Los Angeles, California) ... Maf oncoproteins

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The Atlas of Genetics and Cytogenetics in Oncology and Haematology is a peer reviewed on-line journal in open

access, devoted to genes, cytogenetics, and clinical entities in cancer, and cancer-prone diseases.

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educational items in the various related topics for students in Medicine and in Sciences.

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Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3)







Editor

Jean-Loup Huret

(Poitiers, France)

Editorial Board

Sreeparna Banerjee (Ankara, Turkey) Solid Tumours Section

Alessandro Beghini (Milan, Italy) Genes Section

Anne von Bergh (Rotterdam, The Netherlands) Genes / Leukaemia Sections

Judith Bovée (Leiden, The Netherlands) Solid Tumours Section

Vasantha Brito-Babapulle (London, UK) Leukaemia Section

Charles Buys (Groningen, The Netherlands) Deep Insights Section

Anne Marie Capodano (Marseille, France) Solid Tumours Section

Fei Chen (Morgantown, West Virginia) Genes / Deep Insights Sections

Antonio Cuneo (Ferrara, Italy) Leukaemia Section

Paola Dal Cin (Boston, Massachussetts) Genes / Solid Tumours Section

Louis Dallaire (Montreal, Canada) Education Section

Brigitte Debuire (Villejuif, France) Deep Insights Section

François Desangles (Paris, France) Leukaemia / Solid Tumours Sections

Enric Domingo-Villanueva (London, UK) Solid Tumours Section

Ayse Erson (Ankara, Turkey) Solid Tumours Section

Richard Gatti (Los Angeles, California) Cancer-Prone Diseases / Deep Insights Sections

Ad Geurts van Kessel (Nijmegen, The Netherlands) Cancer-Prone Diseases Section

Oskar Haas (Vienna, Austria) Genes / Leukaemia Sections

Anne Hagemeijer (Leuven, Belgium) Deep Insights Section

Nyla Heerema (Colombus, Ohio) Leukaemia Section

Jim Heighway (Liverpool, UK) Genes / Deep Insights Sections

Sakari Knuutila (Helsinki, Finland) Deep Insights Section

Lidia Larizza (Milano, Italy) Solid Tumours Section

Lisa Lee-Jones (Newcastle, UK) Solid Tumours Section

Edmond Ma (Hong Kong, China) Leukaemia Section

Roderick McLeod (Braunschweig, Germany) Deep Insights / Education Sections

Cristina Mecucci (Perugia, Italy) Genes / Leukaemia Sections

Yasmin Mehraein (Homburg, Germany) Cancer-Prone Diseases Section

Fredrik Mertens (Lund, Sweden) Solid Tumours Section

Konstantin Miller (Hannover, Germany) Education Section

Felix Mitelman (Lund, Sweden) Deep Insights Section

Hossain Mossafa (Cergy Pontoise, France) Leukaemia Section

Stefan Nagel (Braunschweig, Germany) Deep Insights / Education Sections

Florence Pedeutour (Nice, France) Genes / Solid Tumours Sections

Elizabeth Petty (Ann Harbor, Michigan) Deep Insights Section

Susana Raimondi (Memphis, Tennesse) Genes / Leukaemia Section

Mariano Rocchi (Bari, Italy) Genes Section

Alain Sarasin (Villejuif, France) Cancer-Prone Diseases Section

Albert Schinzel (Schwerzenbach, Switzerland) Education Section

Clelia Storlazzi (Bari, Italy) Genes Section

Sabine Strehl (Vienna, Austria) Genes / Leukaemia Sections

Nancy Uhrhammer (Clermont Ferrand, France) Genes / Cancer-Prone Diseases Sections

Dan Van Dyke (Rochester, Minnesota) Education Section

Roberta Vanni (Montserrato, Italy) Solid Tumours Section

Franck Viguié (Paris, France) Leukaemia Section

José Luis Vizmanos (Pamplona, Spain) Leukaemia Section

Thomas Wan (Hong Kong, China) Genes / Leukaemia Sections




Volume 14, Number 3, March 2010

Table of contents

Gene Section

MAFA (v-maf musculoaponeurotic fibrosarcoma oncogene homolog A (avian)) 235 Celio Pouponnot, Alain Eychène

MAP3K7 (mitogen-activated protein kinase kinase kinase 7) 238 Hui Hui Tang, Kam C Yeung

MCPH1 (microcephalin 1) 243 Yulong Liang, Shiaw-Yih Lin, Kaiyi Li

NKX3-1 (NK3 homeobox 1) 246 Liang-Nian Song, Edward P Gelmann

PLXNB1 (plexin B1) 249 José Javier Gómez-Román, Montserrat Nicolas Martínez,

Servando Lazuén Fernández, José Fernando Val-Bernal

RUVBL1 (RuvB-like 1 (E. coli)) 254 Valérie Haurie, Aude Grigoletto, Jean Rosenbaum

RUVBL2 (RuvB-like 2 (E. coli)) 257 Aude Grigoletto, Valérie Haurie, Jean Rosenbaum

SH3GL2 (SH3-domain GRB2-like 2) 260 Chinmay Kr Panda, Amlan Ghosh, Guru Prasad Maiti

TOPORS (topoisomerase I binding, arginine/serine-rich) 263 Jafar Sharif, Asami Tsuboi, Haruhiko Koseki

TRPV6 (transient receptor potential cation channel, subfamily V, member 6) 267 Yoshiro Suzuki, Matthias A Hediger

ADAM9 (ADAM metallopeptidase domain 9 (meltrin gamma)) 270 Shian-Ying Sung

CYP7B1 (cytochrome P450, family 7, subfamily B, polypeptide 1) 275 Maria Norlin

EPHA3 (EPH receptor A3) 279 Brett Stringer, Bryan Day, Jennifer McCarron, Martin Lackmann, Andrew Boyd

JAZF1 (JAZF zinc finger 1) 286 Hui Li, Jeffrey Sklar

LPAR1 (lysophosphatidic acid receptor 1) 289 Mandi M Murph, Harish Radhakrishna

PIK3CA (phosphoinositide-3-kinase, catalytic, alpha polypeptide) 293 Montserrat Sanchez-Cespedes

SFRP4 (Secreted Frizzled-Related Protein 4) 296 Kendra S Carmon, David S Loose

SRC (v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (avian)) 301 Stephen Hiscox

t(11;14)(q13;q32) in multiple myeloma Huret JL, Laï JL




TACC3 (transforming, acidic coiled-coil containing protein 3) 305 Melissa R Eslinger, Brenda Lauffart, Ivan H Still

TP53INP1 (tumor protein p53 inducible nuclear protein 1) 311 Mylène Seux, Alice Carrier, Juan Iovanna, Nelson Dusetti

Leukaemia Section

del(5q) in myeloid neoplasms 314 Kazunori Kanehira, Rhett P Ketterling, Daniel L Van Dyke

t(11;11)(q13;q23) 317 Jean-Loup Huret

t(11;19)(q23;p13.3) MLL/ACER1 319 Jean-Loup Huret

t(2;5)(p21;q33) 320 Jean-Loup Huret

Solid Tumour Section

Head and Neck: Ear: Endolymphatic Sac Tumor (ELST) 321 Rodney C Diaz

Lymphangioleiomyoma 327 Connie G Glasgow, Angelo M Taveira-DaSilva, Joel Moss

http://edition.inist.fr/




Gene Section Mini Review

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 235



MAFA (v-maf musculoaponeurotic fibrosarcoma oncogene homolog A (avian)) Celio Pouponnot, Alain Eychène

Institut Curie, CNRS UMR 146, F-91405 Orsay, France (CP, AE)

Published in Atlas Database: March 2009

Online updated version: http://AtlasGeneticsOncology.org/Genes/MAFAID41235ch8q24.html DOI: 10.4267/2042/44698

This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity Other names: RIPE3b1; KLRG1; Maf-A,: hMafA; L-

Maf

HGNC (Hugo): MAFA

Location: 8q24.3

Local order: C8orf51, RHPN1, MAFA, ZC3H3,

GSDMD

DNA/RNA

Note

The MAFA open reading frame is encoded by a unique

exon. The entire genomic organization and the putative

existence of non-coding exons remain unknown.

Transcription

MAFA displays a restricted expression pattern. It is

notably expressed in pancreas (in beta-cells) and lens.

Pseudogene

Unknown.

Protein

Note

Maf oncoproteins are b-ZIP transcription factors that

belong to the AP-1 super-family, which notably

includes JUN and FOS. The Maf family contains seven

members, which can be subdivided into two groups; the

large and small Maf proteins. While the small Maf

proteins, MAFF, MAFG and MAFK, are essentially

composed of a b-Zip domain, the large Maf proteins,

MAFA/L-MAF, MAFB, MAF/c-MAF and NRL

contain an additional amino-terminal transactivation

domain. MAFA was initially cloned in quail and

chicken species and named MAFA and L-MAF,

respectively. More recently, mammalian MAFA was

cloned and identi-fied as an essential component of the

RIPE3b1 complex, which binds the insulin promoter.

Schematic representation of the MAFA protein structure. Critical residues involved in post-translational modifications are indicated by the color code. The kinases responsible for S14 and S65 phosphorylation in MAFA remain to be identified. GSK-3 phosphorylates the transactivation domain of MAFA, thereby inducing its ubiquitination and proteasome-dependent degradation. This is linked to an increase in MAFA transactivation. These phosphorylations are required for MAFA transforming activity. In contrast, sumoylation of MAFA transactivation domain decreases its transactivation activity.

MAFA (v-maf musculoaponeurotic fibrosarcoma oncogene homolog A (avian)) Pouponnot C, Eychène A


Description

MAFA, like all large Maf proteins, contains an amino-

terminal transactivation domain and a carboxy-terminal

b-ZIP DNA binding domain. Large Maf proteins

stimulate transcription of their target genes through

their binding to two types of palindromic sequences

called TRE- or CRE- type MARE (Maf Responsive

Element) (TGCTGAC(G) TCAGCA). The leucine

zipper domain allows the formation of homo- or hetero-

dimers, an absolute pre-requisite for DNA binding. As

homodimers, these proteins recognize palindromic

sequences, with the basic domain contacting DNA

directly. Among the AP-1 family, the Maf proteins are

defined by the presence of an additional homolo-gous

domain, called the Extended Homology Region (EHR)

or ancillary domain, which also contacts DNA.

Consequently, they recognize a longer palindromic

sequence than other AP-1 family members. The MARE

sequence is composed of a TRE or CRE core contacted

by the basic domain and a TGC flanking sequence,

which is recognized by the EHR domain. While the

TGC motif is crucial for Maf binding, the TRE/CRE

core can be more degenerate. MAFA transactivation

activity and stability is regulated by post-trans-lational

modifications (phosphorylation, ubiquityla-tion and

sumoylation) mostly occuring on the transactivation

domain. GSK-3 was identified as the major protein

kinase regulating MAFA activity and oncogenic

properties.

Expression

Endogenous MAFA protein is detected and phos-

phorrylated in pancreatic beta cells.

Localisation

Nucleus.

Function

During development, Maf proteins are involved early in

specification and later in terminal differen-tiation.

MAFA is involved in the regulation of insulin gene

expression in pancreatic beta cells. Accordingly,

MAFA ablation in mice leads to diabetes.

Besides their roles during development, large Maf

proteins, MAFA, MAFB, and MAF/c-MAF are also

involved in oncogenesis.

Homology

MAFB and MAF/c-MAF are the closest MAFA

homologs. The MAFA entire protein sequence shares

52%, 48% and 40% identity with those of MAFB,

MAF/c-MAF and NRL, respectively. MAFA DNA

binding domain (EHR + b-ZIP) shares 82%, 83%, 64%

and 55-60% identity with those of MAFB, MAF/c-

MAF, NRL and small MAFs, respectively. MAFA and

JUN share 30% sequence identity in their b-ZIP

domain (20% identity in their entire sequence).

Implicated in

Multiple myeloma

Hybrid/Mutated gene

Two cases reported translocations of MAFA to the

immunoglobulin heavy-chain (IgH) locus, juxta-posing

the MAFA gene with the strong enhancers of the IgH

locus (meeting report, accurate description lacking).

Oncogenesis

Large Maf proteins, MAFA, MAFB, and MAF/c-MAF

are bona fide oncogenes as demonstrated in tissue

culture, animal models and in human cancers. MAFA

displays the strongest transforming activity, in vitro. In

human, MAF/c-MAF, MAFB and MAFA genes are

translocated to the immunoglo-bulin heavy chain (IgH)

locus in 8-10% of multiple myelomas. MAFA

translocations are present in less than 1% of multiple

myelomas. MAF/C-MAF over-expression plays a

causative role in multiple myeloma by promoting

proliferation and patholo-gical interactions with bone

marrow stroma.

The transforming activity of Maf proteins is context

dependent and they can occasionally display tumor

suppressor-like activity in specific cellular settings.

Their transforming activity relies on overexpression

and does not require an activating mutation (no

activating mutation has been identified to be associated

with human cancers). It is regulated by post-

translational modifications, notably phospho-rylation.

References Benkhelifa S, Provot S, Lecoq O, Pouponnot C, Calothy G, Felder-Schmittbuhl MP. mafA, a novel member of the maf proto-oncogene family, displays developmental regulation and mitogenic capacity in avian neuroretina cells. Oncogene. 1998 Jul 16;17(2):247-54

Ogino H, Yasuda K. Induction of lens differentiation by activation of a bZIP transcription factor, L-Maf. Science. 1998 Apr 3;280(5360):115-8

Benkhelifa S, Provot S, Nabais E, Eychène A, Calothy G, Felder-Schmittbuhl MP. Phosphorylation of MafA is essential for its transcriptional and biological properties. Mol Cell Biol. 2001 Jul;21(14):4441-52

Kataoka K, Han SI, Shioda S, Hirai M, Nishizawa M, Handa H. MafA is a glucose-regulated and pancreatic beta-cell-specific transcriptional activator for the insulin gene. J Biol Chem. 2002 Dec 20;277(51):49903-10

Olbrot M, Rud J, Moss LG, Sharma A. Identification of beta-cell-specific insulin gene transcription factor RIPE3b1 as mammalian MafA. Proc Natl Acad Sci U S A. 2002 May 14;99(10):6737-42

Matsuoka TA, Zhao L, Artner I, Jarrett HW, Friedman D, Means A, Stein R. Members of the large Maf transcription family regulate insulin gene transcription in islet beta cells. Mol Cell Biol. 2003 Sep;23(17):6049-62

Nishizawa M, Kataoka K, Vogt PK. MafA has strong cell transforming ability but is a weak transactivator. Oncogene. 2003 Sep 11;22(39):7882-90

MAFA (v-maf musculoaponeurotic fibrosarcoma oncogene homolog A (avian)) Pouponnot C, Eychène A


Hanamura I, Iida S, Ueda R, Kuehl M, Cullraro C, Bergsagel L, Sawyer J, Barlogie B, Shaughnessy Jr J.. Identification of three novel chromosomal translocation partners involving the immunoglobulin loci in newly diagnosed myeloma and human myeloma cell lines. Blood (ASH Annual Meeting Abstracts) 2005; 106:1552.

Sii-Felice K, Pouponnot C, Gillet S, Lecoin L, Girault JA, Eychène A, Felder-Schmittbuhl MP. MafA transcription factor is phosphorylated by p38 MAP kinase. FEBS Lett. 2005 Jul 4;579(17):3547-54

Zhang C, Moriguchi T, Kajihara M, Esaki R, Harada A, Shimohata H, Oishi H, Hamada M, Morito N, Hasegawa K, Kudo T, Engel JD, Yamamoto M, Takahashi S. MafA is a key regulator of glucose-stimulated insulin secretion. Mol Cell Biol. 2005 Jun;25(12):4969-76

Pouponnot C, Sii-Felice K, Hmitou I, Rocques N, Lecoin L, Druillennec S, Felder-Schmittbuhl MP, Eychène A. Cell context reveals a dual role for Maf in oncogenesis. Oncogene. 2006 Mar 2;25(9):1299-310

Chng WJ, Glebov O, Bergsagel PL, Kuehl WM. Genetic events in the pathogenesis of multiple myeloma. Best Pract Res Clin Haematol. 2007 Dec;20(4):571-96

Han SI, Aramata S, Yasuda K, Kataoka K. MafA stability in pancreatic beta cells is regulated by glucose and is dependent on its constitutive phosphorylation at multiple sites by glycogen synthase kinase 3. Mol Cell Biol. 2007 Oct;27(19):6593-605

Rocques N, Abou Zeid N, Sii-Felice K, Lecoin L, Felder-Schmittbuhl MP, Eychène A, Pouponnot C. GSK-3-mediated phosphorylation enhances Maf-transforming activity. Mol Cell. 2007 Nov 30;28(4):584-97

Eychène A, Rocques N, Pouponnot C. A new MAFia in cancer. Nat Rev Cancer. 2008 Sep;8(9):683-93

Shao C, Cobb MH. Sumoylation regulates the transcriptional activity of MafA in pancreatic beta cells. J Biol Chem. 2009 Jan 30;284(5):3117-24

This article should be referenced as such:

Pouponnot C, Eychène A. MAFA (v-maf musculoaponeurotic fibrosarcoma oncogene homolog A (avian)). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3):235-237.

Gene Section Review




MAP3K7 (mitogen-activated protein kinase kinase kinase 7) Hui Hui Tang, Kam C Yeung

Department of Cancer Biology and Biochemistry, College of Medicine, Univeristy of Toledo, Health Science

Campus, 3035 Arlington Ave., Toledo, OH 43614, USA (HHT, KCY)


Online updated version: http://AtlasGeneticsOncology.org/Genes/MAP3K7ID454ch6q15.html DOI: 10.4267/2042/44699


Identity

Other names: TAK1; TGF1a

HGNC (Hugo): MAP3K7

Location: 6q15

DNA/RNA

Description

MAP3K7/TAK1 gene spans 71 kb of DNA and

contains 17 exons and 16 introns. Exon 1 contains the

5' UTR of the mRNA and encodes 40 amino acid of N-

terminal of the protein. Exons 2 to 8 encode the kinase

domain. Exon 17 encodes the carboxyl end of the

TAK1 protein and contains the 3'UTR. Exon 12 and

exon 16 are alternative exons.

The promoter is located between 799 bp and 1215 bp

upsteam of the exon 1. The promoter has the character

of housekeeping genes: the absence of TATA box, the

presence of CpG island and SP1 binding sites.

Transcription

Four alternatively spliced transcripts encoding 4

distinct isoforms because of the presence or absence of

alternative exons 12 or/and 16 are detected.

Variant A: It lacks an in-frame coding segment, exon

12.

Variant B: This variant contains both alternative exons

12 and 16 and encodes the longest isoform.

Variant C: Variant C lacks the exon 16 resulting in a

frame shift in exon 17. The resulting isoform C has a

distinct and shorter C terminus when compared with

variants A and B.

Variant D: Variant D lacks both exons 12 and 16.

The regulation of the TAK1 mRNA alternative splicing

is tissue specific. The different variants of TAK1 may

have specialized functions.

A: The 17 exons are shown as black vertical bars. The exon numbers are shown on top of each exon. The CpG island is shown as a white box. The positions of exons in the cDNA are 1-282, 283-393, 394-459, 460-505, 506-644, 645-768, 770-898, 899-1029, 1030-1111, 1112-1242, 1243-1372, 1373-1453, 1454-1518, 1519-1624, 1625-1686, 1687-1802, and 1803-2850. The sizes (in base pairs) of intron 1 to 16 are 14956, 3073, 6891, 1407, 3451, 2913, 1278, 1499, 2290, 659, 2625, 8150, 12553, 4358, 695, and 1765, respectively.

MAP3K7 (mitogen-activated protein kinase kinase kinase 7) Tang HH, Yeung KC


B: MAP3K7 transcripts.

Pseudogene

No pseudogene of MAP3K7/TAK1 was reported in

human.

Protein

Note

MAP3K7/TAK1 isoform B contains 606 amino acids

(aa) and has a predicted molecular weight of 67 kDa,

isoform D contains 491 aa and has a predicted

molecular weight of 53.7 kDa, isoform C contains 518

aa and has a predicted molecular weight of 56.7 kDa,

and isoform A contains 579 aa and has a predicted

molecular weight of 64 kDa.

Description

MAP3K7/TAK1 was first identified by screening a

mouse cDNA library for clones that could act as

MAPKKKs. The mouse TAK1 cDNA encodes a 579-

amino acid protein. The mouse TAK1 protein contains

a 300-residue COOH-terminal domain and a putative

NH2-terminal protein kinase catalytic domain.

The kinase domain has approximately 30% identity to

the catalytic domains of Raf-1 and MEKK1. Kondo et

al. (1998) cloned human TAK1 from lung cDNA

library by screening with mouse TAK1 sequence.

Human TAK1 gene encodes a 579-amino-acid protein.

The hTAK1 gene has 91.8% identity with the mTAK1

gene at the nucleotide level and has 99.3% to that at the

amino acid level. Human TAK1 mRNA with a size of

3.0 kb was observed to express in all the tissues

examined by Northern blotting. Kondo et al. (1998)

found 2 isoforms of TAK1. Isoform 2 had an insertion

of 27 amino acids between amino acids 403 and 404 of

isoform 1 which corresponded to the mTAK1 sequence

previously identified by Yamaguchi et al. (1995). The

two isoforms were expressed at different ratios.

Isoform 1 (Variant A) was predominantly expressed in

brain, heart and spleen while the isoform 2 (Variant B)

was preferentially in the kidney.

Independently, Sakurai et al. (1998) cloned hTAK1 as

well as two alternatively spliced isoforms. Human

TAK1a (Variant A) has 99.3% identity to murine

TAK1. TAK1b (Variant B) had an insertion of 27

amino acids and TAK1c had a deletion of 39 amino

acids in the carboxyl-terminal region. The catalytic

domains of these three isoforms were 100% identical to

that of murine TAK1. The mRNA for TAK1a and

TAK1b were expressed in Hela, Jurkat and THP1 cells

and TAK1a mRNA expessed predominantly in these

cell lines. TAK1c mRNA (Variant C) was expressed

only in Hela cells. Northern blot analysis revealed the

expression of TAK1 mRNA in all the human tissues

examined with the size of 3.2 and 5.7 kb. Dempsey et

al. (2000) identified a fourth splice variant of TAK1

called TAK1d (Variant D). TAK1d lacked the two

alternative exons and encoded a 491 amino acid

protein. TAK1a and b were the most abundant forms in

most tissues examined. The carboxyl-end variant

TAK1 proteins were unlikely to interfere with the

catalytic activity of TAK1 or its interaction with TAB1

since both of which involve the N terminus, but may

affect its interaction with TAB2 which associates with

the carboxyl-ends of the TAK1 proteins.

Expression

TAK1 was ubiquitously expressed in all tissues.

TAK1a (variant A) was the most abundant form in

heart, liver, skeletal muscle, ovary, spleen and

peripheral blood mononuclear cells; TAK1b (Variant

B) was more abundant in brain, kidney, prostate and

small intestine; TAK1c (Variant C) is ubiquitously

expressed and predominantly in prostate; and TAK1d

(Variant D) existed in most tested tissues as a minor

variant.

Localisation

TAK1 is mostly localized in cytoplasm.

Function

TAK1 is a member of the serine/threonine protein



kinase family. It can be activated by transforming

growth factor-beta (TGF-b) and TAK1 deletion mutant

missing the N-terminal 22 amino acid is constitutively

active. In response to TGF-b, TAK1 can phosphorylate

and activate MAP kinase kinases MKK3, MKK4 and

MKK6. TAK1 can activate NF-kB in the presence of

TAB1. TAK1 is also involved in pro-inflammatory

cytokines signaling by activa-ting two kinase pathways.

One is a MAPK cascade that leads to the activation of

JNK and the other is IkB kinase cascade that causes the

activation of NF-kB. It was shown that TRAF6 is a

signal mediator that activates IKK and JNK in response

to pro-inflammatory cytokine interleukin 1. The

activation of IKK by TRAF6 requires two intermediary

factors, TRAF6-regulated IKK activator 1 (TRIKA1)

and TRIKA2. TRIKA1 is an ubiquitin-conjugating

enzyme complex consisted of Ubc13 and Uev1A.

TRIKA1, together with TRAF6, catalyze the formation

of a Lys63-linked polyubi-quitin chain that mediates

IKK activation. TRIKA2 is composed of TAK1, TAB1

and TAB2. The activation of TAK1 kinase complex is

dependent on its polyubiquitination by the TRAF6-Ubc

complex and phosphorylation of several residues within

the kinase activation loop by yet-to-be identified

kinases. The ubiquitinated TAK1 can phosphorylate

IKKbeta specifically at S177 and S181. Mutation

analysis revealed that a point mutation in the ATP-

binding domain of TAK1 (K63W), which abolished its

kinase activity, was unable to activate IKK. TAK1 was

activated by auto-phosphorylation on Ser192 and dual

phosphorylation of Thr-178 and Thr-184 residues

within the activation loop. Mutation of a conserved

serine residue (Ser192) in the activation loop between

kinase domain VII and VIII abrogated the

phosphorylation and activation of TAK1. TAK1 is

linked to TRAFs by two adaptor proteins TAB2 and

TAB3. The interaction of TAB2/TAB3 with TAK1 is

essential for the activation of signaling pathway

mediated by IL-1.

It was shown that protein phosphatase 2Cepsilon

(PP2Cepsilon) inhibited the IL-1 and TAK1 induced

activation of MKK4-JNK or MKK3-p38 signaling

pathway. PP2Cepsilon inactivated TAK1 by

associating with and dephosphorylating TAK1. A type-

2A phosphatase, protein phosphatase 6 (PP6), was also

identified as a TAK1-binding protein. PP6 repressed

TAK1 activity by dephos-phorylating Thr187.

Homology

Human TAK1-like (TAKL) gene encoded a 242 amino

acid protein which shared a homology with human

TAK1. The amino acid sequences of TAK1 were

highly conserved between human and mouse.

Mutations

Note

No mutation of human MAP3K7 was reported.

Implicated in

Breast cancer

Note

TGF-b1 signaling is involved in tumor angiogenesis

and metastasis by regulating matrix proteosis. MMP-9

is an important component of these TGF-b1 responses.

TAK1 is important for TGF-b1 regulation of MMP9

and metastatic potential of breast cancer cell line

MDA-MB231. Suppression of TAK1 reduces the

expression of MMP9 and tumor cell invasion. TAK1

and NFkB are required for the human MCF10A-CA1a

breast cancer cells to undergo invasion in response to

TGF-b. A novel TAB1:TAK1: IKKb: NFkB signaling

axis forms aberrantly in breast cancer cells and enables

oncogenic signaling by TGF-b.

Lung cancer

Note

Mutation analysis: Study on 39 lung cancer specimens

and 16 lung cancer cell lines indicated that hTAK1 was

not a frequent target for genetic alternations in lung

cancer.

TAK1 variant D activated by siRNAs of specific

sequences leads to down stream activation of p38

MAPK and JNK but not NFkB pathway. In human lung

cancer cell line NCI-H460 the activation of these

pathway cause cell cycle arrest and apoptosis. It

suggests that TAK1 D may be a new and promising

therapeutic target for the treatment of non-small cell

lung cancer. Telomeres are essential elements at the

ends of chromosomes that contribute to chromosomal

stability. The length of the telomere is maintained by

the telomerase holoenzyme, which contains the reverse

trans-criptase hTERT as a major enzymatic subunit.

The activity of telomerase is absent in most normal

human cells because of the downregulation of the

hTERT transcript resulting in the shortening of

telomeres after each replicative cycle. However, in

immortalized cells and cancer cells, the telomere

lengths are maintained through an increase in hTERT

expression. TAK1 can repress the transcription of

hTERT in A549 human lung adenocarcinoma cell line

and this repression is caused by recruitment of HDAC

to the hTERT promoter.

Cervical carcinoma

Note

Tumor necrosis factor (TNF)-related apoptosis-

inducing ligand (TRAIL), a member of TNFa ligand

family, induces apoptosis in a variety of tumor cells.

TRAIL induced the delayed phospho-rylation of TAK1

in human cervical carcinoma HeLa cells. TRAIL

induced apoptosis was enhanced by downregulation of

TAK1.



Head and neck squamous cell carcinoma

Note

NFkB was constitutively activated in head and neck

squamous cell carcinoma (HNSCC). Constitutive

activation of NFkB in HNSCC was caused by

constitutive activation of IKK. Constitutive activa-tion

of NFkB is mediated through the TRADD-TRAF2-

RIP-TAK1-IKK pathway.

Arthritis

Note

Exercise/joint mobility has therapeutic potency for

inflammatory joint diseases such as rheumatoid and

osteoarthritis. The biomechanical signals at

physiological magnitudes are potent inhibitors of

inflammation induced by NFkB activation in

fibrochondrocytes. The biomechanical signals exert

anti-inflammatory effects by inhibiting phosphory-

lation of TAK1.

JNK is essential for metalloproteinase (MMP) gene

expression and joint destruction in inflammatory

arthritis. TAK1 is an upstream kinase of JNK. TAK1

play an important role for the IL1b induced JNK

activation and the JNK induced gene expression in

fibroblast-like synoviocytes (FLSs). It suggests that

TAK1 is a potential therapeutic target to modulate

synoviocyte activation in rheumatoid arthritis (RA).

Inflammation

Note

Pro-inflammatory molecules lipopolysaccharide and

Interleukin 1 trigger the activation of TAK1, which in

turn activates multiple kinase JNK, p38, IKK and

PKB/Akt which are important components of kinase

cascades involved in inflammation. Thus TAK1 plays

an important role in inflammation.

Human airway epithelial cells

Note

Act1/TRAF6/TAK1-mediated NF-kB activation

stimulated by IL-17A regulates gene induction in

human airway epithelial cells. Dominant negative

TAK1 reduces IL-17A induced gene expression.

References Hirose T, Fujimoto W, Tamaai T, Kim KH, Matsuura H, Jetten AM. TAK1: molecular cloning and characterization of a new member of the nuclear receptor superfamily. Mol Endocrinol. 1994 Dec;8(12):1667-80

Yamaguchi K, Shirakabe K, Shibuya H, Irie K, Oishi I, et al. Identification of a member of the MAPKKK family as a potential mediator of TGF-beta signal transduction. Science. 1995 Dec 22;270(5244):2008-11

Kondo M, Osada H, Uchida K, Yanagisawa K, Masuda A, Takagi K, Takahashi T, Takahashi T. Molecular cloning of human TAK1 and its mutational analysis in human lung cancer. Int J Cancer. 1998 Feb 9;75(4):559-63

Sakurai H, Shigemori N, Hasegawa K, Sugita T. TGF-beta-activated kinase 1 stimulates NF-kappa B activation by an NF-kappa B-inducing kinase-independent mechanism. Biochem Biophys Res Commun. 1998 Feb 13;243(2):545-9

Dempsey CE, Sakurai H, Sugita T, Guesdon F. Alternative splicing and gene structure of the transforming growth factor beta-activated kinase 1. Biochim Biophys Acta. 2000 Dec 15;1517(1):46-52

Kishimoto K, Matsumoto K, Ninomiya-Tsuji J. TAK1 mitogen-activated protein kinase kinase kinase is activated by autophosphorylation within its activation loop. J Biol Chem. 2000 Mar 10;275(10):7359-64

Lee J, Mira-Arbibe L, Ulevitch RJ. TAK1 regulates multiple protein kinase cascades activated by bacterial lipopolysaccharide. J Leukoc Biol. 2000 Dec;68(6):909-15

Wang C, Deng L, Hong M, Akkaraju GR, Inoue J, Chen ZJ. TAK1 is a ubiquitin-dependent kinase of MKK and IKK. Nature. 2001 Jul 19;412(6844):346-51

Li MG, Katsura K, Nomiyama H, Komaki K, Ninomiya-Tsuji J, Matsumoto K, Kobayashi T, Tamura S. Regulation of the interleukin-1-induced signaling pathways by a novel member of the protein phosphatase 2C family (PP2Cepsilon). J Biol Chem. 2003 Apr 4;278(14):12013-21

Takaesu G, Surabhi RM, Park KJ, Ninomiya-Tsuji J, Matsumoto K, Gaynor RB. TAK1 is critical for IkappaB kinase-mediated activation of the NF-kappaB pathway. J Mol Biol. 2003 Feb 7;326(1):105-15

Li J, Ji C, Yang Q, Chen J, Gu S, Ying K, Xie Y, Mao Y. Cloning and characterization of a novel human TGF-beta activated kinase-like gene. Biochem Genet. 2004 Apr;42(3-4):129-37

Kishida S, Sanjo H, Akira S, Matsumoto K, Ninomiya-Tsuji J. TAK1-binding protein 2 facilitates ubiquitination of TRAF6 and assembly of TRAF6 with IKK in the IL-1 signaling pathway. Genes Cells. 2005 May;10(5):447-54

Choo MK, Kawasaki N, Singhirunnusorn P, Koizumi K, Sato S, Akira S, Saiki I, Sakurai H. Blockade of transforming growth factor-beta-activated kinase 1 activity enhances TRAIL-induced apoptosis through activation of a caspase cascade. Mol Cancer Ther. 2006 Dec;5(12):2970-6

Kajino T, Ren H, Iemura S, Natsume T, Stefansson B, Brautigan DL, Matsumoto K, Ninomiya-Tsuji J. Protein phosphatase 6 down-regulates TAK1 kinase activation in the IL-1 signaling pathway. J Biol Chem. 2006 Dec 29;281(52):39891-6

Besse A, Lamothe B, Campos AD, Webster WK, Maddineni U, Lin SC, Wu H, Darnay BG. TAK1-dependent signaling requires functional interaction with TAB2/TAB3. J Biol Chem. 2007 Feb 9;282(6):3918-28

Hammaker DR, Boyle DL, Inoue T, Firestein GS. Regulation of the JNK pathway by TGF-beta activated kinase 1 in rheumatoid arthritis synoviocytes. Arthritis Res Ther. 2007;9(3):R57

Jackson-Bernitsas DG, Ichikawa H, Takada Y, Myers JN, Lin XL, Darnay BG, Chaturvedi MM, Aggarwal BB. Evidence that TNF-TNFR1-TRADD-TRAF2-RIP-TAK1-IKK pathway mediates constitutive NF-kappaB activation and proliferation in human head and neck squamous cell carcinoma. Oncogene. 2007 Mar 1;26(10):1385-97

Madhavan S, Anghelina M, Sjostrom D, Dossumbekova A, Guttridge DC, Agarwal S. Biomechanical signals suppress TAK1 activation to inhibit NF-kappaB transcriptional activation in fibrochondrocytes. J Immunol. 2007 Nov 1;179(9):6246-54



Maura M, Katakura Y, Miura T, Fujiki T, Shiraishi H, Shirahata S.. Molecular Mechanism of TAK1-Induced Repression of hTERT Transcription. Cell Technology for Cell Products, R. Smith (ed.), 91-93. 2007 Springer.

Honorato B, Alcalde J, Martinez-Monge R, Zabalegui N, Garcia-Foncillas J. TAK1 mRNA expression in the tumor tissue of locally advanced head and neck Cancer Patients. Gene Regulation and Systems Biology. 2008;2: 63-70.

Kodym R, Kodym E, Story MD. Sequence-specific activation of TAK1-D by short double-stranded RNAs induces apoptosis in NCI-H460 cells. RNA. 2008 Mar;14(3):535-42

Neil JR, Schiemann WP. Altered TAB1:I kappaB kinase interaction promotes transforming growth factor beta-mediated nuclear factor-kappaB activation during breast cancer progression. Cancer Res. 2008 Mar 1;68(5):1462-70

Safina A, Ren MQ, Vandette E, Bakin AV. TAK1 is required for TGF-beta 1-mediated regulation of matrix metalloproteinase-9 and metastasis. Oncogene. 2008 Feb 21;27(9):1198-207

Yu Y, Ge N, Xie M, Sun W, Burlingame S, Pass AK, et al. Phosphorylation of Thr-178 and Thr-184 in the TAK1 T-loop is required for interleukin (IL)-1-mediated optimal NFkappaB and AP-1 activation as well as IL-6 gene expression. J Biol Chem. 2008 Sep 5;283(36):24497-505


Tang HH, Yeung KC. MAP3K7 (mitogen-activated protein kinase kinase kinase 7). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3):238-242.





MCPH1 (microcephalin 1) Yulong Liang, Shiaw-Yih Lin, Kaiyi Li

Department of Surgery, Baylor College of Medicine, Houston, Texas 77030, USA (YL, KL); Department of

Systems Biology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77054, USA

(SYL)


Online updated version: http://AtlasGeneticsOncology.org/Genes/MCPH1ID44370ch8p23.html DOI: 10.4267/2042/44700


Identity

Other names: BRIT1; MCT

HGNC (Hugo): MCPH1

Location: 8p23.1

Local order: According to NCBI Map Viewer, genes

flanking MCPH1 in telomere to centromere direction

on 8p23.1 are: ANGPT2 (angiopoietin 2); MCPH1

(also BRIT1); AGPAT5 (1-acylglycerol-3-phosphate

O-acyltransferase 5 (lysophosphatidic acid

acyltransferase, epsilon)); XKR5 (XK, Kell blood

group complex subunit-related family, member 5);

DEFB1 (defensin, beta 1); DEFA6 (defensin, alpha 6,

Paneth cell-specific).

Note

MCPH1 is one of DNA damage response proteins that

interact with other DNA damage and repair proteins

and signal transducers, form a DNA damage response

protein complex which can be seen through

immunofluorescent microscopy, and participate into

DNA repair, cell cycle checkpoint control, and

eventually maintain genomic integrity. The aberrant

expression of MCPH1 is observed in ovarian cancer

and breast cancer tissues and cell lines. Thus,

functional impairment of MCPH1 may significantly

contribute to tumour susceptibility

and/or tumour development. In addition, indivi-duals

who harbor a germline mutation of MCPH1 gene may

be highly susceptible to an autosomal recessive

neurological disorder, called primary microcephaly.

DNA/RNA

Description

According to Entrez-Gene, MCPH1 gene maps to

NC_000008.9 in the region between 6251529 and

6493434 on the plus strand and spans across 241.9 kilo

bases. According to GenBank, MCPH1 has 14 exons,

the sizes being 90, 92, 119, 88, 115, 144, 90, 1155, 110,

38, 163, 78, 238, and 5512 bp.

Transcription

8032 bp mRNA (NM_024596.2), 2508 bp open reading

frame.

Protein

Note

MCPH1 has three BRCA1 carboxyl-terminal (BRCT)

domains, so it is regarded as a protein family member

involved in DNA damage repair and checkpoint

control.

The protein of MCPH1 contains three BRCT domains, the nuclear localization signal motif and the large middle IMPDH domain. (AA, amino acids).

MCPH1 (microcephalin 1) Liang Y, et al.


Description

MCPH1 protein contains 835 amino acids with about

110 kDa of the molecular weight. According to

MotifScan prediction, MCPH1 has three BRCT

domains, one nuclear localization signal motif and the

large central IMPDH domain as depicted in the

diagram above. The BRCT domains of MCPH1, one in

N-terminus (N-BRCT), the other two tandemly

arranged in C-terminus (C-BRCTs), specifically bind to

the phosphorylated proteins commonly involved in

DNA damage response pathways. The N-BRCT is

required for centrosomal localization in irradiated cells,

and also essential to rescue the premature chromosome

condensation in MCPH1-deficient cells. C-BRCTs

direct self-oligo-merization of MCPH1, and are

necessary for ionizing radiation-induced foci formation.

The function of IMPDH domain predicted by

MotifScan is not clear yet. However, the region

(residues 376-485) in the central IMPDH domain (or

middle domain), binding with Condension II,

participates in homologous recombination.

Expression

MCPH1 is ubiquitously expressed in human with the

higher levels observed in the brain, testes, pancreas and

liver. It is a putative tumor suppressor and the aberrant

expression of MCPH1 is correlated with ovarian and

breast cancer. This reduced expression of MCPH1 may

have been caused by gene deletion detected by high-

density array comparative genomic hybridization

(CGH).

Localisation

Mainly localized in nucleus.

Function

MCPH1 function in DNA damage response: MCPH1

can modulate activities of two distinct DNA damage

repair networks, the ATM (ataxia telangiectaisia

mutated) pathway and the ATR (ATM and Rad3-

related) pathway. Upon exposure to DNA damaging

reagents, MCPH1 co-localizes with numerous proteins

associated with these two signaling pathways including

gamma-H2AX, MDC1, 53BP1, NBS1, p-ATM, ATR,

p-RAD17 and p-RPA34. In the absence of MCPH1, all

of these proteins with the exception of gamma-H2AX,

fail to localize to sites of DNA damage. The depletion

of MCPH1 inhibits the recruitment of phosphorylated

ATM to double-stranded DNA break ends, and

subsequently impair t phosphory-lation of multiple

down-stream members of the ATM pathway. MCPH1

deficiency also abolishes the UV-induced

phosphorylation of RPA34 and reduces the levels of

phosphorylated RAD17, suggesting the roles of

MCPH1 in the ATR path-way. Rad51, a homolog of

the bacterial RecA, is a central executioner in

homologous recombination (HR), catalyzing the

invasion of the single stranded DNA in a homologous

duplex and facilitating the homology search during the

establishment of joint molecules. Lack of MCPH1 can

alleviate localization of RAD51 onto the DNA break

sites. So MCPH1 is strongly implicated in HR.

Role of BRIT1 in cell cycle control: MCPH1 has been

demonstrated to regulate the expression of BRCA1 and

Chk1 and required for activation of intra-S and G2/M

cell cycle checkpoint after cellular exposure to ionizing

radiation. In the absence of MCPH1, BRCA1 and

ChK1 expression is significantly reduced and NBS1

fails to be phosphorylated, leading to loss of intra-S and

G2/M checkpoint control. Cells derived from a micro-

cephaly patient (MCPH1 defective) maintain a

persistent level of CDC25A and reduced level of Cdk1-

cyclin B complex, both of which attributes to entry of

mitosis. So besides expression control of ChK1 and

BRCA1, MCPH1 prevents premature entry into mitosis

in an ATR-dependent and ATR-independent manner.

Homology

According to NCBI-HomoloGene:

Chimpanzee (Pan troglodytes): MCPH1

(NP_001009010.1, 835 aa)

Dog (Canis familiaris): MCPH1 (NP_001003366.1,

850 aa)

Rat (Rattus norvegicus): MCPH1 (XP_225006.4, 986

aa)

Mouse (Mus musculus): MCPH1 (NP_775281.2, 822

aa)

Zebrafish (Danio rerio): zgc:136403 (NP_001035453.1,

422 aa)

Drosophila (Drosophila melanogaster): CG30038

(NP_725086.2, 219 aa)

Mutations

Note

Three point mutations in the autosomal recessive

mental retardation patients have been described for

MCPH1 so far. Two mutations (S25X and 427insA)

lead to premature stop condon, and one (T27R) leads to

missense mutation in the N-terminal BRCT domain. A

non-synonymous SNP (V761A in BRCA1 C-terminus

(BRCT) domain) of MCPH1 is significantly associated

with cranial volume in Chinese males. In addition, a

deletion of approximately 150-200 kb, encompassing

the promoter and the first six exons of the MCPH1

gene, was revealed by Array-based homozygosity

mapping and high-resolution microarray-based

comparative genomic hybridization (array CGH).

However, the patients with this deletion just showed

borderline of mild microcephaly.

Implicated in

Ovarian cancers

Note

Aberrations of MCPH1 have been identified in various

human cancers.

MCPH1 (microcephalin 1) Liang Y, et al.


Disease

MCPH1 DNA copy number was substatially decreased

in 40% of advanced epithelial ovarian cancer, and its

mRNA levels were also dramatically decreased in 63%

of ovarian cancer.

Breast cancers

Disease

MCPH1 mRNA and protein levels was aberrantly

reduced in several breast cancer cell lines.

Prognosis

Additionally, reduced MCPH1 expression correla-ted

with the duration of the relapse-free intervals and with

the occurrence of metastasis in breast cancers. BRIT1

deficiency may contribute to development and

aggressive nature of breast tumors.

Primary microcephaly

Disease

Primary microcephaly is an autosomal recessive

disorder, in which there is a marked reduction in brain

size. One form of primary microcephaly, MCPH, is

caused by mutation in the gene encoding microcephalin

1 (that is, MCPH1). In these patients, the MCPH1-

deficient cells show cellular phenotype of premature

chromosome condensation in the early G2 phase of the

cell cycle, which, therefore, appears to be a useful

diagnostic marker for these individuals. As mentioned

above, several mutations of MCPH1 have been

observed in these patients, including S25X, 427insA,

T27R, V761A and 5'-deletion of a large portion

encompassing the promoter region and first six exons,

especially the later two showing strong correlation with

micro-cephaly.

PCC syndrome

Disease

Premature chromosome condensation (PCC) syndrome

is characterized by premature chromosome

condensation in the early G2 phase. This disorder is

similar to microcephalin 1, and can also be caused by

MCPH1 mutations.

References Jackson AP, McHale DP, Campbell DA, Jafri H, Rashid Y, Mannan J, Karbani G, Corry P, Levene MI, Mueller RF, Markham AF, Lench NJ, Woods CG. Primary autosomal recessive microcephaly (MCPH1) maps to chromosome 8p22-pter. Am J Hum Genet. 1998 Aug;63(2):541-6

Jackson AP, Eastwood H, Bell SM, Adu J, Toomes C, Carr IM, Roberts E, Hampshire DJ, Crow YJ, Mighell AJ, Karbani G, Jafri H, Rashid Y, Mueller RF, Markham AF, Woods CG. Identification of microcephalin, a protein implicated in determining the size of the human brain. Am J Hum Genet. 2002 Jul;71(1):136-42

Trimborn M, Bell SM, Felix C, Rashid Y, Jafri H, Griffiths PD, Neumann LM, Krebs A, Reis A, Sperling K, Neitzel H, Jackson AP. Mutations in microcephalin cause aberrant regulation of chromosome condensation. Am J Hum Genet. 2004 Aug;75(2):261-6

Xu X, Lee J, Stern DF. Microcephalin is a DNA damage response protein involved in regulation of CHK1 and BRCA1. J Biol Chem. 2004 Aug 13;279(33):34091-4

Lin SY, Rai R, Li K, Xu ZX, Elledge SJ. BRIT1/MCPH1 is a DNA damage responsive protein that regulates the Brca1-Chk1 pathway, implicating checkpoint dysfunction in microcephaly. Proc Natl Acad Sci U S A. 2005 Oct 18;102(42):15105-9

Trimborn M, Richter R, Sternberg N, Gavvovidis I, Schindler D, Jackson AP, Prott EC, Sperling K, Gillessen-Kaesbach G, Neitzel H. The first missense alteration in the MCPH1 gene causes autosomal recessive microcephaly with an extremely mild cellular and clinical phenotype. Hum Mutat. 2005 Nov;26(5):496

Alderton GK, Galbiati L, Griffith E, Surinya KH, Neitzel H, Jackson AP, Jeggo PA, O'Driscoll M. Regulation of mitotic entry by microcephalin and its overlap with ATR signalling. Nat Cell Biol. 2006 Jul;8(7):725-33

Chaplet M, Rai R, Jackson-Bernitsas D, Li K, Lin SY. BRIT1/MCPH1: a guardian of genome and an enemy of tumors. Cell Cycle. 2006 Nov;5(22):2579-83

Garshasbi M, Motazacker MM, Kahrizi K, Behjati F, Abedini SS, Nieh SE, Firouzabadi SG, Becker C, Rüschendorf F, Nürnberg P, Tzschach A, Vazifehmand R, Erdogan F, Ullmann R, Lenzner S, Kuss AW, Ropers HH, Najmabadi H. SNP array-based homozygosity mapping reveals MCPH1 deletion in family with autosomal recessive mental retardation and mild microcephaly. Hum Genet. 2006 Feb;118(6):708-15

Rai R, Dai H, Multani AS, Li K, Chin K, Gray J, Lahad JP, Liang J, Mills GB, Meric-Bernstam F, Lin SY. BRIT1 regulates early DNA damage response, chromosomal integrity, and cancer. Cancer Cell. 2006 Aug;10(2):145-57

Wood JL, Singh N, Mer G, Chen J. MCPH1 functions in an H2AX-dependent but MDC1-independent pathway in response to DNA damage. J Biol Chem. 2007 Nov 30;282(48):35416-23

Jeffers LJ, Coull BJ, Stack SJ, Morrison CG. Distinct BRCT domains in Mcph1/Brit1 mediate ionizing radiation-induced focus formation and centrosomal localization. Oncogene. 2008 Jan 3;27(1):139-44

Wang JK, Li Y, Su B. A common SNP of MCPH1 is associated with cranial volume variation in Chinese population. Hum Mol Genet. 2008 May 1;17(9):1329-35

Wood JL, Liang Y, Li K, Chen J. Microcephalin/MCPH1 associates with the Condensin II complex to function in homologous recombination repair. J Biol Chem. 2008 Oct 24;283(43):29586-92

Yang SZ, Lin FT, Lin WC. MCPH1/BRIT1 cooperates with E2F1 in the activation of checkpoint, DNA repair and apoptosis. EMBO Rep. 2008 Sep;9(9):907-15


Liang Y, Lin SY, Li K. MCPH1 (microcephalin 1). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3):243-245.





NKX3-1 (NK3 homeobox 1) Liang-Nian Song, Edward P Gelmann

Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA (LNS,

EPG)


Online updated version: http://AtlasGeneticsOncology.org/Genes/NKX31ID41541ch8p21.html DOI: 10.4267/2042/44701


Identity

Other names: NKX3 BAPX2; NKX3A; NKX3.1

HGNC (Hugo): NKX3-1

Location: 8p21.2

Local order: Gene orientation: telomere-3' NKX3.1 5'-

centromere.

DNA/RNA

Description

The gene has two exons and one intron.

Transcription

Transcription takes place in a centromere --> telomere

orientation. The length of the processed mRNA is

about 3200 bp.

Pseudogene

Not known.

Protein

Description

234 amino acids; 35-38 kDa, contains one N-

terminal domain (residues 1-123), one homeo-domain

(residues 124-183), and one C-terminal domain

(residues 184-234).

Expression

Expression is restricted to the adult murine prostate and

bulbourethral gland. During early murine

embryogenesis NKX3-1 expression has also been

detected in developing somites and testes. In the adult

human expression is seen in prostate epithelium, testis,

ureter, and pulmonary bronchial mucous glands.

Localisation

Nuclear.

Function

Binds to DNA to suppress transcription. Interacts with

transcription factors, e.g. serum response factor, to

enhance transcriptional activation. Binds to and

potentiates topoisomerase I DNA resolving activity.

Acts as prostate tumor suppressor.

Homology

Homeodomain protein with membership of the NKX

family.

The gene for NKX3-1 comprises two exons of 334 and 2947 bp, respectively. The length of the intron is 964 bp. Positions of start and stop codons are indicated.

NKX3-1 contains two exons encoding a 234-amino acid protein including a homeodomain (grey).

NKX3-1 (NK3 homeobox 1) Song LN, Gelmann EP


Mutations

Germinal

Twenty-one germ-line variants have been identified in

159 probands of hereditary prostate cancer families.

These variants were linked to prostate cancer risk in

hereditary prostate cancer families. For example, the

C154T (11% of the population) polymorphism

mutation is associated with prostatic enlargement and

prostate cancer risk. A T164A mutations in one family

cosegregates with prostate cancer in three affected

brothers. For a more complete list of identified

mutations, please visit

http://cancerres.aacrjournals.org/cgi/content/full/66/1/6

9.

Somatic

None.

Implicated in

Prostate Cancer

Disease

Prostate cancer is the most commonly diagnosed cancer

in American men and the second leading cause of

cancer-related deaths. Prostate cancer predominantly

occurs in the peripheral zone of the human prostate,

with roughly 5 to 10% of cases found in the central

zone. Disease development involves the temporal and

spatial loss of the basal epithelial compartment

accompanied by increased proliferation and

dedifferentiation of the luminal (secretory) epithelial

cells. Prostate cancer is a slow developing disease that

is typically found in men greater than 60 years of age

and incidence increases with increasing age.

Prognosis

PSA test combined with digital-rectal exams are used

to screen for the presence of disease. If the digital-

rectal exams are positive, additional tests including

needle core biopsies are taken to assess disease stage

and grade. Patients with localized, prostate-restricted

disease are theoretically curable with complete removal

of the prostate (radical prostatectomy). Patients with

extra-prostatic disease are treated with hormone

(androgen ablation) therapy, radiation, and/or

antiandrogens; however, no curative treatments are

available for nonorgan confined metastatic disease.

Cytogenetics

Various forms of aneuploidy.

Oncogenesis

Nkx3.1 plays an essential role in normal murine

prostate development. Loss of function of Nkx3.1 leads

to defects in prostatic protein secretions and in ductal

morphogenesis. Loss-of-function of Nkx3.1 also

contributes to prostate carcinogenesis. For example,

Nkx3.1 mutant mice develop prostatic dysplasia.

Nkx3.1 loss potentiates prostate carcinogenesis in a

Pten+/-

background. Further-rmore, by a variety of

mechanisms NKX3.1 expression is reduced in

noninvasive and early stage human prostate cancer,

suggesting that its decreased expression is one of the

earliest steps in the majority of human prostate cancers.

References He WW, Sciavolino PJ, Wing J, Augustus M, Hudson P, Meissner PS, Curtis RT, Shell BK, Bostwick DG, Tindall DJ, Gelmann EP, Abate-Shen C, Carter KC. A novel human prostate-specific, androgen-regulated homeobox gene (NKX3.1) that maps to 8p21, a region frequently deleted in prostate cancer. Genomics. 1997 Jul 1;43(1):69-77

Sciavolino PJ, Abrams EW, Yang L, Austenberg LP, Shen MM, Abate-Shen C. Tissue-specific expression of murine Nkx3.1 in the male urogenital system. Dev Dyn. 1997 May;209(1):127-38

Voeller HJ, Augustus M, Madike V, Bova GS, Carter KC, Gelmann EP. Coding region of NKX3.1, a prostate-specific homeobox gene on 8p21, is not mutated in human prostate cancers. Cancer Res. 1997 Oct 15;57(20):4455-9

Prescott JL, Blok L, Tindall DJ. Isolation and androgen regulation of the human homeobox cDNA, NKX3.1. Prostate. 1998 Apr 1;35(1):71-80

Bhatia-Gaur R, Donjacour AA, Sciavolino PJ, Kim M, Desai N, Young P, Norton CR, Gridley T, Cardiff RD, Cunha GR, Abate-Shen C, Shen MM. Roles for Nkx3.1 in prostate development and cancer. Genes Dev. 1999 Apr 15;13(8):966-77

Tanaka M, Lyons GE, Izumo S. Expression of the Nkx3.1 homobox gene during pre and postnatal development. Mech Dev. 1999 Jul;85(1-2):179-82

Bowen C, Bubendorf L, Voeller HJ, Slack R, Willi N, Sauter G, Gasser TC, Koivisto P, Lack EE, Kononen J, Kallioniemi OP, Gelmann EP. Loss of NKX3.1 expression in human prostate cancers correlates with tumor progression. Cancer Res. 2000 Nov 1;60(21):6111-5

Korkmaz KS, Korkmaz CG, Ragnhildstveit E, Kizildag S, Pretlow TG, Saatcioglu F. Full-length cDNA sequence and genomic organization of human NKX3A - alternative forms and regulation by both androgens and estrogens. Gene. 2000 Dec 30;260(1-2):25-36

Schneider A, Brand T, Zweigerdt R, Arnold H. Targeted disruption of the Nkx3.1 gene in mice results in morphogenetic defects of minor salivary glands: parallels to glandular duct morphogenesis in prostate. Mech Dev. 2000 Jul;95(1-2):163-74

Steadman DJ, Giuffrida D, Gelmann EP. DNA-binding sequence of the human prostate-specific homeodomain protein NKX3.1. Nucleic Acids Res. 2000 Jun 15;28(12):2389-95

Tanaka M, Komuro I, Inagaki H, Jenkins NA, Copeland NG, Izumo S. Nkx3.1, a murine homolog of Ddrosophila bagpipe, regulates epithelial ductal branching and proliferation of the prostate and palatine glands. Dev Dyn. 2000 Oct;219(2):248-60

Xu LL, Srikantan V, Sesterhenn IA, Augustus M, Dean R, Moul JW, Carter KC, Srivastava S. Expression profile of an androgen regulated prostate specific homeobox gene NKX3.1 in primary prostate cancer. J Urol. 2000 Mar;163(3):972-9

Ornstein DK, Cinquanta M, Weiler S, Duray PH, Emmert-Buck MR, Vocke CD, Linehan WM, Ferretti JA. Expression studies and mutational analysis of the androgen regulated homeobox gene NKX3.1 in benign and malignant prostate epithelium. J Urol. 2001 Apr;165(4):1329-34



NKX3-1 (NK3 homeobox 1) Song LN, Gelmann EP


Abdulkadir SA, Magee JA, Peters TJ, Kaleem Z, Naughton CK, Humphrey PA, Milbrandt J. Conditional loss of Nkx3.1 in adult mice induces prostatic intraepithelial neoplasia. Mol Cell Biol. 2002 Mar;22(5):1495-503

Gelmann EP, Steadman DJ, Ma J, Ahronovitz N, Voeller HJ, Swope S, Abbaszadegan M, Brown KM, Strand K, Hayes RB, Stampfer MJ. Occurrence of NKX3.1 C154T polymorphism in men with and without prostate cancer and studies of its effect on protein function. Cancer Res. 2002 May 1;62(9):2654-9

Kim MJ, Cardiff RD, Desai N, Banach-Petrosky WA, Parsons R, Shen MM, Abate-Shen C. Cooperativity of Nkx3.1 and Pten loss of function in a mouse model of prostate carcinogenesis. Proc Natl Acad Sci U S A. 2002 Mar 5;99(5):2884-9

Abate-Shen C, Banach-Petrosky WA, Sun X, Economides KD, Desai N, Gregg JP, Borowsky AD, Cardiff RD, Shen MM. Nkx3.1; Pten mutant mice develop invasive prostate adenocarcinoma and lymph node metastases. Cancer Res. 2003 Jul 15;63(14):3886-90

Gelmann EP, Bowen C, Bubendorf L. Expression of NKX3.1 in normal and malignant tissues. Prostate. 2003 May 1;55(2):111-7

Magee JA, Abdulkadir SA, Milbrandt J. Haploinsufficiency at the Nkx3.1 locus. A paradigm for stochastic, dosage-sensitive gene regulation during tumor initiation. Cancer Cell. 2003 Mar;3(3):273-83

Shen MM, Abate-Shen C. Roles of the Nkx3.1 homeobox gene in prostate organogenesis and carcinogenesis. Dev Dyn. 2003 Dec;228(4):767-78

Korkmaz CG, Korkmaz KS, Manola J, Xi Z, Risberg B, Danielsen H, Kung J, Sellers WR, Loda M, Saatcioglu F. Analysis of androgen regulated homeobox gene NKX3.1 during prostate carcinogenesis. J Urol. 2004 Sep;172(3):1134-9

Asatiani E, Huang WX, Wang A, Rodriguez Ortner E, Cavalli LR, Haddad BR, Gelmann EP. Deletion, methylation, and expression of the NKX3.1 suppressor gene in primary human prostate cancer. Cancer Res. 2005 Feb 15;65(4):1164-73

Bethel CR, Faith D, Li X, Guan B, Hicks JL, Lan F, Jenkins RB, Bieberich CJ, De Marzo AM. Decreased NKX3.1 protein expression in focal prostatic atrophy, prostatic intraepithelial neoplasia, and adenocarcinoma: association with gleason score and chromosome 8p deletion. Cancer Res. 2006 Nov 15;66(22):10683-90

Ju JH, Maeng JS, Zemedkun M, Ahronovitz N, Mack JW, Ferretti JA, Gelmann EP, Gruschus JM. Physical and functional interactions between the prostate suppressor

homeoprotein NKX3.1 and serum response factor. J Mol Biol. 2006 Jul 28;360(5):989-99

Li X, Guan B, Maghami S, Bieberich CJ. NKX3.1 is regulated by protein kinase CK2 in prostate tumor cells. Mol Cell Biol. 2006 Apr;26(8):3008-17

Rodriguez Ortner E, Hayes RB, Weissfeld J, Gelmann EP. Effect of homeodomain protein NKX3.1 R52C polymorphism on prostate gland size. Urology. 2006 Feb;67(2):311-5

Simmons SO, Horowitz JM. Nkx3.1 binds and negatively regulates the transcriptional activity of Sp-family members in prostate-derived cells. Biochem J. 2006 Jan 1;393(Pt 1):397-409

Zheng SL, Ju JH, Chang BL, Ortner E, Sun J, Isaacs SD, Sun J, Wiley KE, Liu W, Zemedkun M, Walsh PC, Ferretti J, Gruschus J, Isaacs WB, Gelmann EP, Xu J. Germ-line mutation of NKX3.1 cosegregates with hereditary prostate cancer and alters the homeodomain structure and function. Cancer Res. 2006 Jan 1;66(1):69-77

Bowen C, Stuart A, Ju JH, Tuan J, Blonder J, Conrads TP, Veenstra TD, Gelmann EP. NKX3.1 homeodomain protein binds to topoisomerase I and enhances its activity. Cancer Res. 2007 Jan 15;67(2):455-64

Mogal AP, van der Meer R, Crooke PS, Abdulkadir SA. Haploinsufficient prostate tumor suppression by Nkx3.1: a role for chromatin accessibility in dosage-sensitive gene regulation. J Biol Chem. 2007 Aug 31;282(35):25790-800

Abate-Shen C, Shen MM, Gelmann E. Integrating differentiation and cancer: the Nkx3.1 homeobox gene in prostate organogenesis and carcinogenesis. Differentiation. 2008 Jul;76(6):717-27

Holmes KA, Song JS, Liu XS, Brown M, Carroll JS. Nkx3-1 and LEF-1 function as transcriptional inhibitors of estrogen receptor activity. Cancer Res. 2008 Sep 15;68(18):7380-5

Markowski MC, Bowen C, Gelmann EP. Inflammatory cytokines induce phosphorylation and ubiquitination of prostate suppressor protein NKX3.1. Cancer Res. 2008 Sep 1;68(17):6896-901

Zhang Y, Fillmore RA, Zimmer WE. Structural and functional analysis of domains mediating interaction between the bagpipe homologue, Nkx3.1 and serum response factor. Exp Biol Med (Maywood). 2008 Mar;233(3):297-309


Song LN, Gelmann EP. NKX3-1 (NK3 homeobox 1). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3):246-248.





PLXNB1 (plexin B1) José Javier Gómez-Román, Montserrat Nicolas Martínez, Servando Lazuén Fernández, José

Fernando Val-Bernal

Department of Anatomical Pathology, Marques de Valdecilla University Hospital, Medical Faculty,

University of Cantabria, Santander, Spain (JJGR, MN, SL, JFVB)


Online updated version: http://AtlasGeneticsOncology.org/Genes/PLXNB1ID43413ch3p21.html DOI: 10.4267/2042/44702


Identity

Other names: KIAA0407; MGC149167;

OTTHUMP00000164806; PLEXIN-B1; PLXN5; SEP

HGNC (Hugo): PLXNB1

Location: 3p21.31

Local order: The Plexin B1 gene is located between

FBXW12 and CCDC51 genes.

Note

Size: 26,200 bases.

Orientation: minus strand.

DNA/RNA

Description

Functioning gene. 21.00 kb; 37 Exons.

Transcription

7097.00 bp; Number of transcripts: 1; Type:

Messenger.

Two alternatively truncated spliced variant, coding

secreted proteins (lacking the part of the extracellular

domains).

Pseudogene

No.

Protein

Description

2135 Amino acids (AA). Plexins are receptors for axon

molecular guidance molecules semaphorins. Plexin

signalling is important in pathfinding and patterning of

both neurons and developing blood vessels. Plexin-B1

is a surface cell receptor. When it binds to its ligand

SEMA4D it activates several pathways by binding of

cytoplasmic ligands, like RHOA activation and

subsequent changes of the actin cytoskeleton, axon

guidance, invasive growth and cell migration.

It monomers and heterodimers with PLXNB2 after

proteolytic processing. Binds RAC1 that has been

activated by GTP binding.

It binds PLXNA1 and by similarity ARHGEF11,

ARHGEF12, ERBB2, MET, MST1R, RND1, NRP1

and NRP2.

This family features the C-terminal regions of various

plexins. The cytoplasmic region, which has been called

a SEX domain in some members of this family is

involved in downstream signalling pathways, by

interaction with proteins such as Rac1, RhoD, Rnd1

and other plexins.

Three copies of a cysteine rich repeat are found in

Plexin. The function of the repeat is unknown.

Expression

It is highly expressed in fetal kidney, digestive system

(from esophagus to colon), thyroid, prostate and

trachea and at slightly lower levels in fetal brain, lung,

PLXNB1 (plexin B1) Gómez-Román JJ, et al.


female reproductive system (breast, uterus and ovary) and liver.

Plexin B1 policlonal antibody in foetal human central nervous system. Positive staining in developing neurons.

Localisation

Three isoforms have been identified: The isoform 1 is

located in cell membrane and the isoforms 2 and 3 are

secreted proteins.

Function

Plexin B1 has several molecular functions, like a

receptor activity, transmembrane receptor activity,

protein binding, semaphorin receptor and semaphorin

receptor binding. It is implicated in the next biological

processes: Signal transduction, intracellular signalling

cascade, multicellular organismal development, cell

migration and posi-tive regulation of axonogenesis.

Homology

It belongs to the plexin family and it contains 3

IPT/TIG domains and one Sema domain.

Mutations

Somatic

Wong et al. (2007) identified 13 different somatic

mutations in the cytoplasmic domain of the PLXNB1

gene in prostate cancer tissue. Mutations were found in

8 (89%) of 9 prostate cancer bone metastases, in 7

(41%) of 17 lymph node meta-stases, and in 41 (46%)

of 89 primary cancers. Forty percent of prostate cancers

contained the same mutation, and the majority of the

primary tumors showed overexpression of the plexin-

B1 protein. In vitro functional expression studies of the

3 most common mutations showed that the mutant

proteins resulted in increased cell motility, inva-sion,

adhesion, and lamellipodia extension compared to

wildtype. The mutations acted by hindering RAC1 and

RRAS binding and GTP activity.

Implicated in

Breast cancer

Prognosis

Loss of protein Plexin B1 expression is associated with

poor outcome in breast cancer ER (estrogen positive)

patients.



Renal cell carcinoma

Note

By reverse transcription-polymerase chain reaction

plexin B1 is expressed in nonneoplastic renal tissue,

and it is severely downregulated in clear cell renal

carcinomas. By immunohistochemistry on tissue

microarrays it was shown that plexin B1 protein is

absent in more than 80% of renal cell carcinomas.

Otherwise, all kinds of renal tubules showed strong

membrane reactivity.

When plexin B1 expression is induced with an

expression vector in the renal adenocarcinoma cell line

ACHN, a marked reduction in proliferation rate is

found.

Prostate carcinoma

Note

13 somatic missense mutations in the cytoplasmic

domain of the Plexin-B1 gene have been reported.

Mutations were found in cancer bone metastases,

lymph node metastases, and in primary cancers.

Forty percent of prostate cancers contained the same

mutation. Overexpression of the Plexin-B1 protein was

found in the majority of primary tumors. The mutations

hinder Rac and R-Ras binding and R-RasGAP activity,

resulting in an increase in cell motility, invasion,

adhesion, and lamellipodia.

Plexin B1 in normal kidney tissue. Tubular cortical and medular cells reactive The same immunostaining after blocking peptide incubation.



Plexin B1 loss of expression in three cases of renal cell carcinoma (clear cell upper right and left), and papillary (bottom right). One case of renal clear cell carcinoma with PlexinB1 expression (bottom left).

Osteoarthritis

Note

Using semi-quantitative reverse transcription

polymerase chain reaction (RT-PCR) analysis, plexin

B1 (PLXNB1) was confirmed to be consis-tently

expressed at lower levels in osteoarthritis.

Disease

Degenerative bone disease.

References Maestrini E, Tamagnone L, Longati P, Cremona O, Gulisano M, Bione S, Tamanini F, Neel BG, Toniolo D, Comoglio PM. A family of transmembrane proteins with homology to the MET-hepatocyte growth factor receptor. Proc Natl Acad Sci U S A. 1996 Jan 23;93(2):674-8

Fujii T, Nakao F, Shibata Y, Shioi G, Kodama E, Fujisawa H, Takagi S. Caenorhabditis elegans PlexinA, PLX-1, interacts with transmembrane semaphorins and regulates epidermal morphogenesis. Development. 2002 May;129(9):2053-63

Lorenzato A, Olivero M, Patanè S, Rosso E, Oliaro A, Comoglio PM, Di Renzo MF. Novel somatic mutations of the MET oncogene in human carcinoma metastases activating cell motility and invasion. Cancer Res. 2002 Dec 1;62(23):7025-30

Oinuma I, Katoh H, Harada A, Negishi M. Direct interaction of Rnd1 with Plexin-B1 regulates PDZ-RhoGEF-mediated Rho

activation by Plexin-B1 and induces cell contraction in COS-7 cells. J Biol Chem. 2003 Jul 11;278(28):25671-7

Usui H, Taniguchi M, Yokomizo T, Shimizu T. Plexin-A1 and plexin-B1 specifically interact at their cytoplasmic domains. Biochem Biophys Res Commun. 2003 Jan 24;300(4):927-31

Conrotto P, Corso S, Gamberini S, Comoglio PM, Giordano S. Interplay between scatter factor receptors and B plexins controls invasive growth. Oncogene. 2004 Jul 1;23(30):5131-7

Oinuma I, Ishikawa Y, Katoh H, Negishi M. The Semaphorin 4D receptor Plexin-B1 is a GTPase activating protein for R-Ras. Science. 2004 Aug 6;305(5685):862-5

Swiercz JM, Kuner R, Offermanns S. Plexin-B1/RhoGEF-mediated RhoA activation involves the receptor tyrosine kinase ErbB-2. J Cell Biol. 2004 Jun 21;165(6):869-80

Torres-Vázquez J, Gitler AD, Fraser SD, Berk JD, Van N Pham, Fishman MC, Childs S, Epstein JA, Weinstein BM. Semaphorin-plexin signaling guides patterning of the developing vasculature. Dev Cell. 2004 Jul;7(1):117-23

Basile JR, Afkhami T, Gutkind JS. Semaphorin 4D/plexin-B1 induces endothelial cell migration through the activation of PYK2, Src, and the phosphatidylinositol 3-kinase-Akt pathway. Mol Cell Biol. 2005 Aug;25(16):6889-98

Conrotto P, Valdembri D, Corso S, Serini G, Tamagnone L, Comoglio PM, Bussolino F, Giordano S. Sema4D induces angiogenesis through Met recruitment by Plexin B1. Blood. 2005 Jun 1;105(11):4321-9



Basile JR, Gavard J, Gutkind JS. Plexin-B1 utilizes RhoA and Rho kinase to promote the integrin-dependent activation of Akt and ERK and endothelial cell motility. J Biol Chem. 2007 Nov 30;282(48):34888-95

Harduf H, Goldman S, Shalev E. Human uterine epithelial RL95-2 and HEC-1A cell-line adhesiveness: the role of plexin B1. Fertil Steril. 2007 Jun;87(6):1419-27

Tong Y, Chugha P, Hota PK, Alviani RS, Li M, Tempel W, Shen L, Park HW, Buck M. Binding of Rac1, Rnd1, and RhoD to a novel Rho GTPase interaction motif destabilizes dimerization of the plexin-B1 effector domain. J Biol Chem. 2007 Dec 21;282(51):37215-24

Wong OG, Nitkunan T, Oinuma I, Zhou C, Blanc V, Brown RS, Bott SR, Nariculam J, Box G, Munson P, Constantinou J, Feneley MR, Klocker H, Eccles SA, Negishi M, Freeman A, Masters JR, Williamson M. Plexin-B1 mutations in prostate cancer. Proc Natl Acad Sci U S A. 2007 Nov 27;104(48):19040-5

Bouguet-Bonnet S, Buck M. Compensatory and long-range changes in picosecond-nanosecond main-chain dynamics upon complex formation: 15N relaxation analysis of the free and bound states of the ubiquitin-like domain of human plexin-

B1 and the small GTPase Rac1. J Mol Biol. 2008 Apr 11;377(5):1474-87

Gómez Román JJ, Garay GO, Saenz P, Escuredo K, Sanz Ibayondo C, Gutkind S, Junquera C, Simón L, Martínez A, Fernández Luna JL, Val-Bernal JF. Plexin B1 is downregulated in renal cell carcinomas and modulates cell growth. Transl Res. 2008 Mar;151(3):134-40

Swiercz JM, Worzfeld T, Offermanns S. ErbB-2 and met reciprocally regulate cellular signaling via plexin-B1. J Biol Chem. 2008 Jan 25;283(4):1893-901

Tong Y, Hota PK, Hamaneh MB, Buck M. Insights into oncogenic mutations of plexin-B1 based on the solution structure of the Rho GTPase binding domain. Structure. 2008 Feb;16(2):246-58


Gómez-Román JJ, Nicolas Martínez M, Lazuén Fernández S, Val-Bernal JF. PLXNB1 (plexin B1). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3):249-253.





RUVBL1 (RuvB-like 1 (E. coli)) Valérie Haurie, Aude Grigoletto, Jean Rosenbaum

INSERM U889, Universite Victor Segalen Bordeaux 2, 146 rue Leo Saignat, 33076 Bordeaux, France (VH,

AG, JR)


Online updated version: http://AtlasGeneticsOncology.org/Genes/RUVBL1ID44415ch3q21.html DOI: 10.4267/2042/44703


Identity

Other names: ECP54; INO80H; NMP238; PONTIN;

Pontin52; RVB1; TAP54-alpha; TIH1; TIP49; TIP49A

HGNC (Hugo): RUVBL1

Location: 3q21.3

DNA/RNA

Description

11 exons spamming 42840bp, 1371bp open reading

frame.

Transcription

1785bp mRNA.

Protein

Description

456 amino acids, 50.2 kDa. RUVBL1 belongs to the

AAA+ ATPase superfamily (ATPases associa-ted with

diverse cellular activities) sharing conserved Walker A

and B motifs, arginine fingers, and sensor domains.

The structure of RuvBL1 has been determined by X-ray

crystallography and published in 2006 (Matias et al.,

2006).

The monomers contain three domains, of which the

first and the third are involved in ATP binding and

hydrolysis. The second domain is a DNA/RNA-binding

domain as demonstrated by structural homology and

nucleic acid binding assays. RUVBL1 assembles into

an hexameric structure with a central channel. Pure

RUVBL1 displays a marginal ATPase activity in vitro

and no detectable helicase activity (Matias et al., 2006).

RUVBL1 interacts with RUVBL2 to form a dodecamer

(Puri et al., 2007). This RUVBL1/ RUVBL2 complex

displays a significant ATPase activity and is likely one

of the functional forms of the proteins.

Sumoylation of RUVBL1 was reported in metastatic

prostate cancer cells (Kim et al., 2007).

Expression

Expression is ubiquitous but especially abundant in

heart, skeletal muscle and testis (Salzer et al., 1999).

RUVBL1 is overexpressed in several tumors : liver (Li

et al., 2005), colon (Carlson et al., 2003; Lauscher et

al., 2007), lymphoma (Nishiu et al., 2002), non-small

cell lung (Dehan et al., 2007). Overexpressions of

RUVBL1 in a large number of cancers and its possible

role in human cancers have been reported (reviewed in

Huber et al., 2008).

Localisation

Cytoplasm and nucleus.

RUVBL1 (RuvB-like 1 (E. coli)) Haurie V, et al.


Function

RUVBL1 plays roles in essential signaling path-ways

such as the c-Myc and beta-catenin pathways.

RUVBL1 appears notably required for the trans-

forming activity of c-myc (Wood et al., 2000), beta-

catenin (Feng et al., 2003) and of the viral oncoprotein

E1A (Dugan et al., 2002).

RUVBL1 participates in the remodelling of chromatin

as a member of several complexes such as TRRAP,

several distinct HAT complexes and BAF53 (Wood et

al., 2000; Park et al., 2002; Feng et al., 2003).

It is also involved in transcriptional regulation

(reviewed in Gallant, 2007), DNA repair (Gospodinov

et al., 2008), snoRNP biogenesis (Watkins et al., 2002),

and telomerase activity (Venteicher et al., 2008).

RUVBL1 has a mitosis-specific function in regulating

microtubule assembly (Ducat et al., 2008).

RUVBL1 has been found expressed on the cell surface

where it participates in the activation of plasminogen

(Hawley et al., 2001).

Implicated in

Colon cancer

Disease

By immunohistochemistry, RUVBL1 expression was

found higher in 22 out of 26 cases where information

was available (Lauscher et al., 2007). The staining was

increased at the invasive margin of the tumors.

Increased RUVBL1 transcripts levels were also

reported in a smaller series (Carlson et al., 2003).

Large B cell lymphoma

Disease

Microarray analysis has identified an over-expression

of RUVBL1 in Advanced lymphomas as compared

with localized lymphomas (Nishiu et al., 2002).

Non Small cell lung cancer

Disease

Microarray analysis and subsequent RT-PCR have

shown an overexpression of RUVBL1 in NSCLC

(Dehan et al., 2007).

Cytogenetics

There is a frequent amplification of 3q21 in the same

samples (Dehan et al., 2007).

Hepatocellular carcinoma

Disease

Proteomic analysis found an overexpression of

RUVBL1 in 4 out of 10 cases (Li et al., 2005).

Autoimmune diseases

Disease

Auto-antibodies to RUVBL1 were found in the serum

of patients with polymyositis/dermato-myositis and

autoimmune hepatitis (Makino et al., 1998).

References Makino Y, Mimori T, Koike C, Kanemaki M, Kurokawa Y, Inoue S, Kishimoto T, Tamura T. TIP49, homologous to the bacterial DNA helicase RuvB, acts as an autoantigen in human. Biochem Biophys Res Commun. 1998 Apr 28;245(3):819-23

Salzer U, Kubicek M, Prohaska R. Isolation, molecular characterization, and tissue-specific expression of ECP-51 and ECP-54 (TIP49), two homologous, interacting erythroid cytosolic proteins. Biochim Biophys Acta. 1999 Sep 3;1446(3):365-70

Wood MA, McMahon SB, Cole MD. An ATPase/helicase complex is an essential cofactor for oncogenic transformation by c-Myc. Mol Cell. 2000 Feb;5(2):321-30

Hawley SB, Tamura T, Miles LA. Purification, cloning, and characterization of a profibrinolytic plasminogen-binding protein, TIP49a. J Biol Chem. 2001 Jan 5;276(1):179-86

Dugan KA, Wood MA, Cole MD. TIP49, but not TRRAP, modulates c-Myc and E2F1 dependent apoptosis. Oncogene. 2002 Aug 29;21(38):5835-43

Nishiu M, Yanagawa R, Nakatsuka S, Yao M, Tsunoda T, Nakamura Y, Aozasa K. Microarray analysis of gene-expression profiles in diffuse large B-cell lymphoma: identification of genes related to disease progression. Jpn J Cancer Res. 2002 Aug;93(8):894-901

Park J, Wood MA, Cole MD. BAF53 forms distinct nuclear complexes and functions as a critical c-Myc-interacting nuclear cofactor for oncogenic transformation. Mol Cell Biol. 2002 Mar;22(5):1307-16

Watkins NJ, Dickmanns A, Lührmann R. Conserved stem II of the box C/D motif is essential for nucleolar localization and is required, along with the 15.5K protein, for the hierarchical assembly of the box C/D snoRNP. Mol Cell Biol. 2002 Dec;22(23):8342-52

Carlson ML, Wilson ET, Prescott SM. Regulation of COX-2 transcription in a colon cancer cell line by Pontin52/TIP49a. Mol Cancer. 2003 Dec 15;2:42

Feng Y, Lee N, Fearon ER. TIP49 regulates beta-catenin-mediated neoplastic transformation and T-cell factor target gene induction via effects on chromatin remodeling. Cancer Res. 2003 Dec 15;63(24):8726-34

Li C, Tan YX, Zhou H, Ding SJ, Li SJ, Ma DJ, Man XB, Hong Y, Zhang L, Li L, Xia QC, Wu JR, Wang HY, Zeng R. Proteomic analysis of hepatitis B virus-associated hepatocellular carcinoma: Identification of potential tumor markers. Proteomics. 2005 Mar;5(4):1125-39

Matias PM, Gorynia S, Donner P, Carrondo MA. Crystal structure of the human AAA+ protein RuvBL1. J Biol Chem. 2006 Dec 15;281(50):38918-29

Dehan E, Ben-Dor A, Liao W, Lipson D, Frimer H, Rienstein S, Simansky D, Krupsky M, Yaron P, Friedman E, Rechavi G, Perlman M, Aviram-Goldring A, Izraeli S, Bittner M, Yakhini Z, Kaminski N. Chromosomal aberrations and gene expression profiles in non-small cell lung cancer. Lung Cancer. 2007 May;56(2):175-84

Gallant P. Control of transcription by Pontin and Reptin. Trends Cell Biol. 2007 Apr;17(4):187-92

Kim JH, Lee JM, Nam HJ, Choi HJ, Yang JW, Lee JS, Kim MH, Kim SI, Chung CH, Kim KI, Baek SH. SUMOylation of pontin chromatin-remodeling complex reveals a signal integration code in prostate cancer cells. Proc Natl Acad Sci U S A. 2007 Dec 26;104(52):20793-8

RUVBL1 (RuvB-like 1 (E. coli)) Haurie V, et al.


Lauscher JC, Loddenkemper C, Kosel L, Gröne J, Buhr HJ, Huber O. Increased pontin expression in human colorectal cancer tissue. Hum Pathol. 2007 Jul;38(7):978-85

Puri T, Wendler P, Sigala B, Saibil H, Tsaneva IR. Dodecameric structure and ATPase activity of the human TIP48/TIP49 complex. J Mol Biol. 2007 Feb 9;366(1):179-92

Ducat D, Kawaguchi S, Liu H, Yates JR 3rd, Zheng Y. Regulation of microtubule assembly and organization in mitosis by the AAA+ ATPase Pontin. Mol Biol Cell. 2008 Jul;19(7):3097-110

Huber O, Ménard L, Haurie V, Nicou A, Taras D, Rosenbaum J. Pontin and reptin, two related ATPases with multiple roles in cancer. Cancer Res. 2008 Sep 1;68(17):6873-6

Venteicher AS, Meng Z, Mason PJ, Veenstra TD, Artandi SE. Identification of ATPases pontin and reptin as telomerase components essential for holoenzyme assembly. Cell. 2008 Mar 21;132(6):945-57

Gospodinov A, Tsaneva I, Anachkova B. RAD51 foci formation in response to DNA damage is modulated by TIP49. Int J Biochem Cell Biol. 2009 Apr;41(4):925-33


Haurie V, Grigoletto A, Rosenbaum J. RUVBL1 (RuvB-like 1 (E. coli)). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3):254-256.





RUVBL2 (RuvB-like 2 (E. coli)) Aude Grigoletto, Valérie Haurie, Jean Rosenbaum

INSERM U889, Universite Victor Segalen Bordeaux 2, 146 rue Leo Saignat, 33076 Bordeaux, France (AG,

VH, JR)


Online updated version: http://AtlasGeneticsOncology.org/Genes/RUVBL2ID42185ch19q13.html DOI: 10.4267/2042/44704


Identity

Other names: CGI-46; ECP51; INO80J; REPTIN;

RVB2; Reptin52; Rvb2; TAP54-beta; TIH2; TIP48;

TIP49B

HGNC (Hugo): RUVBL2

Location: 19q13.33

DNA/RNA

Description

15 exons, 14 introns (Parfait et al., 2000).

Transcription

1518bp mRNA with 463aa open reading frame.

Protein

Description

463 amino acids, 52 kDa.

RUVBL2 belongs to the AAA+ ATPase super-family

(ATPases associated with diverse cellular activities)

sharing conserved Walker A and B motifs, arginine

fingers, and sensor domains. The monomers contain

two domains, which are involved in ATP binding and

hydrolysis respectively. RUVBL2 assembles into an

hexameric structure with a central channel.

RUVBL2 interacts with RUVBL1 to form a dodecamer

(Puri et al., 2007). This RUVBL1/ RUVBL2 complex

displays a significant ATPase activity and is likely one

of the functional forms of the proteins. Sumoylation of

RUVBL2 has been reported on

Lys456 in invasive prostate cancer cells (Kim et al.,

2006).

RUVBL2 is phosphorylated on an ATM/ATR

consensus site following DNA damage (Matsuoka et

al., 2007).

Expression

Expression of RUVBL2 is ubiquitous but especially

abundant in thymus and testis (Salzer et al., 1999;

Parfait et al., 2000).

RUVBL2 is overexpressed in hepatocellular carci-

noma (Rousseau et al., 2007). Overexpression of

RUVBL2 in several cancers and its possible role in

human cancers has been reported (reviewed in Huber et

al., 2008).

Localisation

Cytoplasm and nucleus.

Function

RUVBL2 interacts with c-myc (Wood et al., 2000) and

also modulates transcriptional regulation by the beta-

catenin/TCF-LEF complex (Bauer et al., 2000) and

ATF2 (Cho et al., 2001). RUVBL2 participates in the

remodelling of chromatin as a member of several

complexes such as TIP60 (Ikura et al., 2000), INO80

(Jin et al., 2005), SRCAP (Cai et al., 2005).

It is also involved in transcriptional regulation

(reviewed in Gallant, 2007), DNA repair (Gospodinov

et al., 2008), snoRNP biogenesis (Watkins et al., 2002),

and telomerase activity (Venteicher et al., 2008).

RUVBL2 silencing in fibroblasts induces a senescent

phenotype (Chan et al., 2005).

Implicated in

Hepatocellular carcinoma (HCC)

Disease

RUVBL2 (RuvB-like 2 (E. coli)) Grigoletto A, et al.


RUVBL2 was found to be overexpressed in 75% of

cases in a series of 96 human HCC studied with real-

time RT-PCR (Rousseau et al., 2007). It was also

increased in a smaller 15 cases series (Iizuka et al.,

2006). No mutations in the coding sequence were

identified (Rousseau et al., 2007).

Prognosis

Overexpression of RUVBL2 was an independent factor

of poor prognosis (Rousseau et al., 2007).

Oncogenesis

RUVBL2 depletion with siRNAs led to HCC cell

growth arrest and apoptosis, whereas over-expression

in HCC cells allowed these cells to give rise to more

progressive tumors in xenografts than control cells

(Rousseau et al., 2007).

Colon cancer

Disease

RUVBL2 was overexpressed in a series of 18 colon

cancers (Graudens et al., 2006).

Melanoma

Disease

RUVBL2 was overexpressed in a series of 45

melanomas (Talantov et al., 2005).

Bladder carcinoma

Disease

RUVBL2 was overexpressed in a series of 108 bladder

carcinomas (Sanchez-Carbayo et al., 2006).

Prostate cancer

Oncogenesis

In conjunction with beta-catenin, RUVBL2 represses

the expression of the anti-metastasis gene KAI-1 (Kim

et al., 2005) and is involved in the invasive phenotype

of cultured prostate cancer cells (Kim et al., 2006).

References Salzer U, Kubicek M, Prohaska R. Isolation, molecular characterization, and tissue-specific expression of ECP-51 and ECP-54 (TIP49), two homologous, interacting erythroid cytosolic proteins. Biochim Biophys Acta. 1999 Sep 3;1446(3):365-70

Bauer A, Chauvet S, Huber O, Usseglio F, Rothbächer U, Aragnol D, Kemler R, Pradel J. Pontin52 and reptin52 function as antagonistic regulators of beta-catenin signalling activity. EMBO J. 2000 Nov 15;19(22):6121-30

Ikura T, Ogryzko VV, Grigoriev M, Groisman R, Wang J, Horikoshi M, Scully R, Qin J, Nakatani Y. Involvement of the TIP60 histone acetylase complex in DNA repair and apoptosis. Cell. 2000 Aug 18;102(4):463-73

Parfait B, Giovangrandi Y, Asheuer M, Laurendeau I, Olivi M, Vodovar N, Vidaud D, Vidaud M, Bièche I. Human TIP49b/RUVBL2 gene: genomic structure, expression pattern, physical link to the human CGB/LHB gene cluster on chromosome 19q13.3. Ann Genet. 2000 Apr-Jun;43(2):69-74

Wood MA, McMahon SB, Cole MD. An ATPase/helicase complex is an essential cofactor for oncogenic transformation by c-Myc. Mol Cell. 2000 Feb;5(2):321-30

Cho SG, Bhoumik A, Broday L, Ivanov V, Rosenstein B, Ronai Z. TIP49b, a regulator of activating transcription factor 2 response to stress and DNA damage. Mol Cell Biol. 2001 Dec;21(24):8398-413

Watkins NJ, Dickmanns A, Lührmann R. Conserved stem II of the box C/D motif is essential for nucleolar localization and is required, along with the 15.5K protein, for the hierarchical assembly of the box C/D snoRNP. Mol Cell Biol. 2002 Dec;22(23):8342-52

Cai Y, Jin J, Florens L, Swanson SK, Kusch T, Li B, Workman JL, Washburn MP, Conaway RC, Conaway JW. The mammalian YL1 protein is a shared subunit of the TRRAP/TIP60 histone acetyltransferase and SRCAP complexes. J Biol Chem. 2005 Apr 8;280(14):13665-70

Chan HM, Narita M, Lowe SW, Livingston DM. The p400 E1A-associated protein is a novel component of the p53 --> p21 senescence pathway. Genes Dev. 2005 Jan 15;19(2):196-201

Jin J, Cai Y, Yao T, Gottschalk AJ, Florens L, Swanson SK, Gutiérrez JL, Coleman MK, Workman JL, Mushegian A, Washburn MP, Conaway RC, Conaway JW. A mammalian chromatin remodeling complex with similarities to the yeast INO80 complex. J Biol Chem. 2005 Dec 16;280(50):41207-12

Kim JH, Kim B, Cai L, Choi HJ, Ohgi KA, Tran C, Chen C, Chung CH, Huber O, Rose DW, Sawyers CL, Rosenfeld MG, Baek SH. Transcriptional regulation of a metastasis suppressor gene by Tip60 and beta-catenin complexes. Nature. 2005 Apr 14;434(7035):921-6

Talantov D, Mazumder A, Yu JX, Briggs T, Jiang Y, Backus J, Atkins D, Wang Y. Novel genes associated with malignant melanoma but not benign melanocytic lesions. Clin Cancer Res. 2005 Oct 15;11(20):7234-42

Weiske J, Huber O. The histidine triad protein Hint1 interacts with Pontin and Reptin and inhibits TCF-beta-catenin-mediated transcription. J Cell Sci. 2005 Jul 15;118(Pt 14):3117-29

Graudens E, Boulanger V, Mollard C, Mariage-Samson R, Barlet X, Grémy G, Couillault C, Lajémi M, Piatier-Tonneau D, Zaborski P, Eveno E, Auffray C, Imbeaud S. Deciphering cellular states of innate tumor drug responses. Genome Biol. 2006;7(3):R19

Iizuka N, Tsunedomi R, Tamesa T, Okada T, Sakamoto K, Hamaguchi T, Yamada-Okabe H, Miyamoto T, Uchimura S, Hamamoto Y, Oka M. Involvement of c-myc-regulated genes in hepatocellular carcinoma related to genotype-C hepatitis B virus. J Cancer Res Clin Oncol. 2006 Jul;132(7):473-81

Kim JH, Choi HJ, Kim B, Kim MH, Lee JM, Kim IS, Lee MH, Choi SJ, Kim KI, Kim SI, Chung CH, Baek SH. Roles of sumoylation of a reptin chromatin-remodelling complex in cancer metastasis. Nat Cell Biol. 2006 Jun;8(6):631-9

Sanchez-Carbayo M, Socci ND, Lozano J, Saint F, Cordon-Cardo C. Defining molecular profiles of poor outcome in patients with invasive bladder cancer using oligonucleotide microarrays. J Clin Oncol. 2006 Feb 10;24(5):778-89

Gallant P. Control of transcription by Pontin and Reptin. Trends Cell Biol. 2007 Apr;17(4):187-92

Matsuoka S, Ballif BA, Smogorzewska A, McDonald ER 3rd, Hurov KE, Luo J, Bakalarski CE, Zhao Z, Solimini N, Lerenthal Y, Shiloh Y, Gygi SP, Elledge SJ. ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage. Science. 2007 May 25;316(5828):1160-6

Puri T, Wendler P, Sigala B, Saibil H, Tsaneva IR. Dodecameric structure and ATPase activity of the human TIP48/TIP49 complex. J Mol Biol. 2007 Feb 9;366(1):179-92

Rousseau B, Ménard L, Haurie V, Taras D, Blanc JF, Moreau-Gaudry F, Metzler P, Hugues M, Boyault S, Lemière S, Canron

RUVBL2 (RuvB-like 2 (E. coli)) Grigoletto A, et al.


X, Costet P, Cole M, Balabaud C, Bioulac-Sage P, Zucman-Rossi J, Rosenbaum J. Overexpression and role of the ATPase and putative DNA helicase RuvB-like 2 in human hepatocellular carcinoma. Hepatology. 2007 Oct;46(4):1108-18

Huber O, Ménard L, Haurie V, Nicou A, Taras D, Rosenbaum J. Pontin and reptin, two related ATPases with multiple roles in cancer. Cancer Res. 2008 Sep 1;68(17):6873-6

Venteicher AS, Meng Z, Mason PJ, Veenstra TD, Artandi SE. Identification of ATPases pontin and reptin as telomerase components essential for holoenzyme assembly. Cell. 2008 Mar 21;132(6):945-57

Gospodinov A, Tsaneva I, Anachkova B. RAD51 foci formation in response to DNA damage is modulated by TIP49. Int J Biochem Cell Biol. 2009 Apr;41(4):925-33


Grigoletto A, Haurie V, Rosenbaum J. RUVBL2 (RuvB-like 2 (E. coli)). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3):257-259.





SH3GL2 (SH3-domain GRB2-like 2) Chinmay Kr Panda, Amlan Ghosh, Guru Prasad Maiti

Department of Oncogene Regulation, Chittaranjan National Cancer Institute, Kolkata 700026, India (CKP,

AG, GPM)


Online updated version: http://AtlasGeneticsOncology.org/Genes/SH3GL2ID44345ch9p22.html DOI: 10.4267/2042/44705


Identity

Other names: CNSA2; EEN-B1; Endophilin-1;

FLJ20276; FLJ25015; OTTHUMP00000021084;

SH3D2A; SH3P4

HGNC (Hugo): SH3GL2

Location: 9p22.2

Local order: Next to ADAMTSL1 and FAN154A.

DNA/RNA

Description

10 exons; spans 217.93kb.

Transcription

mRNA of 2483 and 2417bp (there are two transcripts).

Protein

Description

352 amino acids; 39.96kDa and 330 amino acids;

37.51kDa.

Expression

Highest expression found in brain followed by pituitary

gland and kidney. Expression has also been reported in

bladder, eye, heart, cervix, breast, head and neck

tissues etc.

Localisation

Cytoplasmic (diffuse cytoplasmic distribution in resting

cells and a colocalization with EGF receptor in

endocytic vesicles after EGF stimulation).

Function

SH3GL2 is a presynaptic protein that binds to dynamin,

a GTPase that is implicated in endo-cytosis and

recycling of synaptic vesicles. SH3GL2 by its LPAAT

activity may induce negative membrane curvature by

converting an inverted cone shaped lipid to a cone

shaped lipid in the cytoplasmic leaflet of the bilayer.

Through this action, SH3GL2 works with dynamin to

mediate synaptic vesicle invagination from the plasma

membrane and fission. SH3GL2 in complex with CBL

and CIN85 participates in activated EGF receptor

(Stimulated by EGF) endocytosis from the membrane

surface and its subsequent lysosomal degradation.

The SH3 domain of SH3GL2 binds to a 24 amino acid

proline rich domain (PRD) in the third intracellular

loop of the G-protein coupled-1-adrenergic receptor.

SH3GL2 overexpression increased isoproterenol-

induced receptor inter-nalization by 25% and decreased

coupling of receptor to the G-protein.

The SH3 domain of SH3GL2 also binds to a proline

rich domain within the cytoplasmic tail of metallo-

protease disintegrins, transmembrane glycoproteins

acting in cell adhesion and growth factor signaling.

SH3GL2 binds preferentially to the pro-form found in

the trans-Golgi network. Therefore SH3GL2 binding

may regulate intracellular transit and maturation of

metalloprotease disintegrin.

Rat germinal centre kinse-like kinase (rGLK), a

serine/threonine cytosolic kinase, interacted with

SH3GL2. rGLK modulated c-Jun N-terminal kinase

(JNK) activity by phosphorylation and binds to the

SH3 domain of SH3GL2 through a C-terminal proline

rich domain. Coexpression of rGLK and full length

SH3GL2 increased JNK activity two fold, whereas

coexpression with the SH3 domain of SH3GL2

abrogated rGLK-induced JNK activation. SH3GL2,

therefore, modulated the mitogen-activated protein

kinase pathway through physical association with

rGLK.

SH3GL2 (SH3-domain GRB2-like 2) Panda CK, et al.


Homology

SH3GL2 contains a C-terminal SH3 domain, which

shares 92% and 84% amino acid sequence homology

with the SH3 domain of SH3GL3 and SH3GL1,

respectively. The SH3 domain of SH3GL2 also shows

high homology to the C-terminal SH3 domain of

GRB2.

Mutations

Somatic

In SH3GL2, mutation in SH3 domain has only been

reported.

Implicated in

Sporadic cancer

Disease

Reduced expressions of SH3GL2 due to different types

of molecular alterations are involved in tumor

formation in head and neck, breast and gastric tissues.

Prognosis

The prognostic significance of down regulation of

SH3GL2 in sporadic tumors is not understood clearly.

Cytogenetics

Chromosomal deletions, chromosomal gain or

amplification and chromosomal breakpoints are

frequent.

Oncogenesis

LOH on 9p22 is one of the most frequent events

identified in head and neck tumor, breast carcinoma,

pituitary adenoma, neuroblastoma etc. However,

promoter methylation appears to be another common

mechanism of SH3GL2 inactivation.

Alzheimer disease

Disease

The increased expression level of SH3GL2 in neuron is

linked to an increase in the activation of the stress

kinase c-Jun N-terminal kinase with the subsequent

death of the neuron.

Prognosis

SH3GL2 overexpression is now considered as a new

indicator of the progression of Alzhemier disease.

Cytogenetics

Increase in aneuploidy or aberration, but chromosomal

loss or gain in aneuploid cell was not specific. In some

forms of Alzheimer disease, a specific type of

aneuploidy-trisomy 21 mosaicism has been reported.

References Giachino C, Lantelme E, Lanzetti L, Saccone S, Bella Valle G, Migone N. A novel SH3-containing human gene family preferentially expressed in the central nervous system. Genomics. 1997 May 1;41(3):427-34

Howard L, Nelson KK, Maciewicz RA, Blobel CP. Interaction of the metalloprotease disintegrins MDC9 and MDC15 with two SH3 domain-containing proteins, endophilin I and SH3PX1. J Biol Chem. 1999 Oct 29;274(44):31693-9

Schmidt A, Wolde M, Thiele C, Fest W, Kratzin H, Podtelejnikov AV, Witke W, Huttner WB, Söling HD. Endophilin I mediates synaptic vesicle formation by transfer of arachidonate to lysophosphatidic acid. Nature. 1999 Sep 9;401(6749):133-41

Tang Y, Hu LA, Miller WE, Ringstad N, Hall RA, Pitcher JA, DeCamilli P, Lefkowitz RJ. Identification of the endophilins (SH3p4/p8/p13) as novel binding partners for the beta1-adrenergic receptor. Proc Natl Acad Sci U S A. 1999 Oct 26;96(22):12559-64

Huttner WB, Schmidt A. Lipids, lipid modification and lipid-protein interaction in membrane budding and fission--insights from the roles of endophilin A1 and synaptophysin in synaptic vesicle endocytosis. Curr Opin Neurobiol. 2000 Oct;10(5):543-51

Ramjaun AR, Angers A, Legendre-Guillemin V, Tong XK, McPherson PS. Endophilin regulates JNK activation through its interaction with the germinal center kinase-like kinase. J Biol Chem. 2001 Aug 3;276(31):28913-9

Reutens AT, Begley CG. Endophilin-1: a multifunctional protein. Int J Biochem Cell Biol. 2002 Oct;34(10):1173-7

Soubeyran P, Kowanetz K, Szymkiewicz I, Langdon WY, Dikic I. Cbl-CIN85-endophilin complex mediates ligand-induced downregulation of EGF receptors. Nature. 2002 Mar 14;416(6877):183-7

Verstreken P, Kjaerulff O, Lloyd TE, Atkinson R, Zhou Y, Meinertzhagen IA, Bellen HJ. Endophilin mutations block clathrin-mediated endocytosis but not neurotransmitter release. Cell. 2002 Apr 5;109(1):101-12

Chen Y, Deng L, Maeno-Hikichi Y, Lai M, Chang S, Chen G, Zhang JF. Formation of an endophilin-Ca2+ channel complex is critical for clathrin-mediated synaptic vesicle endocytosis. Cell. 2003 Oct 3;115(1):37-48

Hirayama S, Bajari TM, Nimpf J, Schneider WJ. Receptor-mediated chicken oocyte growth: differential expression of endophilin isoforms in developing follicles. Biol Reprod. 2003 May;68(5):1850-60

Otsuki M, Itoh T, Takenawa T. Neural Wiskott-Aldrich syndrome protein is recruited to rafts and associates with endophilin A in response to epidermal growth factor. J Biol Chem. 2003 Feb 21;278(8):6461-9

Masuda M, Takeda S, Sone M, Ohki T, Mori H, Kamioka Y, Mochizuki N. Endophilin BAR domain drives membrane curvature by two newly identified structure-based mechanisms. EMBO J. 2006 Jun 21;25(12):2889-97

Shang C, Fu WN, Guo Y, Huang DF, Sun KL. Study of the SH3-domain GRB2-like 2 gene expression in laryngeal carcinoma. Chin Med J (Engl). 2007 Mar 5;120(5):385-8

Potter N, Karakoula A, Phipps KP, Harkness W, Hayward R, Thompson DN, Jacques TS, Harding B, Thomas DG, Palmer RW, Rees J, Darling J, Warr TJ. Genomic deletions correlate with underexpression of novel candidate genes at six loci in pediatric pilocytic astrocytoma. Neoplasia. 2008 Aug;10(8):757-72

Ren Y, Xu HW, Davey F, Taylor M, Aiton J, Coote P, Fang F, Yao J, Chen D, Chen JX, Yan SD, Gunn-Moore FJ. Endophilin I expression is increased in the brains of Alzheimer disease patients. J Biol Chem. 2008 Feb 29;283(9):5685-91

Sinha S, Chunder N, Mukherjee N, Alam N, Roy A, Roychoudhury S, Kumar Panda C. Frequent deletion and

SH3GL2 (SH3-domain GRB2-like 2) Panda CK, et al.


methylation in SH3GL2 and CDKN2A loci are associated with early- and late-onset breast carcinoma. Ann Surg Oncol. 2008 Apr;15(4):1070-80

Ghosh A, Ghosh S, Maiti GP, Sabbir MG, Alam N, Sikdar N, Roy B, Roychoudhury S, Panda CK. SH3GL2 and CDKN2A/2B loci are independently altered in early dysplastic lesions of head and neck: correlation with HPV infection and tobacco habit. J Pathol. 2009 Feb;217(3):408-19


Panda CK, Ghosh A, Maiti GP. SH3GL2 (SH3-domain GRB2-like 2). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3):260-262.

Gene Section Review




TOPORS (topoisomerase I binding, arginine/serine-rich) Jafar Sharif, Asami Tsuboi, Haruhiko Koseki

Developmental Genetics Group, RIKEN Center for Allergy and Immunology (RCAI), Suehirocho 1-7-22,

Tsurumi-ku, Yokohama-shi, Kanagawa-ken, Japan 230-0045 (JS, AT, HK)


Online updated version: http://AtlasGeneticsOncology.org/Genes/TOPORSID42663ch9p21.html DOI: 10.4267/2042/44706


Identity Other names: EC 6.3.2.-; LUN;

OTTHUMP00000021182; OTTHUMP00000021184;

OTTHUMP00000045227; P53BP3; RP31; TP53BPL;

p53BP3

HGNC (Hugo): TOPORS

Location: 9p21.1

DNA/RNA

Description

Spans approximately 8kbs of DNA in the reverse strand

of chromosome 9.

Transcription

Two splicing variants.

Transcript 1 (ENST00000360538): Transcript length

4145 bps, three exons, first one non-coding.

Transcript 2 (ENST00000379858): Transcript length

3,621 bps, two exons, first one non-coding.

Pseudogene

None reported.

Protein

Description

TOPORS transcript 1 encodes a protein containing

1,045 amino acids (ENSP00000353735).

TOPORS transcript 2 encodes a protein containing 980

amino acids (ENSP00000369187).

The 1045aa human TOPORS contains a RING family

zinc-finger domain and a leucine zipper (LZ) domain in

the N-terminal. It also possesses a C-terminal bipartite

nuclear localization signal (NLS), five sequences rich

in proline, glutamine, serine and threonine (PEST

sequences) and an arginine rich domain.

Expression

Widely expressed.

Localisation

Nucleus.

The two splicing variants of TOPORS are shown. Transcript 1 (ENST00000360538) has three exons, the first one non-coding. Transcript 2 (ENST00000379858) has two exons, the first one non-coding. The coding regions are shown in yellow boxes and the non-coding regions (untranslated regions, UTRs) are shown in open boxes.

TOPORS (topoisomerase I binding, arginine/serine-rich) Sharif J, et al.


Homology between murine Topors and human TOPORS is shown. The N-terminal Ring-finger (RF, red) and leucine zipper (LZ, green) domains show 93% homology and the C-terminal nuclear localization signal (NLS, blue) domain shows 90% homology between mouse and human. The P53 binding regions of TOPORS, located inside the NLS domain, are highlighted with red lines.

Function

The RING finger protein TOPORS contains a RING

family zinc-finger domain, a putative leucine zipper

(LZ) domain, five sequences rich in proline, glutamine,

serine and threonine (PEST sequences), an

arginine/serine (RS) domain and a bipartite nuclear

localization signal (NLS). TOPORS was first identified

as a human topoisomerase I-interacting protein by yeast

two-hybrid screening (Haluska et al., 1999). TOPORS

is localized in the nucleus and has been reported to be

closely associated with the PML bodies (Weger et al.,

2003; Rasheed et al., 2002). An important role of

TOPORS is its ability to interact with the tumor

suppressor protein P53 (Zhou et al., 1999). Forced

expression of murine Topors during DNA damage

stabilizes p53, enhances the p53-dependent

transcriptional activities of waf1, MDM2 and Bax

promoters and elevates the level of endogenous p21waf1

mRNA (Lin et al., 2005). These findings suggest an

anti-oncogenic role for TOPORS. Indeed, it was shown

that TOPORS expression is decreased or undetectable

in colon adenocarcinomas relative to normal colon

tissue, and the protein level of TOPORS is undetected

in several colon cancer cell lines (Saleem et al., 2004).

Repression of TOPORS expression was also reported

in progression and development of non-small cell lung

cancer (Oyanagi et al., 2004).

Furthermore, loss of heterozygosity in the region 9p21,

the chromosomal locus harboring TOPORS, has been

frequently associated with different malignancies (Puig

et al., 2005). A high-resolution genomewide mapping

study identified deletion of the TOPORS genomic

locus in human glial tumors, suggesting a possible role

for TOPORS in gliomagenesis (Bredel et al., 2005). A

missense mutation in the TOPORS gene was

implicated in autosomal dominant pericentral retinal

dystrophy, showing that mutations in the TOPORS

gene can lead to genetic disorders (Selmer et al., 2009).

Concomitant with these observations, point mutations

and small insertions and deletions in the TOPORS gene

was found to cause approximately 1% of autosomal

dominant retinitis pigmentosa (Bowne et al., 2008).

Another study reported that mutations in TOPORS

cause autosomal dominant retinitis pigmentosa with

perivascular retinal pigment epithelium atrophy

(Chakarova et al., 2007).

Valuable information on the cellular roles for TOPORS

came through several biochemical studies. It was

shown that in the nucleus TOPORS undergoes SUMO-

1 modifications (Weger et al., 2003). Interestingly,

TOPORS itself has the ability to sumoylate other

proteins by functioning as a SUMO-1 E3 ligase. For

example, TOPORS can sumoylate p53 and the

chromatin modifying protein Sin3A (Shinbo et al.,

2005; Weger et al., 2005; Pungaliya et al., 2007).

Furthermore, TOPORS induce the accumulation of

polysumoylated forms of DNA topoisomerase I in vitro

and in vivo (Hammer et al., 2007). Intriguingly, apart

from its role as a SUMO-1 E3 ligase, TOPORS can

also function as an E3 ubiquitin ligase. In fact,

TOPORS was the first example of a protein that

possesses dual-roles as an E3 ligase for sumoylation

and ubiquitination of other proteins. It was reported

that Topors works as an E3 ubiquitin ligase with

specific E2 enzymes to ubiquitinate the p53 protein and

the prostrate tumor suppressor protein NKX3.1

(Rajendra et al., 2004; Guan et al., 2008). Intense

investigations have been undertaken in recent years to

elucidate the mechanisms of molecules that have dual

E3 ligase activities for sumoylation and ubiquitination

such as TOPORS. These studies have discovered a new

family of proteins, designated as the small ubiquitin-

related modifier (SUMO)-targeted ubiquitin ligases

(STUbLs), which directly links sumoylation and

ubiquitination (Perry et al., 2008). It has been

suggested that similar to STUbLs, TOPORS may be

recruited to its targets through SUMO-associated

interactions and stimulate their ubiquitination in a

RING finger-dependent manner (Perry et al., 2008).

Furthermore, TOPORS has been connected with

transcriptional regulation because of its role as an E3

ubiquitin ligase. In drosophila, the homolog of human

TOPORS (dTopors) ubiquitinates the Hairy

transcriptional repressor, suggesting that TOPORS

could be involved in regulating other transcription

factors as well (Secombe et al., 2004). Indeed, it was

shown that TOPORS interacts with the adeno-

associated virus type 2 (AAV-2) Rep78/68 proteins and

enhances the expression of a Rep78/68 dependent

AAV-2 gene in the absence of the helper virus (Weger

et al., 2002). Finally, it was shown that drosophila

dTopors was required for the nuclear organization of a

chromatin insulator, suggesting a role for TOPORS in

regulation of the chromatin (Capelson et al., 2005).

Homology

Widely conserved among different species. Murine

Topors shows high similarity with human TOPORS.



Mutations

Germinal

TOPORS has been implicated in autosomal dominant

pericentral retinal dystrophy (adPRD), an atypical form

of retinitis pigmentosa. Retinitis pigmentosa is the

collective name for a group of genetically induced eye

disorders that are frequenctly associated with night

blindness and tunnel vision. The TOPORS gene was

sequenced in 19 affected members of a large

Norwegian family. A novel missense mutation,

c.1205a>c, resulting in an amino acid substitution

p.Q402P, was found in all of the cases. Furthermore,

the mutation showed complete co-segregation with the

disease in the family, with the LOD score of 7.3. This

mutation was not detected in 207 unrelated and healthy

Norwegian subjects (Selmer et al., 2009). A separate

study showed that mutations in the TOPORS gene are

responsible for autosomal dominant retinitis

pigmentosa (adRP). Mutations that included an

insertion and a deletion were identified in two adRP-

affected families (Chakarova et al., 2007). Finally,

another recent study investigated whether mutation(s)

in the TOPORS gene is associated with autosomal

dominant retinitis pigmentosa (adRP). The frequency

of TOPORS mutation was analyzed in an adRP cohort

of 215 families and two different mutations, namely,

p.Glu808X and p.Arg857GlyfsX9, were identified.

This study concluded that point mutations and small

insertions or deletions in TOPORS may cause

approximately 1% of adRP (Bowne et al., 2008).

Implicated in

Non-small cell lung cancer (NSCLC)

Disease

Non-small cell lung cancer (NSCLC) is the major form

of lung cancer, with a frequency of 80~90% of all lung

carcinomas. NSCLCs are usually classified into three

groups, namely, squamous cell carcinoma,

adenocarcinoma and large-cell carci-noma. The

squamous cell carcinoma is linked with smoking and

accounts for approximately 25~30% of all lung

cancers, which are usually found in the middle of the

lungs or near a bronchus. Adenocarci-noma is

frequently spotted in the outer part of the lungs and is

thought to be responsible for ~40% of all lung cancers.

About 10~15% of lung cancers are large-cell

carcinomas, which can start in any part of the lung and

has the ability to grow and spread quickly, making this

type of lung cancers difficult to treat.

Oncogenesis

Expression of TOPORS was found to be signifi-cantly

repressed in lung cancer tissues compared to normal

lung tissues. TOPORS gene expression was slightly

down-regulated along with progression of primary

tumors, and strongly downregulated along with nodal

metastases. Interestingly, in normal tissues TOPORS

gene expression was down-regulated in smokers

(Oyanagi et al., 2004). These findings show that there

is a reverse correlation between NSCLC and TOPORS

expression and suggest that TOPORS may act as a

tumor sup-pressor gene for lung cancers.

Glial brain tumor

Disease

Glial brain tumors arise from glial cells and are highly

lethal. Glial brain tumors include astrocytomas,

oligodendrogliomas and oligoastro-cytomas.

Oncogenesis

A recent study investigated copy number alterations of

42,000 mapped human cDNA clones in a series of 54

gliomas of varying histogenesis and tumor grade by

comparative genomic hybridization technology. This

study reported a set of genetic alterations

predominantly associated with either astrocytic or

oligodendrocytic tumor phenotype. Among these

genetic alterations, a minimally deleted region

containing the TOPORS gene was identified,

suggesting a role for TOPORS in gliomagenesis

(Bredel et al., 2005).

Colon cancer

Disease

Cancerous growth in colon, rectum or the appendix are

collectively addressed as colon cancer or colorectal

cancer. This is the third most frequent form of cancer

and a major cause of cancer-related death all over the

world.

Oncogenesis

TOPORS expression is decreased or undetected in

colon adenocarcinomas compared to normal colon

tissues. Furthermore, TOPORS protein is not detectable

in several colon cancer cell lines, suggesting an anti-

oncogenic role for TOPORS (Saleem et al., 2004).

Autosomal dominant retinitis pigmentosa (adRP)

Disease

Autosomal dominant retinitis pigmentosa (adRP) is a

form of retinitis pigmentosa, a collective title for a

group of genetically induced eye disorders that are

frequenctly associated with night blindness and tunnel

vision.

Prognosis

Mutations and small insertions or deletions of the

TOPORS gene have been associated with adRP.

TOPORS has been associated with autosomal dominant

pericentral retinal dystrophy (adPRD), which has a

favorable prognosis compared to classical retinitis

pigmentosa (RP). A novel mis-sense mutation,

c.1205a>c, resulting in an amino acid substitution

p.Q402P, was observed in all affected members of a

large Norweigian family (Selmer et al., 2009). In

another study, an adRP cohort of 215 families was

investigated and two different mutations, namely,



p.Glu808X and p.Arg857GlyfsX9, were identified

(Bowne at al., 2008). TOPORS has also been

implicated in autosomal dominant retinitis pigmentosa

with perivascular retinal pigment atrophy, a disorder

that showed a distinct phenotype at the earlier stage of

the disease, with an unusual perivascular cuff of retinal

pigment epithelium atrophy, which was found

surrounding the superior and inferior arcades in the

retina. This study reported mutations in the TOPORS

gene that included an insertion and a deletion was

identified in two adRP-affected families (Chakarova et

al., 2007).

References Puig S, Ruiz A, Lázaro C, Castel T, Lynch M, Palou J, Vilalta A, Weissenbach J, Mascaro JM, Estivill X. Chromosome 9p deletions in cutaneous malignant melanoma tumors: the minimal deleted region involves markers outside the p16 (CDKN2) gene. Am J Hum Genet. 1995 Aug;57(2):395-402

Haluska P Jr, Saleem A, Rasheed Z, Ahmed F, Su EW, Liu LF, Rubin EH. Interaction between human topoisomerase I and a novel RING finger/arginine-serine protein. Nucleic Acids Res. 1999 Jun 15;27(12):2538-44

Zhou R, Wen H, Ao SZ. Identification of a novel gene encoding a p53-associated protein. Gene. 1999 Jul 22;235(1-2):93-101

Rasheed ZA, Saleem A, Ravee Y, Pandolfi PP, Rubin EH. The topoisomerase I-binding RING protein, topors, is associated with promyelocytic leukemia nuclear bodies. Exp Cell Res. 2002 Jul 15;277(2):152-60

Weger S, Hammer E, Heilbronn R. Topors, a p53 and topoisomerase I binding protein, interacts with the adeno-associated virus (AAV-2) Rep78/68 proteins and enhances AAV-2 gene expression. J Gen Virol. 2002 Mar;83(Pt 3):511-6

Oyanagi H, Takenaka K, Ishikawa S, Kawano Y, Adachi Y, Ueda K, Wada H, Tanaka F. Expression of LUN gene that encodes a novel RING finger protein is correlated with development and progression of non-small cell lung cancer. Lung Cancer. 2004 Oct;46(1):21-8

Rajendra R, Malegaonkar D, Pungaliya P, Marshall H, Rasheed Z, Brownell J, Liu LF, Lutzker S, Saleem A, Rubin EH. Topors functions as an E3 ubiquitin ligase with specific E2 enzymes and ubiquitinates p53. J Biol Chem. 2004 Aug 27;279(35):36440-4

Saleem A, Dutta J, Malegaonkar D, Rasheed F, Rasheed Z, Rajendra R, Marshall H, Luo M, Li H, Rubin EH. The topoisomerase I- and p53-binding protein topors is differentially expressed in normal and malignant human tissues and may function as a tumor suppressor. Oncogene. 2004 Jul 8;23(31):5293-300

Secombe J, Parkhurst SM. Drosophila Topors is a RING finger-containing protein that functions as a ubiquitin-protein isopeptide ligase for the hairy basic helix-loop-helix repressor protein. J Biol Chem. 2004 Apr 23;279(17):17126-33

Bredel M, Bredel C, Juric D, Harsh GR, Vogel H, Recht LD, Sikic BI. High-resolution genome-wide mapping of genetic alterations in human glial brain tumors. Cancer Res. 2005 May 15;65(10):4088-96

Capelson M, Corces VG. The ubiquitin ligase dTopors directs the nuclear organization of a chromatin insulator. Mol Cell. 2005 Oct 7;20(1):105-16

Lin L, Ozaki T, Takada Y, Kageyama H, Nakamura Y, Hata A, Zhang JH, Simonds WF, Nakagawara A, Koseki H. topors, a p53 and topoisomerase I-binding RING finger protein, is a coactivator of p53 in growth suppression induced by DNA damage. Oncogene. 2005 May 12;24(21):3385-96

Shinbo Y, Taira T, Niki T, Iguchi-Ariga SM, Ariga H. DJ-1 restores p53 transcription activity inhibited by Topors/p53BP3. Int J Oncol. 2005 Mar;26(3):641-8

Weger S, Hammer E, Heilbronn R. Topors acts as a SUMO-1 E3 ligase for p53 in vitro and in vivo. FEBS Lett. 2005 Sep 12;579(22):5007-12

Chakarova CF, Papaioannou MG, Khanna H, Lopez I, Waseem N, Shah A, Theis T, Friedman J, Maubaret C, Bujakowska K, Veraitch B, Abd El-Aziz MM, Prescott de Q, Parapuram SK, Bickmore WA, Munro PM, Gal A, Hamel CP, Marigo V, Ponting CP, Wissinger B, Zrenner E, Matter K, Swaroop A, Koenekoop RK, Bhattacharya SS. Mutations in TOPORS cause autosomal dominant retinitis pigmentosa with perivascular retinal pigment epithelium atrophy. Am J Hum Genet. 2007 Nov;81(5):1098-103

Hammer E, Heilbronn R, Weger S. The E3 ligase Topors induces the accumulation of polysumoylated forms of DNA topoisomerase I in vitro and in vivo. FEBS Lett. 2007 Nov 27;581(28):5418-24

Pungaliya P, Kulkarni D, Park HJ, Marshall H, Zheng H, Lackland H, Saleem A, Rubin EH. TOPORS functions as a SUMO-1 E3 ligase for chromatin-modifying proteins. J Proteome Res. 2007 Oct;6(10):3918-23

Bowne SJ, Sullivan LS, Gire AI, Birch DG, Hughbanks-Wheaton D, Heckenlively JR, Daiger SP. Mutations in the TOPORS gene cause 1% of autosomal dominant retinitis pigmentosa. Mol Vis. 2008 May 19;14:922-7

Guan B, Pungaliya P, Li X, Uquillas C, Mutton LN, Rubin EH, Bieberich CJ. Ubiquitination by TOPORS regulates the prostate tumor suppressor NKX3.1. J Biol Chem. 2008 Feb 22;283(8):4834-40

Perry JJ, Tainer JA, Boddy MN. A SIM-ultaneous role for SUMO and ubiquitin. Trends Biochem Sci. 2008 May;33(5):201-8

Selmer KK, Grøndahl J, Riise R, Brandal K, Braaten O, Bragadottir R, Undlien DE. Autosomal dominant pericentral retinal dystrophy caused by a novel missense mutation in the TOPORS gene. Acta Ophthalmol. 2010 May;88(3):323-8


Sharif J, Tsuboi A, Koseki H. TOPORS (topoisomerase I binding, arginine/serine-rich). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3):263-266.





TRPV6 (transient receptor potential cation channel, subfamily V, member 6) Yoshiro Suzuki, Matthias A Hediger

Institute of Biochemistry and Molecular Medicine, University of Bern, Bühlstrasse 28, 3012 Bern,

Switzerland (YS, MAH)


Online updated version: http://AtlasGeneticsOncology.org/Genes/TRPV6ID44425ch7q34.html DOI: 10.4267/2042/44707


Identity Other names: CaT1; ECaC2; CATL; ABP/ZF;

LP6728; ZFAB

HGNC (Hugo): TRPV6

Location: 7q34

Local order: Colocalized with another Ca2+

-selective

epithelial channel gene, TRPV5.

DNA/RNA

Description

TRPV6 gene consists of 15 exons and 14 introns

including a coding, and a 5'-/3'- non-coding region.

The regions encoding the ankyrin repeats, 6 trans-

membrane domains and a pore region are indicated.

Several VDREs (vitamin D responsive element) have

been identified in its promoter region.

A haplotype containing 3 non-synonymous

polymorphisms (C157R+M378V+M681T) repre-sent a

recent positive selection in human evolution. The same

haplotype seems to be associated with renal calcium

stone formation.

Transcription

There is an alterative splice variant which missed 25-

192 (a.a.). In EST database, there seems to be at least

one more variant using different exon 1 (V2) and a

variant starting from another site (P3) just upstream of

exon 2 (V3).

Schematic representation of human TRPV6 gene and neighbouring genes.

Genomic structure of human TRPV6. The coding region is shown by open bars. The non-translated regions are shown by filled bars.

TRPV6 (transient receptor potential cation channel, subfamily V, member 6) Suzuki Y, Hediger MA


Protein

Schematic representation of TRPV6 protein. Four subunits makes one channel pore. Several ankyrin repeats, one N-

glycosylation site and several calmodulin binding sites (CaM) are indicated.

Description

Glycosylated membrane protein (725 a.a., MW ~70

kDa) with 6 transmembrane regions and a pore-forming

loop. N- and C-terminal tails are in cytoplasmic side.

This protein forms a Ca2+-

selective ion channel in the

plasma membrane. TRPV6 interacts with

calmodulin which contribute to the intracellular

Ca2+

-dependent inactivation to avoid an increase

of free Ca2+

concentration. The ankyrin repeats

may play a role in the interaction between

subunits. TRPV6 can form a homo-tetramer as

well as a hetero-tetramer with TRPV5, which

exhibits distinct channel properties.

Expression

Highly expressed in placenta, moderately expressed in

exocrine pancreas, mammary gland and salivary gland.

Highly induced in small intestine under low calcium

conditions or by 1,25-dihydroxyvitamin D3 treatment.

Highly induced in prostate, breast and other cancer

tissues during tumor progression.

Localisation

Plasma membrane. Localized in the apical membrane

of the epithelial cells in the duodenum, and

syncytiotrophoblasts in placenta.

Function

Apical Ca2+

entry pathway for total body calcium

homeostasis in the small intestine under the control of

1,25-dihydroxyvitamin D3. TRPV6 likely also be

involved in the placental Ca2+

transport from mother to

fetus to maintain fetal bone mineralization.

TRPV6 may play a role in the Ca2+

entry pathway

essential for keratinocyte differentiation. Although its

exact function in cancer cells and tumor progression is

still under investigation, TRPV6 is involved in an

increase in proliferation and apoptotic resistance in

cancer cells.

Homology

73% identity with human TRPV5. 89% identity with

mouse TRPV6.

Implicated in

Prostate cancer

Oncogenesis

Expression of TRPV6 may be a predictor for prostate

cancer progression since TRPV6 mRNA and protein

levels are elevated in prostatic carcinoma compared to

benign prostatic hyperplasia and positively correlated

with Gleason grade/score in prostatic carcinoma.

TRPV6 is involved in an increase in proliferation and

apoptotic resistance in cancer cells, suggesting that

TRPV6 could be a new therapeutic target for the

treatment for advanced prostate cancer.

Breast cancer

Oncogenesis

TRPV6 mRNA was also found to be increased in breast

cancer tissues compared to normal breast tissues.

TRPV6 could be a prognostic marker for breast cancer

and therapeutic target for breast cancer treatment.

References Hediger MA, Peng JB, Brown EM Inventors.. Compositions Corresponding to a Calcium Transporter and Methods of Making and Using Same. US patent 6,534,642.

Peng JB, Chen XZ, Berger UV, Vassilev PM, Tsukaguchi H, Brown EM, Hediger MA. Molecular cloning and characterization of a channel-like transporter mediating intestinal calcium absorption. J Biol Chem. 1999 Aug 6;274(32):22739-46

Peng JB, Chen XZ, Berger UV, Weremowicz S, Morton CC, Vassilev PM, Brown EM, Hediger MA. Human calcium transport protein CaT1. Biochem Biophys Res Commun. 2000 Nov 19;278(2):326-32

Niemeyer BA, Bergs C, Wissenbach U, Flockerzi V, Trost C. Competitive regulation of CaT-like-mediated Ca2+ entry by protein kinase C and calmodulin. Proc Natl Acad Sci U S A. 2001 Mar 13;98(6):3600-5

Peng JB, Brown EM, Hediger MA. Structural conservation of the genes encoding CaT1, CaT2, and related cation channels. Genomics. 2001 Aug;76(1-3):99-109

Peng JB, Zhuang L, Berger UV, Adam RM, Williams BJ, Brown EM, Hediger MA, Freeman MR. CaT1 expression correlates with tumor grade in prostate cancer. Biochem Biophys Res Commun. 2001 Apr 6;282(3):729-34

Van Cromphaut SJ, Dewerchin M, Hoenderop JG, Stockmans I, Van Herck E, Kato S, Bindels RJ, Collen D, Carmeliet P, Bouillon R, Carmeliet G. Duodenal calcium absorption in vitamin D receptor-knockout mice: functional and molecular aspects. Proc Natl Acad Sci U S A. 2001 Nov 6;98(23):13324-9

Wissenbach U, Niemeyer BA, Fixemer T, Schneidewind A, Trost C, Cavalie A, Reus K, Meese E, Bonkhoff H, Flockerzi V. Expression of CaT-like, a novel calcium-selective channel,

TRPV6 (transient receptor potential cation channel, subfamily V, member 6) Suzuki Y, Hediger MA


correlates with the malignancy of prostate cancer. J Biol Chem. 2001 Jun 1;276(22):19461-8

Nilius B, Prenen J, Hoenderop JG, Vennekens R, Hoefs S, Weidema AF, Droogmans G, Bindels RJ. Fast and slow inactivation kinetics of the Ca2+ channels ECaC1 and ECaC2 (TRPV5 and TRPV6). Role of the intracellular loop located between transmembrane segments 2 and 3. J Biol Chem. 2002 Aug 23;277(34):30852-8

Zhuang L, Peng JB, Tou L, Takanaga H, Adam RM, Hediger MA, Freeman MR. Calcium-selective ion channel, CaT1, is apically localized in gastrointestinal tract epithelia and is aberrantly expressed in human malignancies. Lab Invest. 2002 Dec;82(12):1755-64

Fixemer T, Wissenbach U, Flockerzi V, Bonkhoff H. Expression of the Ca2+-selective cation channel TRPV6 in human prostate cancer: a novel prognostic marker for tumor progression. Oncogene. 2003 Oct 30;22(49):7858-61

Hoenderop JG, Voets T, Hoefs S, Weidema F, Prenen J, Nilius B, Bindels RJ. Homo- and heterotetrameric architecture of the epithelial Ca2+ channels TRPV5 and TRPV6. EMBO J. 2003 Feb 17;22(4):776-85

Moreau R, Simoneau L, Lafond J. Calcium fluxes in human trophoblast (BeWo) cells: calcium channels, calcium-ATPase, and sodium-calcium exchanger expression. Mol Reprod Dev. 2003 Feb;64(2):189-98

Erler I, Hirnet D, Wissenbach U, Flockerzi V, Niemeyer BA. Ca2+-selective transient receptor potential V channel architecture and function require a specific ankyrin repeat. J Biol Chem. 2004 Aug 13;279(33):34456-63

Hoenderop JG, Nilius B, Bindels RJ. Calcium absorption across epithelia. Physiol Rev. 2005 Jan;85(1):373-422

Akey JM, Swanson WJ, Madeoy J, Eberle M, Shriver MD. TRPV6 exhibits unusual patterns of polymorphism and divergence in worldwide populations. Hum Mol Genet. 2006 Jul 1;15(13):2106-13

Meyer MB, Watanuki M, Kim S, Shevde NK, Pike JW. The human transient receptor potential vanilloid type 6 distal promoter contains multiple vitamin D receptor binding sites that mediate activation by 1,25-dihydroxyvitamin D3 in intestinal cells. Mol Endocrinol. 2006 Jun;20(6):1447-61

Bianco SD, Peng JB, Takanaga H, Suzuki Y, Crescenzi A, Kos CH, Zhuang L, Freeman MR, Gouveia CH, Wu J, Luo H, Mauro T, Brown EM, Hediger MA. Marked disturbance of calcium homeostasis in mice with targeted disruption of the Trpv6 calcium channel gene. J Bone Miner Res. 2007 Feb;22(2):274-85

Lehen'kyi V, Beck B, Polakowska R, Charveron M, Bordat P, Skryma R, Prevarskaya N. TRPV6 is a Ca2+ entry channel essential for Ca2+-induced differentiation of human keratinocytes. J Biol Chem. 2007 Aug 3;282(31):22582-91

Lehen'kyi V, Flourakis M, Skryma R, Prevarskaya N. TRPV6 channel controls prostate cancer cell proliferation via Ca(2+)/NFAT-dependent pathways. Oncogene. 2007 Nov 15;26(52):7380-5

Bolanz KA, Hediger MA, Landowski CP. The role of TRPV6 in breast carcinogenesis. Mol Cancer Ther. 2008 Feb;7(2):271-9

Hughes DA, Tang K, Strotmann R, Schöneberg T, Prenen J, Nilius B, Stoneking M. Parallel selection on TRPV6 in human populations. PLoS One. 2008 Feb 27;3(2):e1686

Stumpf T, Zhang Q, Hirnet D, Lewandrowski U, Sickmann A, Wissenbach U, Dörr J, Lohr C, Deitmer JW, Fecher-Trost C. The human TRPV6 channel protein is associated with cyclophilin B in human placenta. J Biol Chem. 2008 Jun 27;283(26):18086-98

Suzuki Y, Kovacs CS, Takanaga H, Peng JB, Landowski CP, Hediger MA. Calcium channel TRPV6 is involved in murine maternal-fetal calcium transport. J Bone Miner Res. 2008 Aug;23(8):1249-56

Suzuki Y, Landowski CP, Hediger MA. Mechanisms and regulation of epithelial Ca2+ absorption in health and disease. Annu Rev Physiol. 2008;70:257-71

Suzuki Y, Pasch A, Bonny O, Mohaupt MG, Hediger MA, Frey FJ. Gain-of-function haplotype in the epithelial calcium channel TRPV6 is a risk factor for renal calcium stone formation. Hum Mol Genet. 2008 Jun 1;17(11):1613-8


Suzuki Y, Hediger MA. TRPV6 (transient receptor potential cation channel, subfamily V, member 6). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3):267-269.

Gene Section Review




ADAM9 (ADAM metallopeptidase domain 9 (meltrin gamma)) Shian-Ying Sung

Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University and

Hospital, Taichung, Taiwan (SYS)

Published in Atlas Database: April 2009

Online updated version: http://AtlasGeneticsOncology.org/Genes/ADAM9ID573ch8p11.html DOI: 10.4267/2042/44708


Identity Other names: MDC9; Meltrin-gamma; MLTNG;

MCMP; KIAA0021

HGNC (Hugo): ADAM9

Location: 8p11.23

Local order: TACC1 - PLEKHA2 - HTRA4 - TM2D2

- ADAM9 - ADAM32 - ADAM5p - ADAM3A -

ADAM18 - ADAM2; TACC1; 8P11; Transforming,

acidic coiled-coil containing protein 1; PLEKHA2;

8P11.23; Pleckstrin homology domain containing,

family A member 2; HTRA4; 8P11.23; HtrA serine

peptidase 4; TM2D2; 8P11.23; TM2 domain containing

2; ADAM9; 8P11.23; a disintegrin and

metalloproteinase domain 9; ADAM32; 8p11.23;

ADAM metalloproteinase domain 32; ADAM5P;

8p11.23; ADAM metallopeptidase domain 5

pseudogene; ADAM3A; 8p11.23; ADAM

metallopeptidase domain 3A (Cyritestin 1); ADAM18;

8p11.22; ADAM metallopeptidase domain 18;

ADAM2; 8p11.22; ADAM metallopeptidase domain 2.

Note

The ADAM9 gene, a member of the ADAM super-

family has metalloprotease, integrin binding and cell

adhesion capacities. It shown the metallo-protease

domain cleaves insulin beta-chain, TNF-alpha, gelatin,

beta-casein, fibronectin, as well as shedding of EGF,

HB-EGF and FGFR2IIIB. The integrin domain

mediates cellular adhesion through alpha6beta1 and

alphavbeta5 integrins. The cytoplasmic tail of ADAM9

has been reported to interact with endophilin 1

(SH3GL2), SH3PX1 and

mitotic arrest deficient 2beta. ADAM9 has implicated

mediated by stress, such as oxidation during

inflammation and cancer progression.

DNA/RNA

Note

The ADAM9 gene transcript 2 isoforms of mRNA with

altered splicing results the lost of exon 18 in the second

isoform of ADAM9 mRNA and early stop codon.

Description

ADAM9 gene extends 108,276 base pairs with 22

exons which gives rise to 2 different ADAM9 trans-

cripts with differential splicing. The mRNA of

ADAM9 isoform 1 is 4111 base pair and isoform 2 is

4005. ADAM9 isoform 2 lacks exon 18 of iso-form 1

in the coding region, which results in a frameshift and

an early stop codon. The isoform 2 lacks the c-terminal

transmembrane and cyto-plasmic domains and is a

secreted form.

Transcription

Isoform 1 mRNA of ADAM9 (NM_003816) has a size

of 4111 bp, isoform 2 mRNA (NM_001005845) has a

size of 4005 bp. ADAM9 mRNA is equally expressed

in many tissue. Among cancer progression, ADAM9

mRNA is relatively highly expressed in prostate cancer

and breast cancer. However, little is known of

differential expression between different isoform of

ADAM9.

Pseudogene

No pseudogene has reported for ADAM9.

ADAM9 (ADAM metallopeptidase domain 9 (meltrin gamma)) Sung SY


ADAM9 gene is located on chromosome 8p11.23 spread out on 108,276 deoxynucleotides contained 22 exons. The coding sequence of ADAM9 is 2460 nucleotides. Two isoforms reported, isoform 1 of ADAM9 carried full-length membrane bond ADAM9 and isoform 2 carried soluble form of ADAM9 (sADAM9). The sADAM9 is due to alternative splicing in which lost of exon 18 and results in early stop translation in exon 19.

Protein

Note

Two different isoform of ADAM9 was reported, the

full length and soluble form of ADAM9. Recent report

suggests promoter polymorphisms regulated ADAM9

transcription that plays a protective role against

Alzheimer's disease.

Description

The predicted molecular mass of ADAM9 is about 84

KDa. ADAM9 contained coding sequence of 2460

nucleotides which encoding amino acid of 819

residues. The full length of active ADAM9 contained

several functional regions including metalloproteinase,

disintegrin, cystein rich, EGF-like, transmembrane and

cytoplasmic domains. The pro-domain of ADAM9 was

removed by furin-type convertase during ADAM9

translocated onto membrane and become active form.

Recent reports indicated soluble form of ADAM9

cloned from human cDNA library that showed

increased of cancer invasion in malignant progression.

Expression

ADAM9 is ubiquitously expressed. SAGE analyses of

ADAM9 expression demonstrated that ADAM9 is

expressed in the bone marrow, lymph node, brain,

retina, heart, skin, muscle, lung, prostate, breast and

placenta. Increased expression of ADAM9 was

reported in several cancers, including gastric, breast,

prostate, colon, and pancreatic cancers. Splicing

alteration and lost of exon 18 of ADAM9 causes lost of

transmembrane domain and early stop in soluble form

of ADAM9.

Localisation

Full length has N-terminal signal peptide and a single

hydrophobic region predicted to be transmembrane

domain. Hence, the full length of ADAM9 is localized

to the plasma membrane. Soluble ADAM9 lack the

transmembrane domain and cytoplasmic domain and to

be released out of cell.

Function

1. Ectodomain shedding: Metalloproteinase domain of

ADAM9 is zinc dependent. Metallo-proteinase has

been showed to involve ectodomain shedding (see table

below). One such protein is the heparin-binding EGF-

like growth factor (HB-EGF) and amyloid precursor

protein (APP).

2. Matrix Degradation: purified metalloproteinase

domain of ADAM9 showed the ability to digest

fibronectin, gelatin and beta-casein. Secreted form of

ADAM9 showed the ability to digest laminin and

promote cancer invasion.

3. Cell contact: ADAM9 specifically bind to integrin

alpha6beta1, a laminin receptor, via disintegrin region of

ADAM9 through non-RGD mechanism. ADAM9 also

have been implicated in binding of avbeta5 in divalent

cation dependent condition, suggests ADAM9 can

function as adhesion molecule for cell-cell and cell-

martrix interaction. Secreted form of ADAM9 binds

directly to alpha6beta4 and alpha2beta1 integrin and



Two isoforms of ADAM9 with their specific function. Soluble form of ADAM9 has function to active APP either on the same cell or neighbor cell.

ability to cleave laminin and promote cancer

progression.

4. Cysteine-Rich domain: The ADAM Cysteine-rich

domain is not found in other organisms, such as virus,

archaeal, bacterial or plant. The function of cysteine-

rich domain might involved in complement the binding

ability of disintegrin-mediated interactions.

TABLE: Substrate and Peptide Sequence Cleaved.

Substrate Peptide sequence cleaved

(*: cleave site)

Amyloid

precursor

protein

EVHH*QKLVFFAE

TNF-a SPLA*QAVRS*SSR

P75 TNF

receptor SMAPGAVH*LPQP

c-kit ligand LPPVA*A*S*SLRND

Insulin B

Chain LVEALY*LVCGERGFFY*TPKA

HB-EGF GLSLPVE*NRLYTYD

Homology

The table below gives homology between the human

ADAM9 and others organisms.

Mutations

Note

Single nucleotide polymorphosim analyses of

chromosome 8 demonstrated about 356 SNP in the

chromosome 8p11.23. Most of them are located in

intron of ADAM9. No mutation was reported in

ADAM9 coding sequence. Recent evidence sug-gests

promoter polymorphisms that may upregulate ADAM9

transcription, such as -1314C has higher of

transcription activities.



ADAM9 gene promoter region contained 4 polymorphisms: -542C/T, -600A/C, -963A/G and -1314T/C. 1314C showed higher ADAM9 transcription compared to 1314T.

Implicated in

Prostate cancer

Note

ADAM9 has been implicated in prostate cancer

progression and the production of reactive oxygen

species. Large cohort of clinic evaluation demonst-

rated ADAM9 is upregulated in prostate cancer in both

mRNA and protein level. ADAM9 protein expression

can be upregulated by androgen in AR-positive but not

in AR-negative prostate cancer cells that is through

downstream ROS as mediator to induce ADAM9

expression. ADAM9 protein expression is associated

with shortened PSA-relapse-free survival in clinic

evaluation.

Pancreatic cancer

Note

Pancreatic ductal adenocarcinomas showing increased

of ADAM9 expression in microarray analyses and

clinic evaluation that correlated with poor tumor

differentiation and shorter overall survival rate.

Breast cancer

Note

ADAM9 expression is 24% positive in normal breast

tissue and 66% positive in breast carcinomas. Western

blot studies demonstrated multiform of ADAM9 were

expressed in breast carcinoma. In addition, recent study

demonstrated copy number abnormalities occurred in

ADAM9 gene.

Lung cancer

Note

The increased of ADAM9 expression in lung cancer

enhanced cell adhesion and invasion of non-small cell

lung cancer through change adhesion properties and

sensitivity to growth factors, and increase its capacity

of brain metastasis.

Renal cell carcinoma

Note

ADAM9 was implicated increased expression in renal

cell carcinoma and associated with tumor progression.

It also showed higher of ADAM9 expression is

associated with shorten patient survival rate.

Alzheimer's disease

Note

The amyloid precursor protein (APP) of Alzheimer's

disease is a transmembrane protein processed via either

the non-amyloidogenic or amyloidogenic pathways. In

the non-amyloidogenic pathway, alpha-secretase

cleaves APP within the Abeta peptide region releasing

a large soluble fragment sAPPalpha that has

neuroprotective properties. In the amyloidogenic

pathway, beta-secretase and gamma-secretase

sequentially cleave APP to generate the intact Abeta

peptide, which is neurotoxic.



In ADAM9 expression analyses showed increase in

production of sAPPalpha upon phorbol ester treatment

of cell that co-express of ADAM9 and APP. ADAM9

did not cleave at the Lys16-Leu17 bone but at the

His14-Gln15 bone in the Abeta domain of APP cleave

site. Hence, ADAM9 might play role in protective

against sporadic Alzheimer's disease.

References Shuttleworth A. Violence to healthcare staff must be tackled nationally. Prof Nurse. 1992 Jun;7(9):560

Izumi Y, Hirata M, Hasuwa H, Iwamoto R, Umata T, et al. A metalloprotease-disintegrin, MDC9/meltrin-gamma/ADAM9 and PKCdelta are involved in TPA-induced ectodomain shedding of membrane-anchored heparin-binding EGF-like growth factor. EMBO J. 1998 Dec 15;17(24):7260-72

Nelson KK, Schlöndorff J, Blobel CP. Evidence for an interaction of the metalloprotease-disintegrin tumour necrosis factor alpha convertase (TACE) with mitotic arrest deficient 2 (MAD2), and of the metalloprotease-disintegrin MDC9 with a novel MAD2-related protein, MAD2beta. Biochem J. 1999 Nov 1;343 Pt 3:673-80

Cao Y, Kang Q, Zhao Z, Zolkiewska A. Intracellular processing of metalloprotease disintegrin ADAM12. J Biol Chem. 2002 Jul 19;277(29):26403-11

Hotoda N, Koike H, Sasagawa N, Ishiura S. A secreted form of human ADAM9 has an alpha-secretase activity for APP. Biochem Biophys Res Commun. 2002 May 3;293(2):800-5

Grützmann R, Foerder M, Alldinger I, Staub E, Brümmendorf T, Röpcke S, Li X, Kristiansen G, Jesnowski R, Sipos B, Löhr M, Lüttges J, Ockert D, Klöppel G, Saeger HD, Pilarsky C. Gene expression profiles of microdissected pancreatic ductal adenocarcinoma. Virchows Arch. 2003 Oct;443(4):508-17

Fischer OM, Hart S, Gschwind A, Prenzel N, Ullrich A. Oxidative and osmotic stress signaling in tumor cells is mediated by ADAM proteases and heparin-binding epidermal growth factor. Mol Cell Biol. 2004 Jun;24(12):5172-83

Grützmann R, Lüttges J, Sipos B, Ammerpohl O, Dobrowolski F, Alldinger I, Kersting S, Ockert D, Koch R, Kalthoff H, Schackert HK, Saeger HD, Klöppel G, Pilarsky C. ADAM9 expression in pancreatic cancer is associated with tumour type and is a prognostic factor in ductal adenocarcinoma. Br J Cancer. 2004 Mar 8;90(5):1053-8

Shintani Y, Higashiyama S, Ohta M, Hirabayashi H, Yamamoto S, Yoshimasu T, Matsuda H, Matsuura N. Overexpression of ADAM9 in non-small cell lung cancer correlates with brain metastasis. Cancer Res. 2004 Jun 15;64(12):4190-6

Asayesh A, Alanentalo T, Khoo NK, Ahlgren U. Developmental expression of metalloproteases ADAM 9, 10, and 17 becomes restricted to divergent pancreatic compartments. Dev Dyn. 2005 Apr;232(4):1105-14

Carl-McGrath S, Lendeckel U, Ebert M, Roessner A, Röcken C. The disintegrin-metalloproteinases ADAM9, ADAM12, and ADAM15 are upregulated in gastric cancer. Int J Oncol. 2005 Jan;26(1):17-24

Mazzocca A, Coppari R, De Franco R, Cho JY, Libermann TA, Pinzani M, Toker A. A secreted form of ADAM9 promotes carcinoma invasion through tumor-stromal interactions. Cancer Res. 2005 Jun 1;65(11):4728-38

Peduto L, Reuter VE, Shaffer DR, Scher HI, Blobel CP. Critical function for ADAM9 in mouse prostate cancer. Cancer Res. 2005 Oct 15;65(20):9312-9

Chin K, DeVries S, Fridlyand J, Spellman PT, et al. Genomic and transcriptional aberrations linked to breast cancer pathophysiologies. Cancer Cell. 2006 Dec;10(6):529-41

Hirao T, Nanba D, Tanaka M, Ishiguro H, Kinugasa Y, Doki Y, Yano M, Matsuura N, Monden M, Higashiyama S. Overexpression of ADAM9 enhances growth factor-mediated recycling of E-cadherin in human colon cancer cell line HT29 cells. Exp Cell Res. 2006 Feb 1;312(3):331-9

Sung SY, Kubo H, Shigemura K, Arnold RS, Logani S, et al. Oxidative stress induces ADAM9 protein expression in human prostate cancer cells. Cancer Res. 2006 Oct 1;66(19):9519-26

Mochizuki S, Okada Y. ADAMs in cancer cell proliferation and progression. Cancer Sci. 2007 May;98(5):621-8

Shigemura K, Sung SY, Kubo H, Arnold RS, Fujisawa M, Gotoh A, Zhau HE, Chung LW. Reactive oxygen species mediate androgen receptor- and serum starvation-elicited downstream signaling of ADAM9 expression in human prostate cancer cells. Prostate. 2007 May 15;67(7):722-31

Fritzsche FR, Jung M, Tölle A, Wild P, Hartmann A, et al. ADAM9 expression is a significant and independent prognostic marker of PSA relapse in prostate cancer. Eur Urol. 2008 Nov;54(5):1097-106

Fritzsche FR, Wassermann K, Jung M, Tölle A, Kristiansen I, Lein M, Johannsen M, Dietel M, Jung K, Kristiansen G. ADAM9 is highly expressed in renal cell cancer and is associated with tumour progression. BMC Cancer. 2008 Jun 26;8:179

Boelens MC, Kok K, van der Vlies P, van der Vries G, Sietsma H, Timens W, Postma DS, Groen HJ, van den Berg A. Genomic aberrations in squamous cell lung carcinoma related to lymph node or distant metastasis. Lung Cancer. 2009 Dec;66(3):372-8

Dijkstra A, Postma DS, Noordhoek JA, Lodewijk ME, Kauffman HF, ten Hacken NH, Timens W. Expression of ADAMs ("a disintegrin and metalloprotease") in the human lung. Virchows Arch. 2009 Apr;454(4):441-9

Guaiquil V, Swendeman S, Yoshida T, Chavala S, Campochiaro PA, Blobel CP. ADAM9 is involved in pathological retinal neovascularization. Mol Cell Biol. 2009 May;29(10):2694-703

Klessner JL, Desai BV, Amargo EV, Getsios S, Green KJ. EGFR and ADAMs cooperate to regulate shedding and endocytic trafficking of the desmosomal cadherin desmoglein 2. Mol Biol Cell. 2009 Jan;20(1):328-37

Nakagawa M, Nabeshima K, Asano S, Hamasaki M, Uesugi N, Tani H, Yamashita Y, Iwasaki H. Up-regulated expression of ADAM17 in gastrointestinal stromal tumors: coexpression with EGFR and EGFR ligands. Cancer Sci. 2009 Apr;100(4):654-62

Singh B, Schneider M, Knyazev P, Ullrich A. UV-induced EGFR signal transactivation is dependent on proligand shedding by activated metalloproteases in skin cancer cell lines. Int J Cancer. 2009 Feb 1;124(3):531-9


Sung SY. ADAM9 (ADAM metallopeptidase domain 9 (meltrin gamma)). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3):270-274.

Gene Section Review




CYP7B1 (cytochrome P450, family 7, subfamily B, polypeptide 1) Maria Norlin

Department of Pharmaceutical Biosciences, Division of Biochemistry, University of Uppsala, Sweden (MN)


Online updated version: http://AtlasGeneticsOncology.org/Genes/CYP7B1ID40255ch8q21.html DOI: 10.4267/2042/44709


Identity

Other names: CBAS3; CP7B; SPG5A; CYP7B

HGNC (Hugo): CYP7B1

Location: 8q21.3

Note

CYP7B1 is a steroid hydroxylase involved in meta-

bolism of sex hormones, oxysterols (a type of

cholesterol derivatives) and neurosteroids.

DNA/RNA

Description

The human CYP7B1 DNA maps to NM_004820

(Entrez-Gene) and spans a region of 202.66 kB.

CYP7B1 is located on chromosome 8 and consists of

six exons.

Transcription

The full length CYP7B1 mRNA is 2,395 bp with an

open reading rame of 1,521 bp.

Pseudogene

No pseudogenes reported.

Protein

Description

The human CYP7B1 protein consists of 506 amino

acids and has a molecular weight of 58,256. The N-

terminal membrane-binding domain (residues 1 to 38)

is highly hydrophobic. The ATG start codon is located

204 nucleotides downstream of the trans-cription start

site (Wu et al., 1999). Similarly as other members of

the cytochrome P450 (CYP) enzyme superfamily,

CYP7B1 contains heme iron as a cofactor. Human

CYP7B1 shares 40% seq-uence identity with human

CYP7A1, the other member of the CYP7 family.

Expression

Expression of CYP7B1 is reported in many human

tissues including brain, kidney, liver, lung, heart,

prostate, testis, ovary, placenta, pancreas, intestine,

colon and thymus (Wu et al., 1999).

Human CYP7B1 gene structure. Exons are represented by red bars with exon numbers at the bottom.

CYP7B1 (cytochrome P450, family 7, subfamily B, polypeptide 1) Norlin M


Localisation

Most reports indicated localization to the membrane of

the endoplasmic reticulum. There are some data

indicating possible CYP7B1-related activity also in

mitochondria but it is unclear whether this activity

represents CYP7B1 or another enzyme species

(Axelson et al., 1992; Pandak et al., 2002).

Function

CYP7B1 converts a number of steroids into their

7alpha-hydroxyderivatives (Toll et al., 1994; Rose et

al., 1997; Yau et al., 2006; Norlin and Wikvall, 2007).

In addition to 7alpha-hydroxylation, forma-tion of

6alpha, 6beta-, and 7beta-hydroxyderiva-tives also has

been reported for this enzyme. Some well-known

substrates for CYP7B1 are: 27-hydro-xycholesterol and

25-hydroxycholesterol (choles-terol derivatives);

dehydroepiandrosterone (DHEA) and pregnenolone

(sex hormone precursors and neurosteroids); 5alpha-

androstane-3beta,17beta-diol and 5-androstene-

3beta,17beta-diol (estrogen recap-tor ligands). The

catalytic reactions performed by CYP7B1 may lead to

elimination of the steroids from the cell and thereby

reduce the cellular levels of the substrates for this

enzyme. Also, several of the products formed by

CYP7B1 are reported to have physiological effects.

Thus, CYP7B1 may in some cases be part of

biosynthetic pathways to form active compounds.

Homology

The CYP7B1 gene is conserved in chimpanzee, dog,

cow, mouse, rat, chicken, and zebrafish.

Mutations

Germinal

A homozygous mutation in the CYP7B1 gene (R388X)

was identified in an infant boy with defective bile acid

synthesis and severe cholestasis (Setchell et al., 1998).

The patient was the offspring of first cousins.

Mutations in the CYP7B1 gene (S363F, G57R, R417H,

F216S, R388X) have been associated with a form of

hereditary spastic paraplegia (HSP type 5)

characterized by motor neuron degeneration in affected

individuals of several families (Tsaousidou et al.,

2008). S363F and F216S was predicted to affect

phosphorylation of the mature protein. In addition,

studies on non-consanguineous cases of hereditary

spastic para-plegia indicate that a coding CYP7B1

polymor-phism (c.971G>A) is associated with a

phenotype of cerebellar signs believed to complicate a

primary HSP phenotype (Schule et al., 2009).

A functional polymorphism was reported in the human

CYP7B1 promoter consisting of a C-G change located -

104 nucleotides from the trans-cription start site

(Jakobsson et al., 2004). The C-G alteration at -104

creates a putative C/EBPbeta binding site and was

shown to result in higher transcriptional activity. In a

study comparing allele frequency in an Oriental

(Korean) population and a Caucasian (Swedish)

population, the frequency of the uncommon G-allele

was found to be much lower in the Oriental population

(Jakobsson et al., 2004).

Implicated in

Prostate cancer

Note

High expression of CYP7B1 protein is found in high-

grade prostatic intraepithelial neoplasia (PIN) and

adenocarcinomas (Olsson et al., 2007). Local

methylation of the CYP7B1 promoter is suggested to

be important for regulation of CYP7B1 in human

prostate tissue. In addition, a functional C-G

polymorphism in the CYP7B1 promoter has been

associated with a different allele frequency in two

ethnic populations with great differences in the

incidence of prostate cancer (Swedes and Koreans)

(Jakobsson et al., 2004). A connection between

CYP7B1 and prostate cancer may be related to the

action of estrogen receptor beta (ERbeta), since

metabolism by CYP7B1 is reported to affect the levels

of ligands for ERbeta, which is believed to have anti-

proliferative effects (Weihua et al., 2002; Martin et al.,

2004). Sex hormones are important for growth of

prostate and other tissues, both during normal and

malignant conditions. A potential role for CYP7B1 in

tissue growth is supported by data indicating that the

Akt/PI3K (phosphoinositide 3-kinase) cascade, a

signalling pathway important for cellular growth,

affects the CYP7B1 gene (Tang et al., 2008). In human

prostate cancer LNCaP cells, CYP7B1 promoter

activity is affected by both androgens and estrogens,

suggesting important functions in hormonal signalling

(Tang and Norlin, 2006).

Spastic Paraplegia Type 5A

Note

Mutations in the coding region of the CYP7B1 gene

has been found in patients with spastic paraplegia type

5, an upper-motor-neuron degenerative disease which

affects lower limb movement and results in extremity

weakness and spasticity, sometimes accompanied by

additional symptoms. Hereditary spastic paraplegia

(HSP) is characterized by axonal degeneration of

neurons in the corticospinal tracts and dorsal columns.

Sequence alterations in CYP7B1, believed to affect the

functionality of the enzyme, have been associated with

a pure form of autosomal-recessive HSP in several

families (Tsaousidou et al., 2008). The association of

an abnormal CYP7B1 gene with this neurodegene-

rative condition suggest that the pathogenic basis for

this disease is related either to effects on cholesterol

homeostasis in the brain (i e on CYP7B1-mediated

control of the levels of 27-hydroxycholesterol) or to

effects on the metabolism of dehydroepiandrosterone

and other neurosteroids.



Congenital Bile Acid Defect Type 3 (CBAS3)

Note

A mutation in the CYP7B1 gene was linked to

defective bile acid production, cholestasis and liver

cirrhosis in an infant boy who died at the age of < 1

year due to complications following liver trans-

plantation (Setchell et al., 1998). Other symptoms

included hepatosplenomegaly, jaundice and increased

bleeding. The pathological findings were consistent

with accumulation of hepatotoxic unsaturated

monohydroxy bile acids. The patient had 4,500 times

higher levels of 27-hydroxycholes-terol than normal

and liver samples showed no 27-hydroxycholesterol

7alpha-hydroxylase activity. Failure to detect CYP7A1-

mediated 7alpha-hydroxylase activity in this patient as

well as in other infants of the same age led the authors

to suggest that CYP7B1 may be more important for

bile acid synthesis in early life than in adulthood

(Setchell et al., 1998).

Alzheimer's Disease

Note

Some patients with Alzheimer's disease, a progress-sive

neurodegenerative disease that strongly impairs

cognition and memory, are reported to have altered

levels of CYP7B1 expression and/or CYP7B1-formed

metabolites. Some studies indi-cate reduced brain

expression of CYP7B1 in Alzheimer's disease (Yau et

al., 2003) whereas others report increased CYP7B1-

formed metabo-lites in serum from patients with this

disease (Attal-Khemis et al., 1998). The potential

role(s) of CYP7B1 in connection with Alzheimer's

disease remains unclear. Alzheimer's disease is

associated with build-up of neuritic plaques and

neurofibrillary tangles and progressive loss of neurons

and synapses in several parts of the brain. The etiology

of Alzheimer's disease is not well understood and the

underlying mechanisms are most likely complex. It has

been suggested that disturbed metabolism of

neurosteroids and/or other brain lipids may be one of

the contributing factors (Yau et al., 2003; Bjorkhem et

al., 2006). In some types of brain cells, CYP7B1-

dependent hydroxylation is the main metabolic fate for

neurosteroids dehydro-epiandrosterone and

pregnenolone. Also, the levels of CYP7B1 are higher in

the hippocampus than in other parts of the brain,

supporting a potential role for this enzyme related to

memory and cognition (Yau et al., 2003).

Rheumatoid Arthritis and Inflammation

Note

Increased production of the CYP7B1-formed

metabolite 7alpha-hydroxy-DHEA has been suggested

to contribute to the chronic inflammation observed in

patients with rheumatoid arthritis (Dulos et al., 2005).

Rheumatoid arthritis is a chronic inflammatory disorder

with unclear etiology characterized by joint

inflammation and progressive destruction of the joints.

Other tissues also may be affected. Studies in a mouse

model for collagen-induced arthritis indicate

correlation of increased CYP7B1 activity with disease

progression (Dulos et al., 2004). In humans, CYP7B1 is

found in synovial tissues (connective tissues

surrounding the joints) from patients with rheumatoid

arthritis and CYP7B1 levels are up-regulated by

proinflammatory cytokines in human synoviocytes

(Dulos et al., 2005). Chronic inflam-matory diseases

including rheumatoid arthritis are known to be

associated with changes in levels of several steroids. It

has been proposed that the CYP7B1-formed 7alpha-

hydroxy-DHEA might counteract the

immunosuppressive effects of gluco-corticoids, which

are used in treatment of rheuma-toid arthritis.

References Axelson M, Shoda J, Sjövall J, Toll A, Wikvall K. Cholesterol is converted to 7 alpha-hydroxy-3-oxo-4-cholestenoic acid in liver mitochondria. Evidence for a mitochondrial sterol 7 alpha-hydroxylase. J Biol Chem. 1992 Jan 25;267(3):1701-4

Toll A, Wikvall K, Sudjana-Sugiaman E, Kondo KH, Björkhem I. 7 alpha hydroxylation of 25-hydroxycholesterol in liver microsomes. Evidence that the enzyme involved is different from cholesterol 7 alpha-hydroxylase. Eur J Biochem. 1994 Sep 1;224(2):309-16

Rose KA, Stapleton G, Dott K, Kieny MP, Best R, Schwarz M, Russell DW, Björkhem I, Seckl J, Lathe R. Cyp7b, a novel brain cytochrome P450, catalyzes the synthesis of neurosteroids 7alpha-hydroxy dehydroepiandrosterone and 7alpha-hydroxy pregnenolone. Proc Natl Acad Sci U S A. 1997 May 13;94(10):4925-30

Attal-Khémis S, Dalmeyda V, Michot JL, Roudier M, Morfin R. Increased total 7 alpha-hydroxy-dehydroepiandrosterone in serum of patients with Alzheimer's disease. J Gerontol A Biol Sci Med Sci. 1998 Mar;53(2):B125-32

Setchell KD, Schwarz M, O'Connell NC, Lund EG, Davis DL, Lathe R, Thompson HR, Weslie Tyson R, Sokol RJ, Russell DW. Identification of a new inborn error in bile acid synthesis: mutation of the oxysterol 7alpha-hydroxylase gene causes severe neonatal liver disease. J Clin Invest. 1998 Nov 1;102(9):1690-703

Wu Z, Martin KO, Javitt NB, Chiang JY. Structure and functions of human oxysterol 7alpha-hydroxylase cDNAs and gene CYP7B1. J Lipid Res. 1999 Dec;40(12):2195-203

Pandak WM, Hylemon PB, Ren S, Marques D, Gil G, Redford K, Mallonee D, Vlahcevic ZR. Regulation of oxysterol 7alpha-hydroxylase (CYP7B1) in primary cultures of rat hepatocytes. Hepatology. 2002 Jun;35(6):1400-8

Weihua Z, Lathe R, Warner M, Gustafsson JA. An endocrine pathway in the prostate, ERbeta, AR, 5alpha-androstane-3beta,17beta-diol, and CYP7B1, regulates prostate growth. Proc Natl Acad Sci U S A. 2002 Oct 15;99(21):13589-94

Yau JL, Rasmuson S, Andrew R, Graham M, Noble J, Olsson T, Fuchs E, Lathe R, Seckl JR. Dehydroepiandrosterone 7-hydroxylase CYP7B: predominant expression in primate hippocampus and reduced expression in Alzheimer's disease. Neuroscience. 2003;121(2):307-14

Dulos J, Verbraak E, Bagchus WM, Boots AM, Kaptein A. Severity of murine collagen-induced arthritis correlates with increased CYP7B activity: enhancement of



dehydroepiandrosterone metabolism by interleukin-1beta. Arthritis Rheum. 2004 Oct;50(10):3346-53

Jakobsson J, Karypidis H, Johansson JE, Roh HK, Rane A, Ekström L. A functional C-G polymorphism in the CYP7B1 promoter region and its different distribution in Orientals and Caucasians. Pharmacogenomics J. 2004;4(4):245-50

Martin C, Ross M, Chapman KE, Andrew R, Bollina P, Seckl JR, Habib FK. CYP7B generates a selective estrogen receptor beta agonist in human prostate. J Clin Endocrinol Metab. 2004 Jun;89(6):2928-35

Dulos J, van der Vleuten MA, Kavelaars A, Heijnen CJ, Boots AM. CYP7B expression and activity in fibroblast-like synoviocytes from patients with rheumatoid arthritis: regulation by proinflammatory cytokines. Arthritis Rheum. 2005 Mar;52(3):770-8

Björkhem I, Heverin M, Leoni V, Meaney S, Diczfalusy U. Oxysterols and Alzheimer's disease. Acta Neurol Scand Suppl. 2006;185:43-9

Tang W, Norlin M. Regulation of steroid hydroxylase CYP7B1 by androgens and estrogens in prostate cancer LNCaP cells. Biochem Biophys Res Commun. 2006 Jun 2;344(2):540-6

Yau JL, Noble J, Graham M, Seckl JR. Central administration of a cytochrome P450-7B product 7 alpha-hydroxypregnenolone improves spatial memory retention in cognitively impaired aged rats. J Neurosci. 2006 Oct 25;26(43):11034-40

Norlin M, Wikvall K. Enzymes in the conversion of cholesterol into bile acids. Curr Mol Med. 2007 Mar;7(2):199-218

Olsson M, Gustafsson O, Skogastierna C, Tolf A, Rietz BD, Morfin R, Rane A, Ekström L. Regulation and expression of human CYP7B1 in prostate: overexpression of CYP7B1 during progression of prostatic adenocarcinoma. Prostate. 2007 Sep 15;67(13):1439-46

Tang W, Pettersson H, Norlin M. Involvement of the PI3K/Akt pathway in estrogen-mediated regulation of human CYP7B1: identification of CYP7B1 as a novel target for PI3K/Akt and MAPK signalling. J Steroid Biochem Mol Biol. 2008 Nov;112(1-3):63-73

Tsaousidou MK, Ouahchi K, Warner TT, Yang Y, Simpson MA, Laing NG, Wilkinson PA, Madrid RE, Patel H, Hentati F, Patton MA, Hentati A, Lamont PJ, Siddique T, Crosby AH. Sequence alterations within CYP7B1 implicate defective cholesterol homeostasis in motor-neuron degeneration. Am J Hum Genet. 2008 Feb;82(2):510-5

Schüle R, Brandt E, Karle KN, Tsaousidou M, Klebe S, Klimpe S, Auer-Grumbach M, Crosby AH, Hübner CA, Schöls L, Deufel T, Beetz C. Analysis of CYP7B1 in non-consanguineous cases of hereditary spastic paraplegia. Neurogenetics. 2009 Apr;10(2):97-104


Norlin M. CYP7B1 (cytochrome P450, family 7, subfamily B, polypeptide 1). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3):275-278.

Gene Section Review




EPHA3 (EPH receptor A3) Brett Stringer, Bryan Day, Jennifer McCarron, Martin Lackmann, Andrew Boyd

Leukaemia Foundation Research Laboratory, Queensland Institute of Medical Research, 300 Herston Road,

Brisbane Queensland 4006, Australia (BS, BD, JM, AB); Department of Biochemistry and Molecular

Biology, PO Box 13D, Monash University, Clayton Victoria 3800, Australia (ML); Department of Medicine,

University of Queensland, St Lucia Queensland 4067, Australia (AB)


Online updated version: http://AtlasGeneticsOncology.org/Genes/EPHA3ID40463ch3p11.html DOI: 10.4267/2042/44710


Identity

Other names: EC 2.7.10.1; ETK; ETK1; EphA3;

HEK; HEK4; TYRO4

HGNC (Hugo): EPHA3

Location: 3p11.2

Local order: (tel) C3orf38 (ENSG00000179021) ->,

949,562bp, EPHA3 (374,609bp) ->, 720,071bp, <-

AC139337.5 (ENSG00000189002) (cen)

Note

EPHA3 is flanked by two gene deserts.

DNA/RNA

Note

EPHA3 spans the human tile path clones CTD-

2532M17, RP11-784B9 and RP11-547K2.

Description

EPHA3 consists of 17 exons and 16 introns and spans

375kb of genomic DNA. It is the second largest of the

EPH genes after EPHA6.

Figure 1: Chromosomal location of EPHA3 (based on Ensembl Homo sapiens version 53.36o (NCBI36)). Figure 2: Genomic neighbourhood of EPHA3 (based on Ensembl Homo sapiens version 53.36o (NCBI36)).

EPHA3 (EPH receptor A3) Stringer B, et al.


Figure 3: Genomic organisation of EPHA3.

Transcription

Two alternatively spliced transcript variants have been

described (NM_005233.5, a 5,807 nucleotide mRNA

and NM_182644.2, a 2,684 nucleotide mRNA). The

shorter transcript results in truncation within the

extracellular domain of EphA3 and is predicted to

produce a soluble protein. The 5' end of EPHA3 is

associated with a CpG island, a feature common to all

EPH genes. The EPHA3 promoter also lacks a TATA

box and transcription initiates from multiple start sites.

Pseudogene

None identified.

Protein

Note

The Eph receptors constitute the largest of the 20

subfamilies of human receptor tyrosine kinases. The

founding member of this group was isolated originally

from an erythropoietin producing hepato-ma cell line.

Figure 4: Domain organisation of EphA3.

Description

The EPHA3 gene encodes a 983 amino acid protein

with a calculated molecular weight of 110.1kDa and an

isoelectric point of 6.7302. Amino acids 1-20 constitute

a signal peptide. The predicted mole-cular mass of the

translated protein minus the signal peptide is 92.8kDa.

The 521 amino acid extra-cellular domain contains five

potential sites for N-glycosylation such that EphA3 is

typically detected as a 135kDa glycoprotein. This

mature isoform of EphA3 is a single-pass

transmembrane receptor tyrosine kinase. At its N-

terminus is a 174 amino acid ligand binding domain, a

14 amino acid EGF-like domain and two membrane

proximal fibro-nectin type III repeats. Amino acids 21-

376 of the extracellular domain also are rich in cysteine

residues. The intracellular domain contains the tyrosine

kinase domain and a sterile alpha motif. EphA3 lacks a

PDZ domain interacting motif present in EphA7,

EphB2, EphB3, EphB5 and EphB6. Activation of the

EphA3 receptor tyrosine kinase domain is associated

with two tyrosine residues in the juxtamembrane region

(Y596, Y602) that are sites of autophosphorylation and

interact with the kinase domain to modulate its activity.

EphA3 belongs to an evolutionarily ancient subfamily

of receptor tyrosine kinases with mem-bers being

present in sponges, worms and fruit flies. The

expansion in the number of Eph receptor-encoding

genes along with genes encoding their ligands, the

ephrins (Eph receptor interacting proteins), is proposed

to have contributed to the increase in complexity of the

bilaterian body plan. Genes encoding EphA3 are found

in the genomes of representative members of at least

five of the seven classes of vertebrates including bony

fish (zebrafish, pufferfish, medaka), amphibians

(African clawed frog), reptiles (green anole lizard),

birds (chicken) and mammals (platypus, possum,

human).

Fourteen Eph receptors have been identified in

vertebrates. These are subdivided into either EphA

(EphA1, EphA2, EphA3, EphA4, EphA5, EphA6,

EphA7, EphA8, EphA10) or EphB (EphB1, EphB2,

EphB3, EphB4, EphB6) subclasses which differ

primarily in the structure of their ligand binding

domains. EphA receptors also exhibit greater affinity

for binding GPI-linked ephrin-A ligands while EphB

receptors bind transmembrane ephrin-B ligands. While

interactions are somewhat promis-cuous, and some

cross-class binding occurs, each Eph receptor displays

distinct affinity for the different ephrin ligands. The

high affinity ligands for EphA3 are ephrin-A2 and

ephrin-A5. EphA3 also binds ephrin-A3 and ephrin-A4

with lower affinity.

Eph-ephrin binding involves contact between cells.

Upon binding, receptor-ligand dimers form

heterotetramers, which further assemble into higher

order signalling clusters. Several moieties in the EphA3

receptor extracellular region mediate ephrin binding. A

high-affinity binding site in the N-terminal ephrin

binding domain mediates inter-cellular Eph-ephrin

interaction. Two additional lower-affinity ephrin-

binding sites, one in the ephrin-binding domain and the

other in the cysteine-rich region, are involved in

clustering of Eph-ephrin complexes.

Following ephrin-A5-mediated EphA3 receptor

clustering, intracellular signalling by EphA3 receptors

is initiated by autophosphorylation of three defined

tyrosine residues, two in the highly conserved

juxtamembrane region and the third in the activation

loop of the kinase domain (Y779). Rapid reorganisation

of the actin and myosin cytoskeleton follows, leading

to retraction of cellular protrusions, membrane

blebbing and cell detachment, following association of

the adaptor protein CrkII with tyrosine phosphorylated

EphA3 and activation of RhoA signalling.

Such Eph-ephrin interaction triggers bidirectional

signalling, that is signalling events within both Eph-

and ephrin-bearing cells, an unusual phenomenon for

receptor tyrosine kinases, most of which interact with

soluble ligands. Subsequently, depending on the

cellular context (including the identity of the

interacting Eph-ephrin receptor-ligand pairs, their

relative levels on interacting cells, the presence of

additional Ephs and ephrins and their alternative



isoforms, and the net effect of interaction with

additional signalling pathways) this either results in

repulsion or promotes adhesion of the interacting cells.

Cellular repulsion and the termination of Eph-ephrin

signalling require disruption of the receptor-ligand

complex. This is brought about either by enzymatic

cleavage of the tethered ephrin ligand in cis or in trans

or by endocytosis of Eph-ephrin complexes. EphA3-

ephrin-A2 receptor-ligand complexes are shed from

ephrin-A2 bearing cells following receptor-ligand

binding when ADAM10 (a disintegrin and

metalloprotease 10), associated with ephrin-A2, cleaves

ephrin-A2. Conversely, intercellular EphA3-ephrin-A5

receptor-ligand complexes are broken when EphA3-

associated ADAM10 cleaves ephrin-A5 on opposing

cells, following binding to EphA3. The post-cleavage

ephrin-A5-EphA3 complex is then endocytosed by the

EphA3-expressing cell.

While cellular repulsion is often the outcome of Eph-

ephrin interaction, in some circumstances adhesion

may persist. For example, ADAM10 has been observed

not to cleave ephrin-A5 following EphA3-ephrin-A5

interaction involving LK63 cells in which high

intracellular protein tyrosine phosphatase activity also

appears to counter ephrin-A5 stimulated

phosphorylation of EphA3, holding the receptor in an

inactive, unphosphorylated state. Also cis interaction

between EphA3 and ephrin-A2 expressed on the same

cell surface has been reported to block EphA3

activation by ephrins acting in trans, the cis interaction

site being independent of the ligand binding domain.

Another mechanism that may favour stable cell-cell

adhesion involves truncated Eph receptor isoforms

acting in a dominant negative manner. While activation

of full length EphA7 by ephrin-A5 results in cellular

repulsion, ephrin-A5-induced phosphorylation of

EphA7 is inhibited by two EphA7 splice variants with

truncated kinase domains and adhesion results. A splice

variant of EPHA3 also has been reported and is

predicted to give rise to a soluble isoform of EphA3.

Whether this soluble variant of EphA3, which is

truncated before the transmembrane domain, functions

in a similar manner to the shorter EphA7 isoforms has

not been established.

While important details of EphA3 signalling have been

determined, more complete understanding of EphA3

activity will require knowledge of the full complement

of EphA3 interacting proteins. Substrates that are

targets for the tyrosine kinase activity of EphA3 have

yet to be defined and potential mediators or modulators

of EphA3 signalling output such as Src family kinases,

additional phosphotyrosine binding adaptors, SAM

domain interacting factors, interaction with other

receptor kinases and crosstalk with other signalling

pathways, and the regulatory role of phosphatases all

remain to be explored. Based on the range of

interacting proteins identified for other Eph receptors

(some common to more than one Eph, others

apparently unique to individual Ephs) additional

effectors of EphA3 signalling output are likely.

Expression

EphA3 was first identified as an antigen expressed at

high levels (10,000-20,000 copies per cell) on the

surface of the LK63 pre-B cell acute lymphoblastic

leukaemia cell line. It also was found to be expressed

by JM, HSB-2 and MOLT-4 T-cell leukaemic cell

lines, in CD28-stimulated Jurkat cells, and in 16 of 42

cases of primary T-cell lymphoma (but not normal

peripheral T lymphocytes nor in any subset of thymus-

derived developing T cells), as well as at low frequency

in acute myeloid leukaemia and chronic lymphocytic

leukaemia EphA3 is not expressed by many other

haematopoietic cell lines.

Subsequently, EphA3 expression has been shown to be

most abundant, and also highly regulated both

temporally and spatially, during vertebrate

development. Prominent EphA3 expression occurs in

the neural system, including the retinal ganglion cells

of the embryonic retina in a graded distribution from

anterior/nasal (lowest) to posterior /temporal (highest);

the cerebrum, thalamus, striatum, olfactory bulb,

anterior commissure, and corpus callosum of the

forebrain; and the medial motor column ventral motor

neurons of the spinal cord; and extraneurally by

mesodermally-derived tissues including the paraxial

musculature, tongue musculature, submucosa of the

soft palate, capsule of the submandibular gland, cortical

rim of bone, thymic septae, media of the pharynx,

trachea, great vessels, small intestine and portal vein,

cardiac valves, and the renal medulla. In adult tissues

EphA3 expression is more restricted and detected at

significantly lower levels than during early

development.

Localisation

Isoform 1: Cell membrane; single-pass type I

membrane protein.

Isoform 2: Secreted.

Function

Eph receptors modulate cell shape and movement

through reorganisation of the cytoskeleton and changes

in cell-cell and cell-substrate adhesion, and are

involved in many cellular migration, sorting (tissue

patterning) and guidance events, most often during

development, and in particular involving the nervous

system. There is evidence too that Eph receptor

signalling influences cell proliferation and cell-fate

determination and growing recognition that Eph

receptors function in adult tissue homeostasis.

EphA3 is thought to play a role in retinotectal mapping,

the tightly patterned projection of retinal ganglion cell

axons from the retina to the optic tectum (or superior

colliculus in mammals). In chicks, posterior retinal

ganglion axons expressing highest levels of EphA3

project to the anterior tectum where the graded



expression of ephrin-A2 and ephrin-A5 is lowest and

are excluded from projecting more posteriorly where

ephrin-A2/A5 expression is highest. More direct

evidence of non-redundant function for EphA3 has

come from phenotypic analysis of EphA3 knockout

mice. Approximately 70-75% of EphA3 null mice die

within 48 hours of birth with post-mortem evidence of

pulmonary oedema secondary to cardiac failure. These

mice exhibit hypoplastic atrioventricular endocardial

cushions and subsequent atri-oventricular valve and

atrial membranous septal defects, with endocardial

cushion explants from these mice giving rise to fewer

migrating cells arising from epithelial to mesenchymal

trans-formation. Expression of EphA3 in the spinal

cord appears to be redundant as axial muscle targeting

by medial motor column motor axons and the

organisation of the motor neuron columns is not

altered. EphA4 is the only other EphA receptor also

expressed by developing spinal cord motor neurons and

in mice lacking EphA3 and EphA4 these receptors

together repel axial motor axons from neighbouring

ephrin-A-expressing sensory axons, inhibiting

intermingling of motor and sensory axons and

preventing mis-projection of motor axons into the

dorsal root ganglia. In contrast to the chick, EphA3 is

not expressed by mouse retinal ganglion cells. Instead

the closely related receptors EphA5 and EphA6 (see

homology below) are expressed in a low nasal to high

temporal gradient. However, if EphA3 is ectopically

expressed in retinal ganglion cells in mice these axons

project to more rostral positions in the superior

colliculus.

A function for soluble EphA3 has not been reported

although potentially this isoform might play a role in

promoting cell adhesion (see above) or act as a tumour

suppressor protein (see below).

Homology

Phylogenetic tree for the Eph receptors. Amino acid

sequences used for this compilation were EphA1

(NP_005223), EphA2 (NM_004431), EphA3

(NP_005224), EphA4 (NP_004429), EphA5

(NM_004439), EphA6 (ENSP00000374323), EphA7

(NP_004431), EphA8 (NP_065387), EphA10

(NP_001092909), EphB1 (NP_004432), EphB2

(NP_004433), EphB3 (NP_004434), EphB4

(NP_004435) and EphB6 (NP_004436).

Mutations

Note

Seven nonsynonymous single nucleotide polymer-

phisms (all missense) are recorded in the dbSNP

database for EPHA3. Recognised allelic variation

occurs for the following EphA3 amino acids: I564V

(rs56081642), C568S (rs56077781), L590P

(rs56081642), T608A (rs17855794), G777A

(rs34437982), W924R (rs35124509) and H914R

(rs17801309).

Germinal

To date no germinal mutations in EPHA3 have been

associated with disease.

Somatic

Somatic mutations in EPHA3 have been detected in

lung adenocarcinoma (T166N, G187R, S229Y,

W250R, M269I, N379K, T393K, A435S, D446Y,

Figure 6: Sites of somatic mutations in EphA3 identified in lung adenocarcinoma colorectal carcinoma, glioblastoma multiforme and metastatic melanoma.



S449F, G518L, T660K, D678E, R728L, K761N,

G766E, T933M), colorectal carcinoma (T37K, N85S,

I621L, S792P, D806N), glioblastoma multi-forme

(K500N, A971P) and metastatic melanoma (G228R).

Implicated in

Prostate cancer

Note

EPHA3 was among the genes whose expression was

upregulated during androgen-independent progresssion

in an LNCaP in vitro cell model of prostate cancer.

Melanoma

Note

A melanoma patient with an especially favourable

evolution of disease, associated with a very strong and

sustained anti-tumour cytotoxic T lymphocyte

response, was found to have a lytic CD4 clone that

recognised an EphA3 antigen presented by the HLA

class II molecule HLA- DRB1*1101. 94% (75 of 80) of

melanomas examined expressed EphA3 in contrast to

normal melanocytes which do not express detectable

EphA3.

Lung cancer, Sarcoma, and Renal cell carcinoma

Note

44% (11 of 25) of small cell lung cancer, 24% (10 of

41) of non-small cell lung cancer, 58% (17 of 29) of

sarcomas, and 31% (12 of 38) of renal cell carcinomas

expressed EphA3 at levels significantly higher than the

corresponding normal tissues.

Breakpoints

Note

No reported breakpoints identified to date nor

recognised fusion proteins involving EphA3.

To be noted

Note

Soluble forms of EphA3 appear to inhibit tumour

angiogenesis and tumour progression suggesting that

specific inhibition by soluble EphA3 may be

therapeutically useful.

The IIIA4 monoclonal antibody originally raised

against LK63 human acute pre-B leukemia cells and

used to affinity isolate EphA3 binds the native EphA3

globular ephrin-binding domain with sub-nanomolar

affinity (KD ~5x10-10

mol/L). Like ephrin-A5, pre-

clustered IIIA4 effectively triggers EphA3 activation,

contraction of the cytoskeleton, and cell rounding.

Moreover, radio-metal conju-gates of ephrin-A5 and

IIIA4 retain their EphA3-binding affinity, and in mouse

xenografts localise to, and are internalised rapidly into

EphA3-positive, human tumours.

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JAZF1 (JAZF zinc finger 1) Hui Li, Jeffrey Sklar

University of Virginia Medical School, Charlottesville, VA 22908, USA (HL), Department of Pathology,

Yale University, New haven, CT, USA (HL, JS)


Online updated version: http://AtlasGeneticsOncology.org/Genes/JAZF1ID41036ch7p15.html DOI: 10.4267/2042/44711


Identity

Other names: TIP27; ZNF802; DKFZp761K2222

HGNC (Hugo): JAZF1

Location: 7p15.2

Metaphase FISH using as probe YAC908B12, which encompasses the entire JAZF1 at 7p15.2.

DNA/RNA

Description

5 exons; spans 350kb.

Transcription

Major transcript: 2,980bp; coding sequence: 52-783.

Protein

Description

243 amino acids.

Expression

Expressed in all the tissues tested with variable level.

The tissues or organs that express JAZF1 include

cerebellum, lung, thymus, liver, kidney,

stomach/esophagus, skeleton muscle, skin and eye.

Localisation

Mostly nucleus.

Function

JAZF1 has three C2H2-type zinc fingers. It is mostly

detected within the nucleus, with lesser amounts found

in the cytoplasm. JAZF1 copurifies with chromatin,

and presumably has DNA-binding properties. It has

been reported to interact with TAK1 and function as a

transcriptional repressor of the TAK1 gene.

SNPs in intron 1 of JAZF1 has been reported to be

associated with type 2 diabetes and body height.

SNPs in intron 2 of JAZF1 have been reported to be

associated with reduced prevalence of prostate cancer.

Chimeric JAZF1-JJAZ1 protein (amino acid sequence

of the first three exons of JAZF1 joined to sequence of

the last 15 exons of JJAZ1) resulting from trans-

splicing of precursor mRNAs and identical to a product

generated from the JAZF1-JJAZ1 gene fusion in

endometrial tumors has been found in normal

endometrium.

Homology

Unkown.

Mutations

Somatic

JAZF1 has been identified at the breakpoints of a

recurrent chromosomal translocation, the

JAZF1 (JAZF zinc finger 1) Li H, Sklar J


t(7;17)(p15;q21), in endometrial stromal tumors

(benign nodules and sarcomas). The translocation leads

to a JAZF1-JJAZ1 fusion gene. This gene fusion is

detected in about 50% of endometrial stromal sarcomas

and most endometrial stromal nodules.

Another common chromosomal translocation in

endometrial stroma sarcomas, the t(6;7)(p21;p15),

results in a JAZF1-PHF1 fusion. About 25-30% of

endometrial stromal sarcomas are reported to contain

this fusion. The sites of fusion within JAZF1 RNA to

JJAZ1 and PHF1 RNA sequence are the same. Both

JJAZ1(also called SUZ12) and PHF1 belong to the

Polycomb group (PcG) gene family.

Implicated in

t(7;17)(p15;q21) / endometrial stromal nodule and endometrial sarcoma

Disease

Endometrial stroma nodule and sarcoma.

Cytogenetics

t(7;17)(p15;q21)

Hybrid/Mutated gene

JAZF1-JJAZ1

Abnormal protein

JAZF1-JJAZ1

Oncogenesis

The fusion protein protects cells from hypoxia-induced

apoptosis, and also promotes proliferation when the

wild-type allele of JJAZ1 is silenced (as it is in

endometrial stromal sarcomas carrying the

t(7;17)(p15;q21)).

t(6;7)(p21;p15)/ endometrial stroma sarcoma

Disease

Endometrial stroma sarcoma.

Cytogenetics

t(6;7)(p21;p15)

Hybrid/Mutated gene

JAZF1-PHF1

Abnormal protein

JAZF1-PHF1

Oncogenesis

The function of the JAZF1-PHF1 fusion is not

currently known.

Prostate carcinoma

Oncogenesis

A SNIP in intron 2 of JAZF1 is associated with a

somewhat decreased risk of prostate cancer, especially

cancers that have been classified as being less

aggressive. The mechanism by which polymer-phisms

alter the susceptibility toward prostate cancer is not

currently known.

Breakpoints

References Koontz JI, Soreng AL, Nucci M, Kuo FC, Pauwels P, van Den Berghe H, Dal Cin P, Fletcher JA, Sklar J. Frequent fusion of the JAZF1 and JJAZ1 genes in endometrial stromal tumors. Proc Natl Acad Sci U S A. 2001 May 22;98(11):6348-53

Micci F, Panagopoulos I, Bjerkehagen B, Heim S. Consistent rearrangement of chromosomal band 6p21 with generation of fusion genes JAZF1/PHF1 and EPC1/PHF1 in endometrial stromal sarcoma. Cancer Res. 2006 Jan 1;66(1):107-12

Li H, Ma X, Wang J, Koontz J, Nucci M, Sklar J. Effects of rearrangement and allelic exclusion of JJAZ1/SUZ12 on cell proliferation and survival. Proc Natl Acad Sci U S A. 2007 Dec 11;104(50):20001-6

Nucci MR, Harburger D, Koontz J, Dal Cin P, Sklar J. Molecular analysis of the JAZF1-JJAZ1 gene fusion by RT-PCR and fluorescence in situ hybridization in endometrial stromal neoplasms. Am J Surg Pathol. 2007 Jan;31(1):65-70

Frayling TM, Colhoun H, Florez JC. A genetic link between type 2 diabetes and prostate cancer. Diabetologia. 2008 Oct;51(10):1757-60

Frayling TM, Colhoun H, Florez JC. A genetic link between type 2 diabetes and prostate cancer. Diabetologia. 2008 Oct;51(10):1757-60

Li H, Wang J, Mor G, Sklar J. A neoplastic gene fusion mimics trans-splicing of RNAs in normal human cells. Science. 2008 Sep 5;321(5894):1357-61

Thomas G, Jacobs KB, Yeager M, Kraft P, Wacholder S, Orr N, Yu K, Chatterjee N, Welch R, Hutchinson A, Crenshaw A, Cancel-Tassin G, Staats BJ, Wang Z, Gonzalez-Bosquet J, Fang J, Deng X, Berndt SI, Calle EE, Feigelson HS, Thun MJ, Rodriguez C, Albanes D, Virtamo J, Weinstein S, Schumacher FR, Giovannucci E, Willett WC, Cussenot O, Valeri A, Andriole GL, Crawford ED, Tucker M, Gerhard DS, Fraumeni JF Jr, Hoover R, Hayes RB, Hunter DJ, Chanock SJ. Multiple loci identified in a genome-wide association study of prostate cancer. Nat Genet. 2008 Mar;40(3):310-5

Zeggini E, Scott LJ, Saxena R, Voight BF, Marchini JL, Hu T, de Bakker PI, Abecasis GR, Almgren P, Andersen G, Ardlie K, Boström KB, Bergman RN, Bonnycastle LL, Borch-Johnsen K, Burtt NP, Chen H, Chines PS, Daly MJ, Deodhar P, Ding CJ, Doney AS, Duren WL, Elliott KS, Erdos MR, Frayling TM,

JAZF1 (JAZF zinc finger 1) Li H, Sklar J


Freathy RM, Gianniny L, Grallert H, Grarup N, Groves CJ, Guiducci C, Hansen T, Herder C, Hitman GA, Hughes TE, Isomaa B, Jackson AU, Jørgensen T, Kong A, Kubalanza K, Kuruvilla FG, Kuusisto J, Langenberg C, Lango H, Lauritzen T, Li Y, Lindgren CM, Lyssenko V, Marvelle AF, Meisinger C, Midthjell K, Mohlke KL, Morken MA, Morris AD, Narisu N, Nilsson P, Owen KR, Palmer CN, Payne F, Perry JR, Pettersen E, Platou C, Prokopenko I, Qi L, Qin L, Rayner NW, Rees M, Roix JJ, Sandbaek A, Shields B, Sjögren M, Steinthorsdottir V, Stringham HM, Swift AJ, Thorleifsson G, Thorsteinsdottir U, Timpson NJ, Tuomi T, Tuomilehto J, Walker M, Watanabe RM, Weedon MN, Willer CJ, Illig T, Hveem K, Hu FB, Laakso M, Stefansson K, Pedersen O, Wareham NJ, Barroso I, Hattersley AT, Collins FS, Groop L, McCarthy MI, Boehnke M, Altshuler D. Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes. Nat Genet. 2008 May;40(5):638-45

Johansson A, Marroni F, Hayward C, Franklin CS, Kirichenko AV, Jonasson I, Hicks AA, Vitart V, Isaacs A, Axenovich T, Campbell S, Dunlop MG, Floyd J, Hastie N, Hofman A, Knott S, Kolcic I, Pichler I, Polasek O, Rivadeneira F, Tenesa A, Uitterlinden AG, Wild SH, Zorkoltseva IV, Meitinger T, Wilson JF, Rudan I, Campbell H, Pattaro C, Pramstaller P, Oostra BA, Wright AF, van Duijn CM, Aulchenko YS, Gyllensten U. Common variants in the JAZF1 gene associated with height identified by linkage and genome-wide association analysis. Hum Mol Genet. 2009 Jan 15;18(2):373-80

Waters KM, Le Marchand L, Kolonel LN, Monroe KR, Stram DO, Henderson BE, Haiman CA. Generalizability of associations from prostate cancer genome-wide association studies in multiple populations. Cancer Epidemiol Biomarkers Prev. 2009 Apr;18(4):1285-9


Li H, Sklar J. JAZF1 (JAZF zinc finger 1). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3):286-288.

Gene Section Review




LPAR1 (lysophosphatidic acid receptor 1) Mandi M Murph, Harish Radhakrishna

University of Georgia College of Pharmacy, Department of Pharmaceutical and Biomedical Sciences, 250 W

Green Street, Rm 376 Athens, Georgia 30602 USA (MMM); Global Research & Technology, The Coca-

Cola Company, 1 Coca-Cola Plaza Atlanta, GA 30313 USA (HR)


Online updated version: http://AtlasGeneticsOncology.org/Genes/LPAR1ID40405ch9q31.html DOI: 10.4267/2042/44712


Identity Other names: EDG2; GPR26; LPA-1; LPA1;

Mrec1.3; VZG1; edg-2; rec.1.3; vzg-1

HGNC (Hugo): LPAR1

Location: 9q31.3

DNA/RNA

Note

mRNA length 3104 or 3182 bp, depending on

alternative splicing.

Protein

Description

LPAR1 is an abbreviation for the LPA1 receptor, the

first receptor cloned and identified from a growing

number of LPA receptors that includes the Edg-family

and the purinergic receptors.

Expression

LPAR1 is ubiquitously expressed throughout cells and

tissues in the body.

High level of expression is found in amygdale,

Figure of the LPAR1, a G protein-coupled receptor, spanning the plasma membrane seven times. The receptor has three numbered extracellular and intracellular loops that are involved in signal transduction. Also shown are the amino terminus and carboxyl terminal tail. Three regions of the carboxyl terminal tail have been shown to be important for the LPAR1 signaling and receptor regulation. LPAR1 contains a canonical Type 1 PDZ binding domain (a.a. 362-364) at the extreme C-terminus. This domain has been shown to be required for LPA-induced cell proliferation and activation of Rho family GTPases via PDZ-Rho guanine nucleotide exchange factors. Further upstream in the carboxyl terminal tail, LPAR1 contains a di-leucine sequence (a.a. 351 and 352), which is required for phorbol ester-

LPAR1 (lysophosphatidic acid receptor 1) Murph MM, Radhakrishna H


induced internalization. Still further upstream lies a serine-rich cluster (a.a. 341-347) that is required for beta-arrestin association, which is critical for signal attenuation and receptor endocytosis.

prefrontal cortex, caudate nucleus, hypothalamus,

medulla oblongata, olfactory bulb, parietal lobe, spinal

cord and thalamus.

Moderately high level of expression is found in

adipocytes, cingulated cortex, occipital lobe, pons,

whole brain, globus pallidus, subthalamic nucleus,

temporal lobe, appendix, monocytes and smooth

muscle.

Slightly above median level of expression is found in

bronchial epithelial cells, cerebellum peduncies, dorsal

root ganglia, ciliary ganglion, uterus, uterus corpus,

atrioventricular node, fetal lung, fetal thyroid, skeletal

muscle, cardiac myocytes, salivary gland, tongue and

lymph node. It is also expressed in tissues during

neuronal development. The expression of LPAR1 is

increased in blister skin compared to normal skin. The

mRNA of LPAR1 is significantly increased 8 days after

unilateral uretheral obstruction in mice kidneys where

expression is higher in the medulla than the cortex. The

expression of LPAR1 is variable in cancer.

Localisation

It is a requirement of G protein-coupled receptor

functioning that receptors are embedded into

membranes for proper structure. The LPAR1 spans the

plasma membrane seven times in a barrel conformation

with three extracellular and three intracellular loops. At

steady state, LPAR1 is located on the plasma

membrane at the cell surface until it binds LPA, which

triggers dynamin2-dependent, clathrin-mediated

endocytosis into the cell. LPAR1 requires membrane

cholesterol for association with beta-arrestin, which

targets the receptor to clathrin-coated pits for

internalization. In addition to LPA, phorbol ester

stimulation of protein kinase C also induces

internalization of LPAR1, but this does not require

beta-arrestin. Rather, phorbol ester-dependent

internalization of LPAR1 requires AP-2 clathrin

adaptors. The LPAR1 is subsequently sorted through

Rab-5 dependent early and recycling endosomes before

it is recycled back to the cell surface or degraded in

lysosomes.

The receptor may also be localized to the nuclear

membrane in the cell. Some evidence indicates that a

portion of the total cellular LPAR1 localizes to the

nuclear membrane in PC12 cells, micro-vascular

endothelial cells, and human bronchial epithelial cells.

The exact function of this nuclear LPAR1 pool is not

known.

Function

The LPAR1 binds LPA and initiates G protein-

dependent signal transduction cascades throughout the

cell that result in a number of functional outcomes,

depending on the specific cell or tissue type. The G

alpha proteins involved are Gi, Gq and G 12/13. The

receptor has critical functions that have been elucidated

through gene knock-out studies in mice. LPAR1-null

mice have deficiencies in olfactory development that

impairs their ability to locate maternal nipples and

initiate suckling required for survival. The lack of

olfactant detection leads to 50% lethality among pups.

Other LPAR1-null mice demonstrate alterations in

neurotransmitters that mimic models of schizophrenia.

LPAR1-null mice are 10-15% shorter than wild-type

mice and have gross anatomical defects due to bone

development, including incisor overgrowth that affects

ability to feed. The LPAR1 functions in normal cortical

development and commits cortical neuroblasts to

differentiate through the neural lineage. It may also

play a role in the formation of dendritic spine synapses.

Through autotoxin-generated LPA, LPAR1 mediates

neuropathic pain induced by nerve injury. Activation of

the LPAR1 functions in the inflammatory response;

receptor activation stimulates the recruitment of

macrophages.

The LPAR1 positively regulates motility in a variety of

cell types, exerting a dominant signal in the absence of

LPAR4.

Homology

The LPAR1 has significant homology with LPAR2

(57%) and LPAR3 (51%), members of the original or

classical endothelial differentiation gene (Edg) family.

It has approximately 33-38% homology with individual

sphingosine 1-phosphate receptors and no significant

homology with the purinergic family of receptors that

also bind LPA.

Mutations

Note

There are several single nucleotide polymorphisms

(SNPs) reported within the LPAR1 gene and several of

these are associated with altered phenotype and disease

states.

A functional SNP located in the promoter region of the

gene (-2,820G/A; rs10980705) is associated with

increased susceptibility to knee osteoarthritis in

Japanese by showing an increase in binding and

activity.

A change in amino acid sequence at position 125 from

glutamine to glutamate in the LPAR1 will result in the

ability of the receptor to recognize both S1P and LPA.

A change in amino acid sequence at position 236 from

threonine to lysine in the LPAR1 will result in the

enhanced activation of serum response factor.

Mutations in the LPAR1 were detected in a small

percentage of adenomas and adenocarcinomas of rats

given BHP in their drinking water. Missense mutations

in the LPAR1 were detected in rat hepatocellular

carcinomas induced by N-nitroso-diethylamine and

choline-deficient l-amino acid-defined diets.

Deletion of the PDZ domain of the receptor prevents

signal attenuation that controls LPA-mediated receptor

activation and cell proliferation.



Implicated in

Various cancers

Note

Overexpression of the LPAR1 in mice contributes to

the tumorigenicity and aggressiveness of ovarian

cancer.

Prognosis

Upregulation of the LPAR1 appears to enhance tumor

progression in the previous examples.

Oncogenesis

The LPAR1 is a proto-oncogene contributing to the

metastatic potential of breast cancers and may require

signals from ErbB2/HER2 dimerization. In a study

designed to assess the functional conseq-uences of

overexpression as it relates to breast carcinogenesis,

1000 selected/suspected cDNAs were inserted into

immortalized MCF-10A cells and a derivative cell line,

MCF-10A.B2 expressing an inducibly active variant of

ErbB2. The study examined three assays (cell

proliferation, migration and 3-D matrigel acinar

morphogenesis) and the LPAR1 scored positive in all

three; thus, it was determined to be a proto-oncogene in

this disease. Several observations are of interest: first,

the LPAR1 induced migration in the absence of ErbB2

activation but not in the absence of dimerization which

suggests that the LPAR1 may require weak signals

from ligand-independent dimerization of ErbB2 to

induce migration; second, in the acinar morphogenesis

assay, phenotypical changes of cells with the LPAR1

included the formation of features of invasive tumor

cells, such as disorganized acinar structure, large

structures and protrusive behavior; third, the LPAR1

was capable of establishing abnormal 3-D

morphogenesis in the absence of conditions to dimerize

ErbB2.

Lung injury

Note

The LPAR1 mediates fibroblast migration and

recruitment in the injured lung. The chemotactic

activity of fibroblasts is dependent on LPAR1

expression.

Disease

Pulmonary fibrosis

The concentration of LPA is elevated in broncho-

alveolar lavage samples from patients with idio-pathic

pulmonary fibrosis. The fibroblasts of these patients

require expression of LPAR1 for the chemotactic

activity present in this pathology. Data suggests that

LPAR1-null mice are substantially protected from

fibroblast accumulation. This corresponds to lung

injury where aberrant wound-healing responses

exacerbate pulmonary fibrosis pathogenesis.

Prognosis

LPAR1 links lung injury with pulmonary fibrosis

development.

References Contos JJ, Fukushima N, Weiner JA, Kaushal D, Chun J. Requirement for the lpA1 lysophosphatidic acid receptor gene in normal suckling behavior. Proc Natl Acad Sci U S A. 2000 Nov 21;97(24):13384-9

Wang DA, Lorincz Z, Bautista DL, Liliom K, Tigyi G, Parrill AL. A single amino acid determines lysophospholipid specificity of the S1P1 (EDG1) and LPA1 (EDG2) phospholipid growth factor receptors. J Biol Chem. 2001 Dec 28;276(52):49213-20

Gobeil F Jr, Bernier SG, Vazquez-Tello A, Brault S, Beauchamp MH, Quiniou C, Marrache AM, Checchin D, Sennlaub F, Hou X, Nader M, Bkaily G, Ribeiro-da-Silva A, Goetzl EJ, Chemtob S. Modulation of pro-inflammatory gene expression by nuclear lysophosphatidic acid receptor type-1. J Biol Chem. 2003 Oct 3;278(40):38875-83

Harrison SM, Reavill C, Brown G, Brown JT, Cluderay JE, Crook B, Davies CH, Dawson LA, Grau E, Heidbreder C, Hemmati P, Hervieu G, Howarth A, Hughes ZA, Hunter AJ, Latcham J, Pickering S, Pugh P, Rogers DC, Shilliam CS, Maycox PR. LPA1 receptor-deficient mice have phenotypic changes observed in psychiatric disease. Mol Cell Neurosci. 2003 Dec;24(4):1170-9

Murph MM, Scaccia LA, Volpicelli LA, Radhakrishna H. Agonist-induced endocytosis of lysophosphatidic acid-coupled LPA1/EDG-2 receptors via a dynamin2- and Rab5-dependent pathway. J Cell Sci. 2003 May 15;116(Pt 10):1969-80

Avendaño-Vázquez SE, García-Caballero A, García-Sáinz JA. Phosphorylation and desensitization of the lysophosphatidic acid receptor LPA1. Biochem J. 2005 Feb 1;385(Pt 3):677-84

Roberts C, Winter P, Shilliam CS, Hughes ZA, Langmead C, Maycox PR, Dawson LA. Neurochemical changes in LPA1 receptor deficient mice--a putative model of schizophrenia. Neurochem Res. 2005 Mar;30(3):371-7

Yamada T, Ohoka Y, Kogo M, Inagaki S. Physical and functional interactions of the lysophosphatidic acid receptors with PDZ domain-containing Rho guanine nucleotide exchange factors (RhoGEFs). J Biol Chem. 2005 May 13;280(19):19358-63

Pilpel Y, Segal M. The role of LPA1 in formation of synapses among cultured hippocampal neurons. J Neurochem. 2006 Jun;97(5):1379-92

Waters CM, Saatian B, Moughal NA, Zhao Y, Tigyi G, Natarajan V, Pyne S, Pyne NJ. Integrin signalling regulates the nuclear localization and function of the lysophosphatidic acid receptor-1 (LPA1) in mammalian cells. Biochem J. 2006 Aug 15;398(1):55-62

Witt AE, Hines LM, Collins NL, Hu Y, Gunawardane RN, Moreira D, Raphael J, Jepson D, Koundinya M, Rolfs A, Taron B, Isakoff SJ, Brugge JS, LaBaer J. Functional proteomics approach to investigate the biological activities of cDNAs implicated in breast cancer. J Proteome Res. 2006 Mar;5(3):599-610

Fukushima N, Shano S, Moriyama R, Chun J. Lysophosphatidic acid stimulates neuronal differentiation of cortical neuroblasts through the LPA1-G(i/o) pathway. Neurochem Int. 2007 Jan;50(2):302-7

Murph MM, Hurst-Kennedy J, Newton V, Brindley DN, Radhakrishna H. Lysophosphatidic acid decreases the nuclear localization and cellular abundance of the p53 tumor suppressor in A549 lung carcinoma cells. Mol Cancer Res. 2007 Nov;5(11):1201-11



Pradère JP, Klein J, Grès S, Guigné C, Neau E, Valet P, Calise D, Chun J, Bascands JL, Saulnier-Blache JS, Schanstra JP. LPA1 receptor activation promotes renal interstitial fibrosis. J Am Soc Nephrol. 2007 Dec;18(12):3110-8

Estivill-Torrús G, Llebrez-Zayas P, Matas-Rico E, Santín L, Pedraza C, De Diego I, Del Arco I, Fernández-Llebrez P, Chun J, De Fonseca FR. Absence of LPA1 signaling results in defective cortical development. Cereb Cortex. 2008 Apr;18(4):938-50

Lee Z, Cheng CT, Zhang H, Subler MA, Wu J, Mukherjee A, Windle JJ, Chen CK, Fang X. Role of LPA4/p2y9/GPR23 in negative regulation of cell motility. Mol Biol Cell. 2008 Dec;19(12):5435-45

Mototani H, Iida A, Nakajima M, Furuichi T, Miyamoto Y, Tsunoda T, Sudo A, Kotani A, Uchida A, Ozaki K, Tanaka Y, Nakamura Y, Tanaka T, Notoya K, Ikegawa S. A functional SNP in EDG2 increases susceptibility to knee osteoarthritis in Japanese. Hum Mol Genet. 2008 Jun 15;17(12):1790-7

Murakami M, Shiraishi A, Tabata K, Fujita N. Identification of the orphan GPCR, P2Y(10) receptor as the sphingosine-1-phosphate and lysophosphatidic acid receptor. Biochem Biophys Res Commun. 2008 Jul 11;371(4):707-12

Murph MM, Nguyen GH, Radhakrishna H, Mills GB. Sharpening the edges of understanding the structure/function of the LPA1 receptor: expression in cancer and mechanisms of regulation. Biochim Biophys Acta. 2008 Sep;1781(9):547-57

Pradère JP, Gonzalez J, Klein J, Valet P, Grès S, Salant D, Bascands JL, Saulnier-Blache JS, Schanstra JP. Lysophosphatidic acid and renal fibrosis. Biochim Biophys Acta. 2008 Sep;1781(9):582-7

Urs NM, Kowalczyk AP, Radhakrishna H. Different mechanisms regulate lysophosphatidic acid (LPA)-dependent versus phorbol ester-dependent internalization of the LPA1 receptor. J Biol Chem. 2008 Feb 29;283(9):5249-57

Yu S, Murph MM, Lu Y, Liu S, Hall HS, Liu J, Stephens C, Fang X, Mills GB. Lysophosphatidic acid receptors determine tumorigenicity and aggressiveness of ovarian cancer cells. J Natl Cancer Inst. 2008 Nov 19;100(22):1630-42

Obo Y, Yamada T, Furukawa M, Hotta M, Honoki K, Fukushima N, Tsujiuchi T. Frequent mutations of lysophosphatidic acid receptor-1 gene in rat liver tumors. Mutat Res. 2009 Jan 15;660(1-2):47-50

Yamada T, Obo Y, Furukawa M, Hotta M, Yamasaki A, Honoki K, Fukushima N, Tsujiuchi T. Mutations of lysophosphatidic acid receptor-1 gene during progression of lung tumors in rats. Biochem Biophys Res Commun. 2009 Jan 16;378(3):424-7


Murph MM, Radhakrishna H. LPAR1 (lysophosphatidic acid receptor 1). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3):289-292.





PIK3CA (phosphoinositide-3-kinase, catalytic, alpha polypeptide) Montserrat Sanchez-Cespedes

Programa d'Epigenetica i Biologia del Cancer-PEBC, Institut d'Investigacions Biomediques Bellvitge

(IDIBELL), Hospital Durant i Reynals, Avinguda Gran Via de l'Hospitalet, 199-203 08907-L'Hospitalet de

Llobregat-Barcelona, Spain (MSC)


Online updated version: http://AtlasGeneticsOncology.org/Genes/PIK3CAID415ch3q26.html DOI: 10.4267/2042/44713


Identity Other names: EC 2.7.1.153; MGC142161;

MGC14216

PI3K; p110-alpha

HGNC (Hugo): PIK3CA

Location: 3q26.32

Local order: centromere-KCNMB2-ZMAT3-

BC032034-PIK3CA-KCNMB3-ZNF639-MFN1-

GNB4- telomere

DNA/RNA

Relative size of the 21 exons of PIK3CA. The entire exon 1 is UTR (untranslated region). Exon numeration corresponds to the prevalent transcript (NM-006218).

Description

The PIK3CA gene spans a total genomic size of 86,190

bases and is composed of 21 exons, 20 of them coding

exons of varying lengths. Putative pseudogenes of

PIK3CA have been described on chromosomes 16 (gi

28913054) and 22q11.2

(gi 5931525), the later one in the Cat Eye Syndrome

region. These regions are highly homolog to the

sequences of exons 9 and 11-13 of the PIK3CA gene.

Transcription

The human PIK3CA transcript has an open reading

frame of 3,207-bp, predicting a protein of 1,068 amino

acid residues.

Protein

Description

The PIK3CA gene encodes the p110alpha protein

which is a catalytic subunit of the class I PI 3-kinases

(PI3K). Class I PI3K are heterodimeric molecules

composed of a catalytic subunit, a p110, and a

regulatory subunit. There are three possible calatytic

subunits p110alpha, beta or delta.

Expression

Widely expressed.

Localisation

The p110alpha localizes in the cytoplasm.

p110alpha conserved domains. Through its adaptor binding domain p110alpha interacts with the regulatory subunit. C2 domain, protein-kinase-C-homology-2 domain.

PIK3CA (phosphoinositide-3-kinase, catalytic, alpha polypeptide) Sanchez-Cespedes M


Function

Class I PI 3-kinases (PI3K) are linked to many cellular

functions, including cell growth, prolifera-tion,

differentiation, motility, survival and intra-cellular

trafficking. PI3K convert PI(4,5)P2 to PI(3,4,5)P3 on

the inner leaflet of the plasma membrane. The

PI(3,4,)P3 provokes the recruitment to cellular

membranes of a variety of signalling proteins,

containing PX domain, pleckstrin homo-logy domains

(PH domains), FYVE domains and other

phosphoinositide-binding domains. One of these is the

protein kinase B (PKB/AKT) a very well known

protein that is activated as a result of its translocation to

the cell membrane where it is then phosphorylated and

activated by another kinase, called phosphoinositide

dependent kinase 1 (PDK1). The phosphorylation of

AKT leads to the activation of the TSC/mTOR

pathway. PTEN, a tumor suppressor inactivated in

many cancers counteracts the action of PI3K by

dephosphoryla-ting the phosphoinositide-3,4,5-

trisphosphate (PIP3) (Lee et al., 2007).The PI3K are

inhibited by the drugs wortmannin and LY294002

although to various degree of sensitivity among the

different classes.

Mutations

Somatic

Somatic mutations at the PIK3CA gene have been

found in tumors and thus, it can be considered a bona

fide oncogene (Samuels et al., 2004). Most of the

mutations cluster in hotspots within the helical or the

catalytic domains.

Implicated in

A wide variety of human cancers

Note

(For example, colon, breast, endometrial, ovarian,

brain, lung, thyroid, head and neck and stomach).

PIK3CA mutations lead to constitutive activation of

p110alpha enzymatic activity, stimulate AKT

signaling, and allow growth factor-independent growth

(Bader et al., 2005). In addition, when expressed in

normal cells, these mutations allow anchorage-

independent growth, further attesting to their important

role in cancer development (Kang et al., 2005).

PIK3CA somatic mutations are frequent in a variety of

human primary tumors and cancer cell lines such as,

among others, those of the colon, breast, and stomach

(Samuels et al., 2004). However, in other tumors, i.e.

those of the lung, head and neck, brain, endometrium,

ovary, prostate, osteosarcoma and pancreas,

hematopoietic malignancies, PIK3CA mutations are not

as common (Angulo et al., 2008; Qiu et al., 2006;

Muller et al., 2007; Samuels et al., 2004; Schonleben et

al., 2006). PIK3CA gene amplifica-

tion has also been proposed as a mechanism for

oncogene activation in some tumors (Angulo et al.,

2008). Because PIK3CA is now considered an

important oncogene implicated in the development of a

wide variety of human cancers, efforts are now being

directed towards the development of mole-cules that

inhibit the activity of PI3K (Garcia-Echeverria et al.,

2008). These could be efficient in the treatment of

those tumors carrying constitutive activation of PI3K

pathway. PTEN is a well known tumor suppressor that

counteracts the action of PI3K by dephosphorylating

the phosphoinositide-3,4,5-trisphosphate (PIP3). Thus,

the treatment with drugs that inhibit p110alpha activity

would be also potentially efficient in patients whose

tumors carry genetic alterations at PTEN.

It has recently been reported that activation of the PI3K

pathway in breast tumors with concomitant ERBB2

gene amplification, either through PIK3CA mutations

or PTEN inactivation, underlies trastuzumab resistance.

These findings may provide a biomarker to identify

patients unlikely to respond to trastuzumab-based

therapy (Berns et al., 2007).

To be noted

Note

Recent evidence has shown that the PIK3CA gene is

mutated and amplified in a range of human cancers.

Due to that p110alpha is believed to be a promising

drug target. A number of pharmaceutical companies are

currently designing and charactering potential

p110alpha isoform specific inhibitors.

References Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S, Yan H, Gazdar A, Powell SM, Riggins GJ, Willson JK, Markowitz S, Kinzler KW, Vogelstein B, Velculescu VE. High frequency of mutations of the PIK3CA gene in human cancers. Science. 2004 Apr 23;304(5670):554

Bader AG, Kang S, Zhao L, Vogt PK. Oncogenic PI3K deregulates transcription and translation. Nat Rev Cancer. 2005 Dec;5(12):921-9

Kang S, Bader AG, Vogt PK. Phosphatidylinositol 3-kinase mutations identified in human cancer are oncogenic. Proc Natl Acad Sci U S A. 2005 Jan 18;102(3):802-7

Qiu W, Schönleben F, Li X, Ho DJ, Close LG, Manolidis S, Bennett BP, Su GH. PIK3CA mutations in head and neck squamous cell carcinoma. Clin Cancer Res. 2006 Mar 1;12(5):1441-6

Schönleben F, Qiu W, Ciau NT, Ho DJ, Li X, Allendorf JD, Remotti HE, Su GH. PIK3CA mutations in intraductal papillary mucinous neoplasm/carcinoma of the pancreas. Clin Cancer Res. 2006 Jun 15;12(12):3851-5

Berns K, Horlings HM, Hennessy BT, Madiredjo M, Hijmans EM, Beelen K, Linn SC, Gonzalez-Angulo AM, Stemke-Hale K, Hauptmann M, Beijersbergen RL, Mills GB, van de Vijver MJ, Bernards R. A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell. 2007 Oct;12(4):395-402

PIK3CA (phosphoinositide-3-kinase, catalytic, alpha polypeptide) Sanchez-Cespedes M


Lee JY, Engelman JA, Cantley LC. Biochemistry. PI3K charges ahead. Science. 2007 Jul 13;317(5835):206-7

Müller CI, Miller CW, Hofmann WK, Gross ME, Walsh CS, Kawamata N, Luong QT, Koeffler HP. Rare mutations of the PIK3CA gene in malignancies of the hematopoietic system as well as endometrium, ovary, prostate and osteosarcomas, and discovery of a PIK3CA pseudogene. Leuk Res. 2007 Jan;31(1):27-32

Angulo B, Suarez-Gauthier A, Lopez-Rios F, Medina PP, Conde E, Tang M, Soler G, Lopez-Encuentra A, Cigudosa JC, Sanchez-Cespedes M. Expression signatures in lung cancer reveal a profile for EGFR-mutant tumours and identify selective

PIK3CA overexpression by gene amplification. J Pathol. 2008 Feb;214(3):347-56

Garcia-Echeverria C, Sellers WR. Drug discovery approaches targeting the PI3K/Akt pathway in cancer. Oncogene. 2008 Sep 18;27(41):5511-26


Sanchez-Cespedes M. PIK3CA (phosphoinositide-3-kinase, catalytic, alpha polypeptide). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3):293-295.

Gene Section Review




SFRP4 (Secreted Frizzled-Related Protein 4) Kendra S Carmon, David S Loose

University of Texas Health Science Center Houston, Houston, TX 77030, USA (KSC, DSL)


Online updated version: http://AtlasGeneticsOncology.org/Genes/SFRP4ID42277ch7p14.html DOI: 10.4267/2042/44714


Identity Other names: FRP-4; sFRP-4; FRPHE; MGC26498;

LOC6424

HGNC (Hugo): SFRP4

Location: 7p14.1

Local order: According to NCBI, SFRP4 is telomeric

to EPDR1 (7p14.1) ependymin related protein 1

(zebrafish) and STARD3NL (7p14-p13) StAR-related

lipid transfer domain containing 3 N-terminal like and

centromeric to TXNDC3 (7p14.1) thioredoxin domain

containing 3 (spermatozoa) and GPR141 (7p14.1) G

protein-coupled receptor 141.

DNA/RNA

Description

The SFRP4 gene spans 10.99 kb on the short arm of

chromosome 7 and is transcribed from the minus strand

in the centromere-to-telomere orientation. The gene is

encoded by six exons with the trans-lation initiation

codon in the first exon.

Transcription

The SFRP4 mRNA transcript is 2974 bp, 1041 bp are

coding sequence. Ensembl data predicts a second

transcript from the SFRP4 gene, lacking the 81 bp exon

2, although this has not been demons-trated.

Protein

Description

SFRP4 protein is comprised of 346 amino acids with a

predicted molecular weight of 39.9 kDa and an actual

molecular weight of approximately 50-55 kDa.

SFRP4 belongs to a family of five SFRPs; these

proteins fold into two independent domains. The N-

terminus contains a secretion signal peptide followed

by a ~120 amino acid cysteine-rich domain (CRD). The

CRD is 30-50% identical to the extracellular putative

Wnt-binding domain of frizzled (Fzd) receptors and is

characterized by the presence of ten cysteine residues at

conserved positions.

Diagram illustrates SFRP4 gene that contains a total of six exons.

SFRP4 (Secreted Frizzled-Related Protein 4) Carmon KS, Loose DS


Diagram illustrates the full length SFRP4 protein which contains a signal peptide sequence of 20-30 amino acids, a cysteine-rich domain (CRD) of approximately 120 amino acids, and a netrin-related motif (NTR) domain. Conserved cysteines of the CRD are indicated by *.

These cysteines form a pattern of disulfide bridges. The

C-terminal portion of the SFRP protein is characterized

by segments of positively charged residues that appear

to confer heparin-binding properties in at least two

SFRPs (SFRP1 and SFRP3) and contains a netrin-

related motif (NTR) with six cysteine residues that

most likely form three disulfide bridges. NTR domains

with similar features are found in a wide range of

unrelated proteins, including Netrin-1, tissue inhibitors

of metallo-proteinases (TIMPs), complement proteins

and type I procollagen C-proteinase enhancer proteins

(PCOLCEs). The six conserved cysteines in the NTR

of SFRP4 share a similar spacing to SFRP3, whereas

those of the SFRP1/SFRP2/SFRP5 subgroup are

distinctively different, indicating a disparity in disulfide

bond formation. Uniquely, SFRP4 contains two

additional cysteine residues. The overall function of the

NTR is unknown, yet there is some evidence that the

NTR may also play a role in Wnt binding. This implies

that multiple Wnt binding sites may exist on SFRP

molecules and/or that SFRPs exhibit differential

affinities for Wnt ligands according to the different

SFRP conformational and post-translational

modifications.

Expression

SFRP4 is expressed in various normal tissues including

endometrium (specifically stromal cells with higher

expression during proliferative phase of menstrual

cycle), ovary, kidney, heart, brain, mammary gland,

cervix, pancreas, stomach, colon, lung, skeletal muscle,

testis, eye, bone, prostate, and liver.

Localisation

Secreted from cell; extracellular matrix; bound to

plasma membrane.

Function

Since SFRPs share a similar CRD with the Fzd family

of receptors; it is believed that SFRPs may act as

soluble modulators that compete with Fzd to bind the

Wnt ligands, thereby altering the Wnt signal. Individual

SFRPs also have distinct binding specificity for distinct

Wnt ligands. Reports have demonstrated that SFRP4

binds Wnt7a and there is conflicting data for SFRP4

binding to Wnt3a. SFRP4 expression is regulated by

estrogen and progesterone and may act as a regulator of

adult uterine morphology and function. SFRP4 has

been shown to increase apoptosis during ovulation.

Transgenic studies have found that SFRP4 decreases

bone formation and inhibits osteoblast proliferation by

attenuating canonical/beta-catenin-Wnt signaling.

SFRP4 reportedly exhibits phospha-turic effects by

specifically inhibiting sodium-dependent phosphate

uptake.

Homology

Of the five human SFRPs (SFRP1, SFRP2, SFRP3,

SFRP4, SFRP5), SFRP4 shares most significant

homology with SFRP3.

Mutations

Note

It was reported that the T allele of the SFRP4 gene

polymorphism ARG262 (CGC to CGT) of exon4 is

associated with decreased bone mineral density in post-

menopausal Japanese women.

Implicated in

Endometrial Carcinoma

Note

SFRP4 was more frequently down-regulated in

(microsatellite instability). MSI cancers as compared

with (microsatellite stable) MSS endo-metrioid

endometrial cancers. Expression of SFRP4 is decreased

in both low-grade endometrial stromal sarcoma and

undifferentiated endometrial sarcoma.

Malignant Pleural Mesothelioma

Note

SFRP4 promoter is frequently methylated in this cancer

leading to inhibition of expression and is associated

with abnormal growth; restoration of SFRP4 results in

growth suppression and apoptosis in mesothelioma cell

lines.

Tumor-induced osteomalacia

Note

Tumor-induced osteomalacia is a disorder in which

there is an increase in renal phosphate excretion and a

reduction in serum phosphate levels leading to

hyperphosphaturia, hypophosphatemia and rickets.



CLUSTAL alignment of the 5 human SFRPs.

SFRP4 is highly expressed in such tumors and

functions as a circulating phosphaturic factor that

antagonizes renal Wnt-signaling.

Breast Cancer

Note

Studies have found evidence for SFRP4 overexpression

in breast cancer.

Pancreatic Cancer

Note

SFRP4 found to be significantly hypermethylated in the

tumors of cancer patients versus matched adjacent

tissue controls.

Gastric Carcinoma

Note

The SFRP4 was highly methylated in gastric carcinoma

samples with greater instance in H. pylori positive

patients.

Prostate Cancer

Note

SFRP4 is overexpressed in prostate cancers and



functions to inhibit cell proliferation and metastatic

potential.

Prognosis

Increased expression of membranous SFRP4 is

associated with a good prognosis in human localized

androgen-dependent prostate cancer, suggesting a role

for sFRP4 in early stage disease.

B-cell chronic lymphocytic leukemia

Note

SFRP4 was found to be frequently methylated and

downregulated in CLL samples.

Colorectal Carcinoma

Note

SFRP4 expression was shown to be up-regulated in

colorectal cancer.

Esophageal Adenocarcinoma

Note

SFRP4 mRNA and protein expression were

significantly decreased due to hypermethylation in

esophageal adenocarcinoma and Barrett's esophagus

patients.

References Finch PW, He X, Kelley MJ, Uren A, Schaudies RP, Popescu NC, Rudikoff S, Aaronson SA, Varmus HE, Rubin JS. Purification and molecular cloning of a secreted, Frizzled-related antagonist of Wnt action. Proc Natl Acad Sci U S A. 1997 Jun 24;94(13):6770-5

Abu-Jawdeh G, Comella N, Tomita Y, Brown LF, Tognazzi K, Sokol SY, Kocher O. Differential expression of frpHE: a novel human stromal protein of the secreted frizzled gene family, during the endometrial cycle and malignancy. Lab Invest. 1999 Apr;79(4):439-47

Bafico A, Gazit A, Pramila T, Finch PW, Yaniv A, Aaronson SA. Interaction of frizzled related protein (FRP) with Wnt ligands and the frizzled receptor suggests alternative mechanisms for FRP inhibition of Wnt signaling. J Biol Chem. 1999 Jun 4;274(23):16180-7

Bányai L, Patthy L. The NTR module: domains of netrins, secreted frizzled related proteins, and type I procollagen C-proteinase enhancer protein are homologous with tissue inhibitors of metalloproteases. Protein Sci. 1999 Aug;8(8):1636-42

Dennis S, Aikawa M, Szeto W, d'Amore PA, Papkoff J. A secreted frizzled related protein, FrzA, selectively associates with Wnt-1 protein and regulates wnt-1 signaling. J Cell Sci. 1999 Nov;112 ( Pt 21):3815-20

Uren A, Reichsman F, Anest V, Taylor WG, Muraiso K, Bottaro DP, Cumberledge S, Rubin JS. Secreted frizzled-related protein-1 binds directly to Wingless and is a biphasic modulator of Wnt signaling. J Biol Chem. 2000 Feb 11;275(6):4374-82

Dann CE, Hsieh JC, Rattner A, Sharma D, Nathans J, Leahy DJ. Insights into Wnt binding and signalling from the structures of two Frizzled cysteine-rich domains. Nature. 2001 Jul 5;412(6842):86-90

Roszmusz E, Patthy A, Trexler M, Patthy L. Localization of disulfide bonds in the frizzled module of Ror1 receptor tyrosine kinase. J Biol Chem. 2001 May 25;276(21):18485-90

Yamaguchi TP. Heads or tails: Wnts and anterior-posterior patterning. Curr Biol. 2001 Sep 4;11(17):R713-24

Chong JM, Uren A, Rubin JS, Speicher DW. Disulfide bond assignments of secreted Frizzled-related protein-1 provide insights about Frizzled homology and netrin modules. J Biol Chem. 2002 Feb 15;277(7):5134-44

Fujita M, Ogawa S, Fukuoka H, Tsukui T, Nemoto N, Tsutsumi O, Ouchi Y, Inoue S. Differential expression of secreted frizzled-related protein 4 in decidual cells during pregnancy. J Mol Endocrinol. 2002 Jun;28(3):213-23

Berndt T, Craig TA, Bowe AE, Vassiliadis J, Reczek D, Finnegan R, Jan De Beur SM, Schiavi SC, Kumar R. Secreted frizzled-related protein 4 is a potent tumor-derived phosphaturic agent. J Clin Invest. 2003 Sep;112(5):785-94

Drake JM, Friis RR, Dharmarajan AM. The role of sFRP4, a secreted frizzled-related protein, in ovulation. Apoptosis. 2003 Aug;8(4):389-97

Ace CI, Okulicz WC. Microarray profiling of progesterone-regulated endometrial genes during the rhesus monkey secretory phase. Reprod Biol Endocrinol. 2004 Jul 7;2:54

Fujita M, Urano T, Shiraki M, Momoeda M, Tsutsumi O, Hosoi T, Orimo H, Ouchi Y, Inoue S.. Association of a single nucleotide polymorphism in the secreted frizzled-related protein 4 (sFRP4) gene with bone mineral density. Ger. Geront. Int. 2004; 4 (3): 175-180.

Horvath LG, Henshall SM, Kench JG, Saunders DN, Lee CS, Golovsky D, Brenner PC, O'Neill GF, Kooner R, Stricker PD, Grygiel JJ, Sutherland RL. Membranous expression of secreted frizzled-related protein 4 predicts for good prognosis in localized prostate cancer and inhibits PC3 cellular proliferation in vitro. Clin Cancer Res. 2004 Jan 15;10(2):615-25

Hrzenjak A, Tippl M, Kremser ML, Strohmeier B, Guelly C, Neumeister D, Lax S, Moinfar F, Tabrizi AD, Isadi-Moud N, Zatloukal K, Denk H. Inverse correlation of secreted frizzled-related protein 4 and beta-catenin expression in endometrial stromal sarcomas. J Pathol. 2004 Sep;204(1):19-27

Lee AY, He B, You L, Dadfarmay S, Xu Z, Mazieres J, Mikami I, McCormick F, Jablons DM. Expression of the secreted frizzled-related protein gene family is downregulated in human mesothelioma. Oncogene. 2004 Aug 26;23(39):6672-6

He B, Lee AY, Dadfarmay S, You L, Xu Z, Reguart N, Mazieres J, Mikami I, McCormick F, Jablons DM. Secreted frizzled-related protein 4 is silenced by hypermethylation and induces apoptosis in beta-catenin-deficient human mesothelioma cells. Cancer Res. 2005 Feb 1;65(3):743-8

Risinger JI, Maxwell GL, Chandramouli GV, Aprelikova O, Litzi T, Umar A, Berchuck A, Barrett JC. Gene expression profiling of microsatellite unstable and microsatellite stable endometrial cancers indicates distinct pathways of aberrant signaling. Cancer Res. 2005 Jun 15;65(12):5031-7

Zou H, Molina JR, Harrington JJ, Osborn NK, Klatt KK, Romero Y, Burgart LJ, Ahlquist DA. Aberrant methylation of secreted frizzled-related protein genes in esophageal adenocarcinoma and Barrett's esophagus. Int J Cancer. 2005 Sep 10;116(4):584-91

Berndt TJ, Bielesz B, Craig TA, Tebben PJ, Bacic D, Wagner CA, O'Brien S, Schiavi S, Biber J, Murer H, Kumar R. Secreted frizzled-related protein-4 reduces sodium-phosphate co-transporter abundance and activity in proximal tubule cells. Pflugers Arch. 2006 Jan;451(4):579-87

Feng Han Q, Zhao W, Bentel J, Shearwood AM, Zeps N, Joseph D, Iacopetta B, Dharmarajan A. Expression of sFRP-4



and beta-catenin in human colorectal carcinoma. Cancer Lett. 2006 Jan 8;231(1):129-37

Liu TH, Raval A, Chen SS, Matkovic JJ, Byrd JC, Plass C. CpG island methylation and expression of the secreted frizzled-related protein gene family in chronic lymphocytic leukemia. Cancer Res. 2006 Jan 15;66(2):653-8

Turashvili G, Bouchal J, Burkadze G, Kolar Z. Wnt signaling pathway in mammary gland development and carcinogenesis. Pathobiology. 2006;73(5):213-23

Wawrzak D, Métioui M, Willems E, Hendrickx M, de Genst E, Leyns L. Wnt3a binds to several sFRPs in the nanomolar range. Biochem Biophys Res Commun. 2007 Jun 15;357(4):1119-23

Bu XM, Zhao CH, Zhang N, Gao F, Lin S, Dai XW. Hypermethylation and aberrant expression of secreted frizzled-related protein genes in pancreatic cancer. World J Gastroenterol. 2008 Jun 7;14(21):3421-4

Carmon KS, Loose DS. Secreted frizzled-related protein 4 regulates two Wnt7a signaling pathways and inhibits proliferation in endometrial cancer cells. Mol Cancer Res. 2008 Jun;6(6):1017-28

Kang GH, Lee S, Cho NY, Gandamihardja T, Long TI, Weisenberger DJ, Campan M, Laird PW. DNA methylation profiles of gastric carcinoma characterized by quantitative DNA methylation analysis. Lab Invest. 2008 Feb;88(2):161-70

Nakanishi R, Akiyama H, Kimura H, Otsuki B, Shimizu M, Tsuboyama T, Nakamura T. Osteoblast-targeted expression of Sfrp4 in mice results in low bone mass. J Bone Miner Res. 2008 Feb;23(2):271-7


Carmon KS, Loose DS. SFRP4 (Secreted Frizzled-Related Protein 4). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3):296-300.

Gene Section Review




SRC (v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (avian)) Stephen Hiscox

Welsh School of Pharmacy, Redwood Building, Cardiff University, Cardiff, UK (SH)


Online updated version: http://AtlasGeneticsOncology.org/Genes/SRCID448ch20q11.html DOI: 10.4267/2042/44715


Identity Other names: ASV (Avian Sarcoma Virus); SRC1; c-

SRC; p60-Src; pp60c-Src

HGNC (Hugo): SRC

Location: 20q11.23

Note

The Src kinase proto-oncogene has a high degree of

similarity to the v-src gene of Rous sarcoma virus,

although the C-terminal domain of v-Src is trunca-ted

and lacks the regulatory Tyr527 and therefore is not

subjected to downregulation by Csk. Src kinase is

implicated in the regulation of embryonic development,

cell differentiation and proliferation. Src has been

suggested to play a key role in cancer, where it may

facilitate tumour spread through promotion of tumour

cell invasion.

DNA/RNA

Note

The gene consists of 14 exons. Two isoforms have been

described differing in their 5' UTRs. Variant 1

represents the longer transcript although both isoforms

1 and 2 encode the same protein.

Description

Size: 61.33 Kb, 14 exons. mRNA: 4145 bases.

Protein

Note

Src can be phosphorylated on Tyr-530 by CSK (c-Src

kinase). The phosphorylated form is termed pp60c-src.

Phosphorylation of this tyrosine allows facilitates

interaction between the C-terminal tail and the SH2

domain, maintaining Src in an inactive formation.

Protein Translation:

MGSNKSKPKDASQRRRSLEPAENVHGAGGGAFP

ASQTPSKPASADGHRGPSAAFAPAAAEPKLFGGF

NSSDTVTSPQRAGPLAGGVTTFVALYDYESRTET

DLSFKKGERLQIVNNTEGDWWLAHSLSTGQTGY

IPSNYVAPSDSIQAEEWYFGKITRREGQGCFGEV

WMGTWNGTTRVAIKTLKPGTMSPEAFLQEAQV

MKKLRHEKLVQLYAVVSEEPIYIVTEYMSKGSLL

DFLKGETGKYLRLPQLVDMAAQIASGMAYVER

MNYVHRDLRAANILVGENLVCKVADFGLARLIE

DNEYTARQGAKFPIKWTAPEAALYGRFTIKSDV

WSFGILLTELTTKGRVPYPGMVNREVLDQVERG

YRMPCPPECPESLHDLMCQCWRKEPEERPTFEYL

QAFLEDYFTSTEPQYQPGENL

Note: This variant (isoform 1) represents the longer Src

transcript although both isoforms 1 and 2 encode the

same protein as the difference is in the 5' UTR.

SRC (v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (avian)) Hiscox S


Linear representation of the protein structure of human Src family members, showing the six distinct domains. N and C denote N- and C-termini respectively. Location of major regulatory phosphorylation sites and the myristolation signal sequence are shown.

Description

Size: 536 amino acids; 59.835 KDa.

Src is 59.6 KDa in size and has a domain structure

comprised of six distinct functional regions (see figure

above). These include an N-terminal SH4 domain that

contains a lipid-modification sequence allowing

targeting of Src to cellular membranes, and an adjacent,

poorly-conserved region thus being unique to each Src

family member. SH3 and SH2 domains adjacent to the

N-terminus facilitate protein-protein interactions

between Src and its interacting proteins whilst the SH1

domain allows ATP and substrate binding and has

tyrosine kinase activity; autophosphorylation of Y419

within this domain is required for the maximum kinase

activity of Src. The negative regulatory tail of Src

contains a tyrosine at 530, the phosphorylation of

which promotes a conformational change to produce an

inactive Src molecule. Sequences within the C-

terminus of Src have been recently identified to

facilitate protein-protein interactions have been shown

to regulate Src function in addition to its kinase

activity.

Expression

Ubiquitously expressed but with particularly high

levels in brain tissue, osteoclasts and platelets.

Localisation

Predominantly cytoplasmic and/or plasma mem-brane,

the latter due to myristolation of the N-terminus.

Activated Src has also been reported in the cell nucleus

in some tumour tissues.

Function

Src can interact with a diverse array of cellular factors

allowing it to regulate a variety of normal and

oncogenic processes that ultimately result in cell

proliferation, differentiation, survival, adhe-sion,

motility, invasion and angiogenesis (Thomas and

Brugge, 1997; Summy and Gallick, 2003). Such

interacting partners include receptor tyrosine kinases

(e.g. the EGF receptor family (Biscardi et al., 1998)),

integrins (Galliher and Schiemann, 2006; Huveneers et

al., 2007), cell-cell adhesion molecules (Giehl and

Menke, 2008), in addition to STATs (Silva, 2004),

FAK (Brunton and Frame, 2008), the adaptor protein

p130Cas (Chang et al., 2008) and GPCRs (McGarrigle

and Huang, 2007). Importantly, Src can also interact

with the oestrogen receptor (Weatherman, 2008), where

it has been shown to be pivotal in both non-genomic

ER activation of signalling pathways and gene

transcription events. The ability of Src to function as

both an effector and regulator of receptor-induced

signalling allows it to mediate cross-talk between

normally distinct signalling pathways and thus regulate

a wide variety of both normal and oncogenic processes,

including proliferation, differentiation, survival,

adhesion, motility, invasion and angiogenesis.

Homology

c-Src is the prototypic member of a family of nine non-

receptor tyrosine kinases which share the same domain

structure (Src, Fyn, Yes, Lyn, Lck, Hck, Blk, Fgr and

Frk) (Erpel and Courtneidge, 1995) and are expressed

in vertebrates. All Src family members have the same

basic structure of an N-terminal, unique domain

containing a myristylation site and frequently a

palmitoylation site; regulatory SH3 and SH2 domains;

a catalytic domain that has its active site wedged

between the two lobes of the molecule, and a C-

terminal regulatory tail that contains the hallmark

regulatory tyrosine residue (Tyr527 in Src). The

activity of Src family kinases is suppressed upon

phosphorylation of Tyr527, allowing binding of the C-

terminal domain to the SH2 domain. The SH2 and SH3

domains bind phosphotyrosine and proline-rich

peptides, respectively; through these interactions, they

participate in intra- and intermolecular regulation of

kinase activity, as well as localization and substrate

recognition. Differences in the SH2 linker sequences

within Src family kinases correlate with the division of

the Src kinase family into two separate subfamilies:

Group A: Src, Fyn, Yes, Fgr and Group B: Lyn, Hck,

Lck and Blk. Frk forms a separate but linked subfamily

but with homologues also found in invertebrates. Src

family members, with the exception of Src, Fyn and

Yes, exhibit tissue-restricted distribution, being found

primarily in cells of a haematopoietic nature. Below is

a table constructed from Src homology analysis

performed by CluSTr:

Src family

member % identity* % similarity**

Fyn 75 10

Yes 73 9

Fgr 66 11

Lck 60 17

Lyn 60 17

Hck 57 17



Blk 62 13

*Percent identity between Src and protein; defined as: (Same AAs/Length of Protein 1) X100% **Percent similarity between Src and protein; defined as: (Sim. AAs/Length of Protein 1) X100%

Mutations

Somatic

The SRC family of kinases is rarely mutated in primary

human tumours, although apparently scarce, a

truncating and activating mutation in Src (at aa 531)

has been described for a small subset of advanced-stage

colorectal cancers (Irby et al., 1999).

Implicated in

Cancer

Note

Elevated Src expression and/or activity has been

reported in many different cancer types, where it may

associate with poor clinical prognosis (Irby and

Yeatman, 2000). Increased Src kinase activity in cancer

is likely to arise from the deregulation of Src

expression and/or activation mechanisms rather than

the presence of activating mutations, since genetic

mutations of this kind are rarely reported for Src (see

above). Whereas constitutively activated forms of Src

are transforming, wild-type Src has a relatively low

transformation potential suggesting that Src may act to

facilitate intracellular signalling through regulation,

either directly or indirectly, of other signalling proteins.

Colorectal cancer

Disease

Increased Src activity has been widely described in

colorectal tumour tissue compared with normal

epithelia and within colon polyps, particularly those

displaying a malignant phenotype (DeSeau et al., 1987;

Cartwright et al., 1994). In colorectal cancer tissue

studies, elevated Src kinase activity is associated with a

poor clinical outcome (Aligayer et al., 2002). In vitro

studies suggest that in colon cancer, Src may contribute

more to disease spread than to increased proliferation

(Jones et al., 2002).

Breast cancer

Disease

Src kinase activity is increased in breast cancer tissue

compared to normal tissues (Verbeek et al., 1996). In

vivo animal models suggest that Src activity is elevated

in breast tumours over-expressing HER2 and

interaction between Src and erbB family members may

promote the develop-ment of a more aggressive disease

clinically (Biscardi et al., 2000; Tan et al., 2005).

Physical interactions between Src and growth factor

receptors are reported in breast cancer tissues and cells,

particularly with receptor tyrosine kinases of the EGFR

family allowing Src to regulate signal-ling pathways

that may contribute to aggressive breast cancer cell

behaviour. Src is also intimately involved with Her2

pathway signalling in breast cancer, the result of which

is the promotion of an invasive phenotype (Vadlamudi

et al., 2003; Tan et al., 2005).

Oestrogenic signalling plays a critical role in promoting

breast cancer cell growth where ligand-induced

activation of oestrogen receptors (ERs) results in gene

transcription mediated by the ER, in complex with

various co-activators/co-repressor molecules. In such

cases, Src is able to potentiate ER-mediated, AF-1

dependent gene transcription through indirect

phosphorylation of nuclear ER via ERK1/ERK2 (Feng

et al., 2001) and Akt (Campbell et al., 2001; Shah et al.,

2005) and through regulation of FAK-p130CAS-JNK

signalling pathway activity and the subsequent

activation of co-activator molecules including CBP

(PAG1) and GRIP1 (NCOA2). Furthermore, Src

appears to mediate non-genomic ER signalling through

ERK and Akt pathways (Castoria et al., 2001; Wessler

et al., 2006) to regulate cellular proliferation and

survival (Castoria et al., 1999; Migliaccio et al., 2000).

That Src is involved in both EGFR/Her2 and ER

signalling has led to Src being implicated in growth

factor-ER cross talk mechanisms in breast cancer and

the development of endocrine resistance (Arpino et al.,

2008; Massarweh and Schiff, 2006; Hiscox et al., 2006;

Hiscox et al., 2009).

Hematopoietic cancers

Disease

The majority of Src family kinases are highly expressed

in cells of a hematopoietic origin where they are

suggested to regulate growth and prolifera-tion. Src

itself is, along with related family kinase members, are

implicated in imatinib-resistant, BCR-ABL-expressing

CML (Li, 2008).

Other tumour types

Disease

Src protein and activity have been identified as being

increased in a number of other tumour types including

gastric, pancreatic, lung and ovarian tumours compared

to normal tissue suggesting a possible role for Src in

these tumours.

References DeSeau V, Rosen N, Bolen JB. Analysis of pp60c-src tyrosine kinase activity and phosphotyrosyl phosphatase activity in human colon carcinoma and normal human colon mucosal cells. J Cell Biochem. 1987 Oct;35(2):113-28

Cartwright CA, Coad CA, Egbert BM. Elevated c-Src tyrosine kinase activity in premalignant epithelia of ulcerative colitis. J Clin Invest. 1994 Feb;93(2):509-15

Erpel T, Courtneidge SA. Src family protein tyrosine kinases and cellular signal transduction pathways. Curr Opin Cell Biol. 1995 Apr;7(2):176-82



Verbeek BS, Vroom TM, Adriaansen-Slot SS, Ottenhoff-Kalff AE, Geertzema JG, Hennipman A, Rijksen G. c-Src protein expression is increased in human breast cancer. An immunohistochemical and biochemical analysis. J Pathol. 1996 Dec;180(4):383-8

Thomas SM, Brugge JS. Cellular functions regulated by Src family kinases. Annu Rev Cell Dev Biol. 1997;13:513-609

Biscardi JS, Belsches AP, Parsons SJ. Characterization of human epidermal growth factor receptor and c-Src interactions in human breast tumor cells. Mol Carcinog. 1998 Apr;21(4):261-72

Castoria G, Barone MV, Di Domenico M, Bilancio A, Ametrano D, Migliaccio A, Auricchio F. Non-transcriptional action of oestradiol and progestin triggers DNA synthesis. EMBO J. 1999 May 4;18(9):2500-10

Irby RB, Mao W, Coppola D, Kang J, Loubeau JM, Trudeau W, Karl R, Fujita DJ, Jove R, Yeatman TJ. Activating SRC mutation in a subset of advanced human colon cancers. Nat Genet. 1999 Feb;21(2):187-90

Biscardi JS, Ishizawar RC, Silva CM, Parsons SJ. Tyrosine kinase signalling in breast cancer: epidermal growth factor receptor and c-Src interactions in breast cancer. Breast Cancer Res. 2000;2(3):203-10

Irby RB, Yeatman TJ. Role of Src expression and activation in human cancer. Oncogene. 2000 Nov 20;19(49):5636-42

Migliaccio A, Castoria G, Di Domenico M, de Falco A, Bilancio A, Lombardi M, Barone MV, Ametrano D, Zannini MS, Abbondanza C, Auricchio F. Steroid-induced androgen receptor-oestradiol receptor beta-Src complex triggers prostate cancer cell proliferation. EMBO J. 2000 Oct 16;19(20):5406-17

Campbell RA, Bhat-Nakshatri P, Patel NM, Constantinidou D, Ali S, Nakshatri H. Phosphatidylinositol 3-kinase/AKT-mediated activation of estrogen receptor alpha: a new model for anti-estrogen resistance. J Biol Chem. 2001 Mar 30;276(13):9817-24

Castoria G, Migliaccio A, Bilancio A, Di Domenico M, de Falco A, Lombardi M, Fiorentino R, Varricchio L, Barone MV, Auricchio F. PI3-kinase in concert with Src promotes the S-phase entry of oestradiol-stimulated MCF-7 cells. EMBO J. 2001 Nov 1;20(21):6050-9

Feng W, Webb P, Nguyen P, Liu X, Li J, Karin M, Kushner PJ. Potentiation of estrogen receptor activation function 1 (AF-1) by Src/JNK through a serine 118-independent pathway. Mol Endocrinol. 2001 Jan;15(1):32-45

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Gene Section Review




TACC3 (transforming, acidic coiled-coil containing protein 3) Melissa R Eslinger, Brenda Lauffart, Ivan H Still

Department of Chemistry and Life Science Bartlett Hall, United States Military Academy, West Point, New

York 10996, USA (MRE), Department of Physical Sciences, Arkansas Tech University, 1701 N Boulder

Ave, Russellville, AR 72801, USA (BL), Department of Biological Sciences, Arkansas Tech University,

1701 N Boulder Ave, Russellville, AR 72801, USA (IHS)


Online updated version: http://AtlasGeneticsOncology.org/Genes/TACC3ID42458ch4p16.html DOI: 10.4267/2042/44716


Identity

Other names: ERIC1; MGC117382; MGC133242

HGNC (Hugo): TACC3

Location: 4p16.3

DNA/RNA

Description

The gene is composed of 16 verified exons spanning

23.6 kb.

Transcription

Encodes a single confirmed 2788 nt transcript

(NM_006342) (Still et al., 1999), although one

additional transcript with two additional small 5' coding

exons between exon 1 and the first coding exon (exon

2), based on NM_006342, is indicated based on several

cDNAs that may however be from suspect cDNA

libraries (see UCSC Genome Bioinformatics Site

(http://genome.ucsc.edu)). Four additional transcripts

variants are suggested based on singleton Expressed

sequence tags in tumor cell lines (AW516785,

BE552327, BX331864) and/or stem cell progenitors

(AV761182, CX872433).

Pseudogene

None.

TACC3 (transforming, acidic coiled-coil containing protein 3) Eslinger MR, et al.


Protein

Description

TACC3 encodes a single protein of 838 amino acids

with a molecular mass of 90 kDa (Still et al., 1999).

The protein is heavily phosphorylated based on direct

evidence and based on predictions from the Xenopus

and mouse orthologs (Beausoleil et al., 2004;

Beausoleil et al., 2008; Kinoshita et al., 2005; Yu et al.,

2007; Cantin et al., 2008; Dephoure et al., 2008). Thus,

human TACC3 migrates at approxi-mately 150 kDa in

SDS-PAGE. Additional variants are suggested based

on singleton cDNAs (see above) but their predicted

protein isoforms have not been confirmed.

Expression

High levels during early (mouse) embryogenesis, in

particular during early differentiation of specific tissues

(Sadek et al., 2003). In adult tissues, expression is

relatively limited, with high levels noted in

hematological tissues such as the thymus, spleen and

leukocytes, and reproductive tissues, especially meiotic

cells of the testes and ovary (Still et al., 1999; Sadek et

al., 2003).



Epithelial layers of the lung, mammary gland and ovary

express TACC3 and alterations in expression are noted

during tumorigenesis (see below). Expression in human

adult tissues is summarized in Lauffart et al. 2006.

Localisation

Human (and mouse) TACC3 is located in the

interphase nucleus and/or cytosol, depending on cell

type and cancer type (Gergely et al., 2000; Aitola et al.,

2003; Lauffart et al., 2005; Jung et al., 2006;

Vettaikkorumakankauv et al., 2008). TACC3 does not

however contain a classical nuclear localisation signal

(Still et al., 1999). TACC3 associates with the

centrosome in a cell cycle dependent manner (Gergely

et al., 2000). Phosphorylation of TACC3 by Aurora A

on key serine residues is required for this interaction

(Kinoshita et al., 2005; LeRoy et al., 2007).

Overexpression of TACC3 from artificial constructs

can result in accumulation in the cytosol of some cells

resulting in oligmerisation in punctate structures

(Gergely et al., 2000).

Function

Gene knockout and knockdown studies in mouse have

indicated that TACC3 is vital for embryonic

development. A functionally null TACC3 mutant dies

during mid to late gestation due to excessive apoptosis

affecting hematopoietic and other organ systems

(Piekorz et al., 2002). Hypomorphic alleles result in

defects in mitosis affecting mesenchymal sclerotome

and therefore the axial skeleton (Yao et al., 2007).

These mutational mouse models indicate that TACC3

has a role in chromosomal alignment, separation and

cytokinesis and that TACC3 can be associated with

p53-mediated apoptosis.

TACC3 has a well characterized function in

microtubule dynamics, particularly during mitosis,

based on mutational analysis (see above) and physical

interactions with Aurora A and Aurora B kinases,

CKAP5 (ch-TOG/XMAP215) and AKAP9 via the

TACC domain (see Peset and Vernos, 2008 for

review). Interaction with CEP120 is important in

interkinetic nuclear migration and maintenance of

neural progenitor self-renewal during the development

of the neocortex (Xie et al., 2007). Phosphorylation of

Ser34, Ser552 and Ser558 by Aurora A are required for

localization to centro-somes and is necessary for

recruitment of CKAP5 and nucleation of microtubules

(Kinoshita et al., 2005; LeRoy et al., 2007). Ser25,

Thr59, Ser71, Ser317, and Ser 434 are presumed

targets for cyclin dependent kinases in mitotic HeLa

cells (Yu et al., 2007; Cantin et al., 2008; Dephoure et

al., 2008). By homology, Ser558 phosphorylation by

TPX2 is required for nucleation of microtubules in

meiotic oocytes (Brunet et al., 2008).

TACC3 also has a defined role in interphase cells as a

transcriptional cofactor for the aryl-nuclear translocator

protein (Sadek, 2000), FOG1 (Garriga-Canut and

Orkin, 2004; Simpson et al., 2004) and is a possible

indirect activator of CREB via FHL family of

coactivator/corepressor proteins (Lauffart et al.,

2007b). Roles in transcriptional regulation

have also been proposed based on TACC3 binding to

GAS41 (YEATS4) via the SDP repeat, histone acetyl

transferases hGCN5L2 (KAT2A), pCAF (KAT2B),

and retinoid X-receptor beta via the TACC domain

(Gangisetty, 2004; Lauffart et al., 2002;

Vettaikkorumakankauv et al., 2008). TACC3

functionally interacts with MBD2 bound to methylated

promoters, promoting transcription by displacement of

HDAC2 and recruitment of KAT2B (Angrisano et al.,

2006). Human TACC3 may be involved in

transcriptional termination and/or pre-mRNA splicing

through TTF2 (Leonard et al., 2003). TACC3 can

interact with BARD1, BRCA1 and p53 and has been

shown to have some protective affects against

adriamycin-mediated DNA damage in ovarian cancer

cells (Lauffart et al., 2007a). Phosphorylation of the

last amino acid of the SDP repeat, Ser434, is noted in

nuclear extracts of HeLa (Beausoleil, 2004; Beausoleil,

2006), although its functional significance is unknown.

Homology

Member of the TACC family, based on the presence of

the evolutionarily conserved approxi-

mately 200 amino acid carboxy terminal coiled coil

domain (TACC domain) (Still et al., 1999; Still et al.,

2004). TACC3 orthologues are noted in all vertebrates

sequenced to date (Still et al., 2004 and Still

unpublished). However, the central region between the

conserved N-terminal region and the TACC domain is

highly variable in size and sequence. The SDP repeats

are noted within the central region in most vertebrates

except mouse and rat (Still et al., 2004).

Mutations

Note

Somatic mutations noted in ovarian cancer samples

(Lauffart et al., 2005; Eslinger, 2006).



See legend for normal protein.

Implicated in

Ovarian cancer

Prognosis

Overexpression of TACC3 is associated with

chemoresistance in ovarian tumors (L'Esperance et al.,

2006).

Oncogenesis

Total cellular expression or nuclear localization lost in

ovarian cancer (Lauffart et al., 2005).

Non-small cell lung cancer

Prognosis

High TACC3 expression is an independent prognostic

indicator associated with significantly shorter median

survival time. TACC3 expression was correlated with

p53 expression and poor prognosis (Jung et al., 2006).

Oncogenesis

A high level of TACC3 expression was observed in

14.8% of cases of non small cell lung cancer,

predominantly of the squamous cell carcinoma type

(Jung et al., 2006).

Breast cancer

Prognosis

Loss of TACC3 is observed as a predictor of poor

prognosis in breast cancer (Conte et al., 2002).

Oncogenesis

TACC3 protein downregulated in breast cancer (Conte

et al., 2002).

Multiple myeloma

Prognosis

TACC3 overexpression correlates with the t(4;14)

translocation that is associated with poor prognosis

(Stewart et al., 2004).

Oncogenesis

TACC3 is located close to the MMSET gene that is

rearranged in t(4;14) translocation (Still et al., 1999).

This rearrangement upregulates the TACC3 gene

(Stewart et al., 2004).

Thyroid cancer

Prognosis

Reduction of expression associated with increased

malignancy in cell line models (Ulisse et al., 2007).

Oncogenesis

Analysis of differentiated thyroid cancers indicates that

TACC3 mRNA levels were either upregulated (44%)

or downregulated (56%) in tumors, in some cases

correlation was observed between TACC3 and Aurora-

A kinase (Ulisse et al., 2007). However protein analysis

was not reported.

Breakpoints

Note

Rearrangements of the human TACC3 gene have not

been described. However, translocation breakpoints in

the WHSC1 gene, associated with multiple myeloma

upregulate the intact TACC3 promoter (Stewart et al.,

2004). Tacc3 in the mouse genome is a site of proviral

integration of MoMuLV transmitted via milk from

infected mothers. This leads to upregulation of the gene

and leads to the development of lymphomas

(Chakraborty et al., 2008).

References Still IH, Vince P, Cowell JK. The third member of the transforming acidic coiled coil-containing gene family, TACC3, maps in 4p16, close to translocation breakpoints in multiple myeloma, and is upregulated in various cancer cell lines. Genomics. 1999 Jun 1;58(2):165-70



Gergely F, Karlsson C, Still I, Cowell J, Kilmartin J, Raff JW. The TACC domain identifies a family of centrosomal proteins that can interact with microtubules. Proc Natl Acad Sci U S A. 2000 Dec 19;97(26):14352-7

Sadek CM, Jalaguier S, Feeney EP, Aitola M, Damdimopoulos AE, Pelto-Huikko M, Gustafsson JA. Isolation and characterization of AINT: a novel ARNT interacting protein expressed during murine embryonic development. Mech Dev. 2000 Oct;97(1-2):13-26

Lauffart B, Howell SJ, Tasch JE, Cowell JK, Still IH. Interaction of the transforming acidic coiled-coil 1 (TACC1) protein with ch-TOG and GAS41/NuBI1 suggests multiple TACC1-containing protein complexes in human cells. Biochem J. 2002 Apr 1;363(Pt 1):195-200

Piekorz RP, Hoffmeyer A, Duntsch CD, McKay C, Nakajima H, Sexl V, Snyder L, Rehg J, Ihle JN. The centrosomal protein TACC3 is essential for hematopoietic stem cell function and genetically interfaces with p53-regulated apoptosis. EMBO J. 2002 Feb 15;21(4):653-64

Aitola M, Sadek CM, Gustafsson JA, Pelto-Huikko M. Aint/Tacc3 is highly expressed in proliferating mouse tissues during development, spermatogenesis, and oogenesis. J Histochem Cytochem. 2003 Apr;51(4):455-69

Leonard D, Ajuh P, Lamond AI, Legerski RJ. hLodestar/HuF2 interacts with CDC5L and is involved in pre-mRNA splicing. Biochem Biophys Res Commun. 2003 Sep 5;308(4):793-801

Sadek CM, Pelto-Huikko M, Tujague M, Steffensen KR, Wennerholm M, Gustafsson JA. TACC3 expression is tightly regulated during early differentiation. Gene Expr Patterns. 2003 May;3(2):203-11

Beausoleil SA, Jedrychowski M, Schwartz D, Elias JE, Villén J, Li J, Cohn MA, Cantley LC, Gygi SP. Large-scale characterization of HeLa cell nuclear phosphoproteins. Proc Natl Acad Sci U S A. 2004 Aug 17;101(33):12130-5

Gangisetty O, Lauffart B, Sondarva GV, Chelsea DM, Still IH. The transforming acidic coiled coil proteins interact with nuclear histone acetyltransferases. Oncogene. 2004 Apr 1;23(14):2559-63

Garriga-Canut M, Orkin SH. Transforming acidic coiled-coil protein 3 (TACC3) controls friend of GATA-1 (FOG-1) subcellular localization and regulates the association between GATA-1 and FOG-1 during hematopoiesis. J Biol Chem. 2004 May 28;279(22):23597-605

Simpson RJ, Yi Lee SH, Bartle N, Sum EY, Visvader JE, Matthews JM, Mackay JP, Crossley M. A classic zinc finger from friend of GATA mediates an interaction with the coiled-coil of transforming acidic coiled-coil 3. J Biol Chem. 2004 Sep 17;279(38):39789-97

Stewart JP, Thompson A, Santra M, Barlogie B, Lappin TR, Shaughnessy J Jr. Correlation of TACC3, FGFR3, MMSET and p21 expression with the t(4;14)(p16.3;q32) in multiple myeloma. Br J Haematol. 2004 Jul;126(1):72-6

Still IH, Vettaikkorumakankauv AK, DiMatteo A, Liang P. Structure-function evolution of the transforming acidic coiled coil genes revealed by analysis of phylogenetically diverse organisms. BMC Evol Biol. 2004 Jun 18;4:16

Jacquemier J, Ginestier C, Rougemont J, Bardou VJ, Charafe-Jauffret E, Geneix J, Adélaïde J, Koki A, Houvenaeghel G, Hassoun J, Maraninchi D, Viens P, Birnbaum D, Bertucci F. Protein expression profiling identifies subclasses of breast cancer and predicts prognosis. Cancer Res. 2005 Feb 1;65(3):767-79

Kinoshita K, Noetzel TL, Pelletier L, Mechtler K, Drechsel DN, Schwager A, Lee M, Raff JW, Hyman AA. Aurora A

phosphorylation of TACC3/maskin is required for centrosome-dependent microtubule assembly in mitosis. J Cell Biol. 2005 Sep 26;170(7):1047-55

Lauffart B, Vaughan MM, Eddy R, Chervinsky D, DiCioccio RA, Black JD, Still IH. Aberrations of TACC1 and TACC3 are associated with ovarian cancer. BMC Womens Health. 2005 May 26;5:8

Angrisano T, Lembo F, Pero R, Natale F, Fusco A, Avvedimento VE, Bruni CB, Chiariotti L. TACC3 mediates the association of MBD2 with histone acetyltransferases and relieves transcriptional repression of methylated promoters. Nucleic Acids Res. 2006;34(1):364-72

Beausoleil SA, Villén J, Gerber SA, Rush J, Gygi SP. A probability-based approach for high-throughput protein phosphorylation analysis and site localization. Nat Biotechnol. 2006 Oct;24(10):1285-92

Eslinger MR.. Molecular Analysis of TACC3 in ovarian cancer. MS thesis, Department of Natural Science, Roswell Park Division, SUNY Buffalo 2006. 106p.

Jung CK, Jung JH, Park GS, Lee A, Kang CS, Lee KY. Expression of transforming acidic coiled-coil containing protein 3 is a novel independent prognostic marker in non-small cell lung cancer. Pathol Int. 2006 Sep;56(9):503-9

Lauffart B, Dimatteo A, Vaughan MM, Cincotta MA, Black JD, Still IH. Temporal and spatial expression of TACC1 in the mouse and human. Dev Dyn. 2006 Jun;235(6):1638-47

L'Espérance S, Popa I, Bachvarova M, Plante M, Patten N, Wu L, Têtu B, Bachvarov D. Gene expression profiling of paired ovarian tumors obtained prior to and following adjuvant chemotherapy: molecular signatures of chemoresistant tumors. Int J Oncol. 2006 Jul;29(1):5-24

Lauffart B, Gangisetty O, Still IH.. Evolutionary conserved interaction of TACC2/TACC3 with BARD1 and BRCA1: potential implications for DNA damage response in breast and ovarian cancer. Cancer Therapy. 2007a Dec;5(2):409-416.

Lauffart B, Sondarva GV, Gangisetty O, Cincotta M, Still IH. Interaction of TACC proteins with the FHL family: implications for ERK signaling. J Cell Commun Signal. 2007 Jun;1(1):5-15

LeRoy PJ, Hunter JJ, Hoar KM, Burke KE, Shinde V, Ruan J, Bowman D, Galvin K, Ecsedy JA. Localization of human TACC3 to mitotic spindles is mediated by phosphorylation on Ser558 by Aurora A: a novel pharmacodynamic method for measuring Aurora A activity. Cancer Res. 2007 Jun 1;67(11):5362-70

Ulisse S, Baldini E, Toller M, Delcros JG, Guého A, Curcio F, De Antoni E, Giacomelli L, Ambesi-Impiombato FS, Bocchini S, D'Armiento M, Arlot-Bonnemains Y. Transforming acidic coiled-coil 3 and Aurora-A interact in human thyrocytes and their expression is deregulated in thyroid cancer tissues. Endocr Relat Cancer. 2007 Sep;14(3):827-37

Xie Z, Moy LY, Sanada K, Zhou Y, Buchman JJ, Tsai LH. Cep120 and TACCs control interkinetic nuclear migration and the neural progenitor pool. Neuron. 2007 Oct 4;56(1):79-93

Yao R, Natsume Y, Noda T. TACC3 is required for the proper mitosis of sclerotome mesenchymal cells during formation of the axial skeleton. Cancer Sci. 2007 Apr;98(4):555-62

Yu LR, Zhu Z, Chan KC, Issaq HJ, Dimitrov DS, Veenstra TD. Improved titanium dioxide enrichment of phosphopeptides from HeLa cells and high confident phosphopeptide identification by cross-validation of MS/MS and MS/MS/MS spectra. J Proteome Res. 2007 Nov;6(11):4150-62

Brunet S, Dumont J, Lee KW, Kinoshita K, Hikal P, Gruss OJ, Maro B, Verlhac MH. Meiotic regulation of TPX2 protein levels



governs cell cycle progression in mouse oocytes. PLoS One. 2008 Oct 3;3(10):e3338

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Chakraborty J, Okonta H, Bagalb H, Lee SJ, Fink B, Changanamkandat R, Duggan J. Retroviral gene insertion in breast milk mediated lymphomagenesis. Virology. 2008 Jul 20;377(1):100-9

Dephoure N, Zhou C, Villén J, Beausoleil SA, Bakalarski CE, Elledge SJ, Gygi SP. A quantitative atlas of mitotic phosphorylation. Proc Natl Acad Sci U S A. 2008 Aug 5;105(31):10762-7

Peset I, Vernos I. The TACC proteins: TACC-ling microtubule dynamics and centrosome function. Trends Cell Biol. 2008 Aug;18(8):379-88

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Eslinger MR, Lauffart B, Still IH. TACC3 (transforming, acidic coiled-coil containing protein 3). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3):305-310.





TP53INP1 (tumor protein p53 inducible nuclear protein 1) Mylène Seux, Alice Carrier, Juan Iovanna, Nelson Dusetti

INSERM U.624, Parc Scientifique de Luminy, Case 915, 13288 Marseille Cedex 9, France (MS, AC, JI,

ND)


Online updated version: http://AtlasGeneticsOncology.org/Genes/TP53INP1ID42672ch8q22.html DOI: 10.4267/2042/44717


Identity Other names: SIP; TEAP; p53DINP1; TP53INP1A;

TP53INP1B; TP53DINP1

HGNC (Hugo): TP53INP1

Location: 8q22.1

DNA/RNA

Description

Gene is ~24 kb, with 5 exons.

Transcription

Alternative splicing: 2 transcripts: TP53INP1alpha

(exons 1, 2, 3, 4 and 5 with a stop codon in the fourth

exon) and TP53INP1beta (exons 1, 2, 3 and 5 with a

stop codon in the fifth exon).

Protein

Description

2 isoforms: TP53INP1alpha, 18 kDa (164 amino acids)

and TP53INP1beta, 27 kDa (240 amino acids). Both

isoforms contain a PEST domain (sequence rich in

proline, glutamic acid, serine and threonine between

amino acids 26 and 62 found in proteins with half-lives

of less than 2 h).

Expression

In mouse: TP53INP1 is expressed in thymus, spleen

and bone marrow. It is also expressed at low levels in

heart, stomach, liver, intestine, testis, kidney and

pancreas. TP53INP1 expression is highly induced

during the acute phase of mouse experimental

pancreatitis (caerulein induced).

In cells lines: TP53INP1 is transcriptionally induced in

response to stress in a p53-dependent and independent

manner. Examples: in mouse fibroblast, it is induced

upon adriamycin, methyl-methane sulfonate, ethanol,

H2O2, UV exposure and heat shock treatment; in

neuronal cells by copper treatment; in pancreatic cancer

cell lines by gemcitabine; in pro-B cells by IL-3

deprivation or treatement with staurosporine, cisplatin,

campto-thecin, methotrexate and paclitaxel; in mouse

embryonic fibroblast (MEF), human fibroblasts and

MCF7 by gamma irradiation; in melanoma cells by UV

mimetic compound (4NQ).

TP53INP1 expression is regulated by different

transcriptional regulators: p53, E2F1, p73 (in p53-/-

cells), myc (in neuroblastoma cell lines) and PLZF (in

hematopoietic cell lines).

Localisation

Nuclear when over-expressed and in PML-bodies

(Promyelocytic leukemia protein) upon PML-IV over-

expression.

TP53INP1 (tumor protein p53 inducible nuclear protein 1) Seux M, et al.


Green boxes: exons, black lines: introns, alternative splicing for TP53INP1beta in black and TP53INP1alpha in red.

Function

TP53INP1 is a tumor suppressor gene induced with

different stress conditions. TP53INP1 overexpres-sion

leads to cell cycle arrest (G1 phase) and p53-dependent

or independent apoptosis. TP53INP1 interacts with p53

and two kinases (HIPK2, and PKCd). These kinases

phosphorylate p53 on serine 46 modifying the p53

activity. TP53INP1 can modulate the p53 and p73

transcriptional activity to potentiate pro-apoptotic

pathways. Colitis and colitis-associated cancer are

exacerbated in mice deficient for TP53INP1.

Homology

TP53INP1 is conserved between species (from fly to

human). In vertebrates, one paralog has been identified,

TP53INP2 localized on chromosome 20q11.2.

TP53INP2 is involved in autophagy.

Mutations

Note

No mutation identified.

Implicated in

Pancreatic Adenocarcinoma

Note

TP53INP1 is lost early during pancreatic cancer

progression (from the neoplasia stages PanIN2). This

downregulation seems to be important for tumour

development. TP53INP1 expression is down regulated

by the oncogenic micro-RNA miR-155 during

pancreatic cancer progression.

Disease

Sporadic cancer, very aggressive, epigenetic disease

with known mutations/deletions of p53, K-Ras,

SMAD4, p16, BRCA2, EGFR and HER2.

Prognosis

Very bad, with only 20% of patients reaching two years

of survival, and 3% after 5 years.

Breast cancer

Note

TP53INP1 expression is lost during breast cancer

development.

Disease

Mainly in female (only 1% in male). Genetic disorders

known: loss of HER2 and ER expression, mutations in

p53 and BRCA1.

Prognosis

Mortality rate: 25%.

Gastric cancer

Note

TP53INP1 expression is lost during cancer

development. The decreased expression of TP53INP1

protein may reflect the malignant grade of gastric

cancer.

Disease

10% are familial. Mutations in APC, p53, Bcl-2.

Prognosis

The 5-year survival after surgical resection is 30-50%

for patients with stage II and 10-25% for patients with

stage III.

Anaplastic carcinoma of the thyroid (ATC)

Note

TP53INP1 is overexpressed in anaplastic thyroid

carcinoma.

Disease

ATC is less than 2% of total thyroid cancer but

represents 40% of death by thyroid cancer. It is a very

aggressive cancer with early dissemination.

Prognosis

5-year survival rate is less than 10%.

References Okamura S, Arakawa H, Tanaka T, Nakanishi H, Ng CC, Taya Y, Monden M, Nakamura Y. p53DINP1, a p53-inducible gene, regulates p53-dependent apoptosis. Mol Cell. 2001 Jul;8(1):85-94

Nowak J, Tomasini R, Mattei MG, Azizi Samir LA, Dagorn JC, Dusetti N, Iovanna JL, Pébusque MJ. Assignment of tumor protein p53 induced nuclear protein 1 (TP53INP1) gene to human chromosome band 8q22 by in situ hybridization. Cytogenet Genome Res. 2002;97(1-2):140E

Tomasini R, Samir AA, Pebusque MJ, Calvo EL, Totaro S, Dagorn JC, Dusetti NJ, Iovanna JL. P53-dependent expression

TP53INP1 (tumor protein p53 inducible nuclear protein 1) Seux M, et al.


of the stress-induced protein (SIP). Eur J Cell Biol. 2002 May;81(5):294-301

Tomasini R, Samir AA, Carrier A, Isnardon D, Cecchinelli B, Soddu S, Malissen B, Dagorn JC, Iovanna JL, Dusetti NJ. TP53INP1s and homeodomain-interacting protein kinase-2 (HIPK2) are partners in regulating p53 activity. J Biol Chem. 2003 Sep 26;278(39):37722-9

Hershko T, Chaussepied M, Oren M, Ginsberg D. Novel link between E2F and p53: proapoptotic cofactors of p53 are transcriptionally upregulated by E2F. Cell Death Differ. 2005 Apr;12(4):377-83

Tomasini R, Seux M, Nowak J, Bontemps C, Carrier A, Dagorn JC, Pébusque MJ, Iovanna JL, Dusetti NJ. TP53INP1 is a novel p73 target gene that induces cell cycle arrest and cell death by modulating p73 transcriptional activity. Oncogene. 2005 Dec 8;24(55):8093-104

Vanlandingham JW, Tassabehji NM, Somers RC, Levenson CW. Expression profiling of p53-target genes in copper-mediated neuronal apoptosis. Neuromolecular Med. 2005;7(4):311-24

Ito Y, Motoo Y, Yoshida H, Iovanna JL, Nakamura Y, Kuma K, Miyauchi A. High level of tumour protein p53-induced nuclear protein 1 (TP53INP1) expression in anaplastic carcinoma of the thyroid. Pathology. 2006 Dec;38(6):545-7

Ito Y, Motoo Y, Yoshida H, Iovanna JL, Takamura Y, Miya A, Kuma K, Miyauchi A. Decreased expression of tumor protein p53-induced nuclear protein 1 (TP53INP1) in breast carcinoma. Anticancer Res. 2006 Nov-Dec;26(6B):4391-5

Jiang PH, Motoo Y, Garcia S, Iovanna JL, Pébusque MJ, Sawabu N. Down-expression of tumor protein p53-induced nuclear protein 1 in human gastric cancer. World J Gastroenterol. 2006 Feb 7;12(5):691-6

Jiang PH, Motoo Y, Sawabu N, Minamoto T. Effect of gemcitabine on the expression of apoptosis-related genes in human pancreatic cancer cells. World J Gastroenterol. 2006 Mar 14;12(10):1597-602

Kis E, Szatmári T, Keszei M, Farkas R, Esik O, Lumniczky K, Falus A, Sáfrány G. Microarray analysis of radiation response

genes in primary human fibroblasts. Int J Radiat Oncol Biol Phys. 2006 Dec 1;66(5):1506-14

Bell E, Lunec J, Tweddle DA. Cell cycle regulation targets of MYCN identified by gene expression microarrays. Cell Cycle. 2007 May 15;6(10):1249-56

Bernardo MV, Yelo E, Gimeno L, Campillo JA, Parrado A. Identification of apoptosis-related PLZF target genes. Biochem Biophys Res Commun. 2007 Jul 27;359(2):317-22

Gironella M, Seux M, Xie MJ, Cano C, Tomasini R, Gommeaux J, Garcia S, Nowak J, Yeung ML, Jeang KT, Chaix A, Fazli L, Motoo Y, Wang Q, Rocchi P, Russo A, Gleave M, Dagorn JC, Iovanna JL, Carrier A, Pébusque MJ, Dusetti NJ. Tumor protein 53-induced nuclear protein 1 expression is repressed by miR-155, and its restoration inhibits pancreatic tumor development. Proc Natl Acad Sci U S A. 2007 Oct 9;104(41):16170-5

Gommeaux J, Cano C, Garcia S, Gironella M, Pietri S, Culcasi M, Pébusque MJ, Malissen B, Dusetti N, Iovanna J, Carrier A. Colitis and colitis-associated cancer are exacerbated in mice deficient for tumor protein 53-induced nuclear protein 1. Mol Cell Biol. 2007 Mar;27(6):2215-28

Cano CE, Gommeaux J, Pietri S, Culcasi M, Garcia S, Seux M, Barelier S, Vasseur S, Spoto RP, Pébusque MJ, Dusetti NJ, Iovanna JL, Carrier A. Tumor protein 53-induced nuclear protein 1 is a major mediator of p53 antioxidant function. Cancer Res. 2009 Jan 1;69(1):219-26

Nowak J, Archange C, Tardivel-Lacombe J, Pontarotti P, Pébusque MJ, Vaccaro MI, Velasco G, Dagorn JC, Iovanna JL. The TP53INP2 protein is required for autophagy in mammalian cells. Mol Biol Cell. 2009 Feb;20(3):870-81

Nowak J, Iovanna JL. TP53INP2 is the new guest at the table of self-eating. Autophagy. 2009 Apr;5(3):383-4


Seux M, Carrier A, Iovanna J, Dusetti N. TP53INP1 (tumor protein p53 inducible nuclear protein 1). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3):311-313.

Leukaemia Section Mini Review




del(5q) in myeloid neoplasms Kazunori Kanehira, Rhett P Ketterling, Daniel L Van Dyke

FACMG, Cytogenetics Laboratory, Mayo Clinic, Rochester, Minnesota, USA (KK, RPK, DLV)


Online updated version: http://AtlasGeneticsOncology.org/Anomalies/del5qID1092.html DOI: 10.4267/2042/44718

This article is an update of: Charrin C. del(5q) in myeloid malignancies. Atlas Genet Cytogenet Oncol Haematol 1998;2(3):88-90 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity

Note

Interstitial del(5q) was first reported as a type of refractory anemia with characteristic clinical features; female

predominance (unlike other MDS), macrocytosis, erythroid hypoplasia, frequent thrombocytosis and

dysmegakaryopoiesis. It is one of the most common structural rearrangements in MDS (10%), seen as an isolated

abnormality or with additional karyotypic anomalies. It is also observed in AML, with important prognostic

significance.

del(5q) G-banding (top) - Courtesy Diane H. Norback, Eric B. Johnson, Sara Morrison-Delap Cytogenetics at theWaisman Center (1 and 5 from the left), Kazunori Kanehira, Rhett P. Ketterling, Daniel L. Van Dyke (2, 4, 6, and 7), and Jean-Luc Lai (3); R-banding (bottom), Courtesy Christiane Charrin (1 and 3), Editor (2).

Clinics and pathology

Disease

5q- syndrome

Note

The World Health Organization (WHO) defined the 5q-

syndrome as a specific type of MDS, restricting

diagnosis to the cases with isolated interstitial del(5q),

without excess blasts in the bone marrow (<5%). It also

defined a new category, therapy-related MDS/AML,

excluding cases with a history of previous

chemotherapy from 5q- syndrome MDS.

del(5q) in myeloid neoplasms Kanehira K, et al.


Clinics

As described above, cases of MDS with isolated

del(5q) show female predominance (M:F=1:1.5-4),

anemia, macrocytosis, normal or moderately decreased

WBC, normal or moderately decreased platelet count,

and dysmegakaryopoiesis.

Treatment

Supportive care including RBC transfusion for anemia

is the mainstay of treatment. It is not infrequent that

transfusions are needed for years, causing iron

overload, and increasing the risk of blood-borne

infections. Anemia of 5q- syndrome does not respond

well to erythropoietin. Leanalidomide, a Thalidomide

derivative, has been investigated for treatment of MDS

with 5q-. Lenalidomide has immunomodulatory

properties, including the suppression of pro-

inflammatory cytokine production by monocytes,

enhancement of T-cell and NK-cell activation, and

inhibition of angiogenesis. In Phase II trials in

transfusion-dependent MDS with 5q-, 168 patients

were enrolled, of whom 76% had isolated 5q- and 29%

had the 5q- syndrome. Transfusion independence was

obtained in 67%. A complete cytogenetic response was

achieved in 45% of patients. Cytogenetic response rate

was not significantly different in isolated del(5q),

del(5q) + 1 and del(5q) + >1 additional chromosome

abnormalities. Although the results of lenalidomide

treatment seem promising, it is not yet clear if the

treatment will affect the natural disease course and

prolongs survival.

Prognosis

The impact of lenalidomide on the prognosis of MDS

patients with 5q- is unknown at this point. Progression

to AML is rare (10%). With the supportive therapy, the

prognosis of 5q- syndrome is favorable, with reported

median survival ranging from 53 to 146 months. MDS

patients with 5q- plus one additional chromosome

abnormality seem to have significantly shorter survival

(with exception of loss of the Y chromosome). MDS

with 5q- as part of a complex karyotype (3 or more

abnormalities) have an unfavorable prognosis.

Disease

AML (Acute Myeloid Leukemia).

Clinics

Deletion of 5q can be observed in both de novo and

therapy related AML. It is also seen as monosomy 5. In

AML, 5q deletion is usually associated with a complex

karyotype.

Prognosis

Prognosis of AML with 5q-/-5 is generally unfavorable,

associated with rapid disease progression and poor

outcome and survival, especially when it is seen as a

part of complex karyotype.

Cytogenetics

Cytogenetics morphological

The most commonly observed interstitial deletions are

del(5)(q13q31), del(5)(q13q33), and del(5)(q22q33),

forming a commonly deleted region (CDR) at 5q31-

q32.

Cytogenetics molecular

The CDR is the approximately 1.5 Mb interval between

D5S413 and GLRA1 gene, containing around 40 genes.

No cases of 5q- syndrome have been reported to have

biallelic deletion within the CDR, and no point

mutations have been found in the genes in the region.

Recently, it is suggested that haploinsufficienty (a gene

dosage effect) of one or more of the genes mapping to

the CDR is the pathogenetic basis of the 5q- syndrome.

Ebert et al. demonstrated that impaired function of the

ribosomal subunit protein RPS14 recapitulated the

characteristic phenotype of the 5q- syndrome, a severe

decrease in the production of erythroid cells with

relative preservation of megakaryocytic cells, in normal

CD34+ human hematopoietic progenitor cells. In

addition, forced expression of RPS14 rescued the

disease phenotype in patient-derived bone marrow

cells.

Germline heterozygous mutations for two other

ribosomal proteins, RPS19 and RPS24, have recently

been described in the congenital disorder known as

Diamond-Blackfan anemia. The conge-nital anemia is

characterized by sever anemia, macrocytosis, relative

preservation of the platelet and neutrophil count,

erythroid hypoplasia in the bone marrow and an

increased risk of leukemia. The erythroid specificity of

5q- syndrome and Diamond-Blackfan anemia in

ribosomal expression is noteworthy.

Additional anomalies

By definition, an interstitial deletion of 5q must be the

sole abnormality for 5q- syndrome. However, 5q

deletion can be seen with other accompanying

abnormalities. Review of the recent Mayo Clinic cases

shows that major abnormalities include -7, +8, -20,

20q-, -13/13q-, and abnormalities in 12p, in the

descending order.

References Van den Berghe H, Cassiman JJ, David G, Fryns JP, Michaux JL, Sokal G. Distinct haematological disorder with deletion of long arm of no. 5 chromosome. Nature. 1974 Oct 4;251(5474):437-8

Pedersen B, Jensen IM. Clinical and prognostic implications of chromosome 5q deletions: 96 high resolution studied patients. Leukemia. 1991 Jul;5(7):566-73

Rubin CM, Arthur DC, Woods WG, Lange BJ, Nowell PC, Rowley JD, Nachman J, Bostrom B, Baum ES, Suarez CR. Therapy-related myelodysplastic syndrome and acute myeloid leukemia in children: correlation between chromosomal abnormalities and prior therapy. Blood. 1991 Dec 1;78(11):2982-8

del(5q) in myeloid neoplasms Kanehira K, et al.


Neuman WL, Rubin CM, Rios RB, Larson RA, Le Beau MM, Rowley JD, Vardiman JW, Schwartz JL, Farber RA. Chromosomal loss and deletion are the most common mechanisms for loss of heterozygosity from chromosomes 5 and 7 in malignant myeloid disorders. Blood. 1992 Mar 15;79(6):1501-10

Baranger L, Szapiro N, Gardais J, Hillion J, Derre J, Francois S, Blanchet O, Boasson M, Berger R. Translocation t(5;12)(q31-q33;p12-p13): a non-random translocation associated with a myeloid disorder with eosinophilia. Br J Haematol. 1994 Oct;88(2):343-7

Boultwood J, Lewis S, Wainscoat JS. The 5q-syndrome. Blood. 1994 Nov 15;84(10):3253-60

Boultwood J, Fidler C. Chromosomal deletions in myelodysplasia. Leuk Lymphoma. 1995 Mar;17(1-2):71-8

Fenaux P. Syndromes myelodysplasiques et deletion 5q. Hematologie. 1995; 1: 35-43.

Van den Berghe H, Michaux L. 5q-, twenty-five years later: a synopsis. Cancer Genet Cytogenet. 1997 Mar;94(1):1-7

Giagounidis AA, Germing U, Wainscoat JS, Boultwood J, Aul C. The 5q- syndrome. Hematology. 2004 Aug;9(4):271-7

Nishino HT, Chang CC. Myelodysplastic syndromes: clinicopathologic features, pathobiology, and molecular pathogenesis. Arch Pathol Lab Med. 2005 Oct;129(10):1299-310

Bernasconi P, Boni M, Cavigliano PM, Calatroni S, Giardini I, Rocca B, Zappatore R, Dambruoso I, Caresana M. Clinical relevance of cytogenetics in myelodysplastic syndromes. Ann N Y Acad Sci. 2006 Nov;1089:395-410

Cherian S, Bagg A. The genetics of the myelodysplastic syndromes: classical cytogenetics and recent molecular insights. Hematology. 2006 Feb;11(1):1-13

Armand P, Kim HT, DeAngelo DJ, Ho VT, Cutler CS, Stone RM, Ritz J, Alyea EP, Antin JH, Soiffer RJ. Impact of cytogenetics on outcome of de novo and therapy-related AML and MDS after allogeneic transplantation. Biol Blood Marrow Transplant. 2007 Jun;13(6):655-64

Haase D. Cytogenetic features in myelodysplastic syndromes. Ann Hematol. 2008 Jul;87(7):515-26

Kelaidi C, Eclache V, Fenaux P. The role of lenalidomide in the management of myelodysplasia with del 5q. Br J Haematol. 2008 Feb;140(3):267-78

Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW.. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th Edition; 2008;102.


Kanehira K, Ketterling RP, Van Dyke DL. del(5q) in myeloid neoplasms. Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3):314-316.

Leukaemia Section Mini Review




t(11;11)(q13;q23) Jean-Loup Huret

Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France

(JLH)


Online updated version: http://AtlasGeneticsOncology.org/Anomalies/t1111q13q23ID1541.html DOI: 10.4267/2042/44719



Epidemiology

The involvement of MLL in 11q23 and ARHGEF17 in

11q13 was ascertained in only 1 case (Teuffel et al.,

2005). It was an unusual case of treatment-related MLL

rearrangement in the absence of leukemia.

Clinics

The case reported by Teuffel et al. (2005), was a five-

year-old girl, who experienced an acute myeloid

leukemia (AML) with a variant t(8;21) and achieved

remission under treatment. Four years later, a follow-up

control of her karyotype revealed a t(11;11)(q13;q23),

in the absence of any sign of leukemia in the bone

marrow, over a period of 30 months following the

discover of the t(11;11).

Other cases of t(11;11)(q13;q23) were:

A 13-year-old girl, who have had a M4eo AML with

inv(16)(p13q22). Eleven month later, a

t(11;11)(q13;q23) was found, but bone marrow

remained normal; however, an overt M5b AML was

diagnosed 6 months later (Leblanc et al., 1994). This

case resembles the case of Teuffel.

There was also the case of a 69-year-old male patient

with a primary M4 AML, who died 5 months after

diagnosis, and an AML (not classified) female patient

(Testa et al., 1985; Mackinnon and Campbell, 2007).

Cytology

In the case reported by Teuffel, the MLL-ARHGEF17

was only seen in the myeloid lineage. The myeloid

differentiation was not perturbed by the presence of the

chimeric protein, and normal mature myeloid cells

carrying the chimeric protein were found in normal

amounts.

Cytogenetics

Cytogenetics morphological

The t(11;11) was apparently the sole anomaly in 3 of

the 4 cases; a complex karyotype with del(5q), a

marker chromosome, and other anomalies was found in

the case reported by Mackinnon and Campbell, 2007.

Genes involved and proteins

ARHGEF17

Location

11q13

Protein

Guanine nucleotide exchange factor (GEF) for RhoA

GTPases. Involved in transduction of various signals

into downstream signaling cascades.

MLL

Location

11q23

DNA/RNA

36 exons, multiple transcripts 13-15 kb.

Protein

3969 amino acids; 431 kDa; contains two DNA binding

motifs (a AT hook and a CXXC domain), a DNA

methyl transferase motif, a bromodomain. MLL is

cleaved by taspase 1 into 2 proteins before entering the

nucleus, called MLL-N and MLL-C.

The FYRN and FRYC domains of native MLL

associate MLL-N and MLL-C in a stable complex; they

form a multiprotein complex with transcription factor

TFIID. MLL is a transcriptional regulatory factor. MLL

can be associated with more than 30 proteins, including

t(11;11)(q13;q23) Huret JL


the core components of the SWI/SNF chromatin

remodeling complex and the transcription complex

TFIID. MLL binds pro-motors of HOX genes through

acetylation and methylation of histones. MLL is a

major regulator of hematopoesis and embryonic

development.

Result of the chromosomal anomaly

Hybrid gene

Description

The fusion between MLL and ARHGEF17 occurred in

introns 12 and 1 respectively.

References Testa JR, Misawa S, Oguma N, Van Sloten K, Wiernik PH. Chromosomal alterations in acute leukemia patients studied with improved culture methods. Cancer Res. 1985 Jan;45(1):430-4

Leblanc T, Hillion J, Derré J, Le Coniat M, Baruchel A, Daniel MT, Berger R. Translocation t(11;11)(q13;q23) and HRX gene rearrangement associated with therapy-related leukemia in a child previously treated with VP16. Leukemia. 1994 Oct;8(10):1646-8

Teuffel O, Betts DR, Thali M, Eberle D, Meyer C, Schneider B, Marschalek R, Trakhtenbrot L, Amariglio N, Niggli FK, Schäfer BW. Clonal expansion of a new MLL rearrangement in the absence of leukemia. Blood. 2005 May 15;105(10):4151-2

Mackinnon RN, Campbell LJ. Dicentric chromosomes and 20q11.2 amplification in MDS/AML with apparent monosomy 20. Cytogenet Genome Res. 2007;119(3-4):211-20


Huret JL. t(11;11)(q13;q23). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3):317-318.

Leukaemia Section Short Communication




t(11;19)(q23;p13.3) MLL/ACER1 Jean-Loup Huret


(JLH)


Online updated version: http://AtlasGeneticsOncology.org/Anomalies/t1119q23p13ID1540.html DOI: 10.4267/2042/44720



Disease

Acute lymphocytic leukemia (ALL)

Epidemiology

Only one case to date, a case of congenital leukemia

(Lo Nigro et al., 2002).


MLL

Location

11q23

DNA/RNA

36 exons, multiple transcripts 13-15 kb.

Protein

3969 amino acids; 431 kDa; contains two DNA binding

motifs (a AT hook and a CXXC domain), a DNA

methyl transferase motif, a bromodomain. MLL is

cleaved by taspase 1 into 2 proteins before entering the

nucleus, called MLL-N and MLL-C. The FYRN and

FRYC domains of native MLL associate MLL-N and

MLL-C in a stable complex; they form a multiprotein

complex with transcription factor TFIID. MLL is a

transcriptional regulatory factor. MLL can be

associated with more than 30 proteins, including the

core components of the SWI/SNF chromatin

remodeling complex and the transcription complex

TFIID. MLL binds pro-motors of HOX genes through

acetylation and methylation of histones. MLL is a

major regulator of hematopoesis and embryonic

development.

ACER1

Location

19p13.3

Protein

ACER1 is the alkaline ceramidase 1. Ceramidases

catalyze hydrolysis of ceramide to generate sphingosine

(SPH), which is phosphorylated to form sphingosine-1-

phosphate (S1P). Ceramide, SPH, and S1P are

bioactive lipids that mediate cell proliferation,

differentiation, apoptosis, adhesion and migration (Mao

and Obeid, 2008).

Result of the chromosomal anomaly

Hybrid gene

Description

5' MLL - 3' ACER1; fusion of MLL intron 8 to

ACER1.

References Lo Nigro L, Slater DJ, Rappaport EF, Biondi A, Maude S, Megnigal MD, Bungaro S, Schiliro G, Felix CA.. Two partner genes of MLL and additional heterogeneity in t(11;19)(q23;p13) translocations. Blood 2002; 2080 p531a.

Mao C, Obeid LM. Ceramidases: regulators of cellular responses mediated by ceramide, sphingosine, and sphingosine-1-phosphate. Biochim Biophys Acta. 2008 Sep;1781(9):424-34


Huret JL. t(11;19)(q23;p13.3) MLL/ACER1. Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3):319.

Leukaemia Section Short Communication




t(2;5)(p21;q33) Jean-Loup Huret


(JLH)


Online updated version: http://AtlasGeneticsOncology.org/Anomalies/t0205p21q33ID1511.html DOI: 10.4267/2042/44721



Disease Atypical myeloproliferative disease with eosino-philia

Epidemiology One case to date, a 73-year-old female patient

(Gallagher et al., 2008).

Prognosis The patient was alive and well after 3 years of therapy

with imatinib.

Cytogenetics Cytogenetics morphological The t(2;5) was the sole anomaly.

Genes involved and proteins SPTBN1

Location

2p16.2 is the exact location

Protein

SPTBN1 (spectrin beta1 non erythrocytic), also called

beta-fodrin, is a cytoskeleton protein. Forms dimers

with alpha-fodrin (SPTAN1, 9q34), which self-

associates head-to-head into tetramers. Mem-brane

skeleton protein associated with ion channels and

pumps (Winkelmann and Forget, 1993); Stabilizes cell

surface membranes; role in mitotic spindles assembly

(Bennett and Baines, 2001).

PDGFRB

Location

5q33

Protein

Comprises an extracellular part with 5 Ig-like C2 type

domains, a transmembrane domain, and an intracellular

part with a tyrosine kinase domain (made of two

tyrosine kinase subdomains) for transduction of the

signal. Receptor tyrosine kinase; receptor for PDGFB

and PDGFD (Bergsten et al., 2001); forms

homodimers, or heterodimer with PDGFRA; upon

dimerization, subsequent activa-tion by

autophosphorylation of the tyrosine kinase intracellular

domains occurs.

Result of the chromosomal anomaly Fusion protein

Description

Constitutive activation of the PDGFRB tyrosine kinase

domain.

References Winkelmann JC, Forget BG. Erythroid and nonerythroid spectrins. Blood. 1993 Jun 15;81(12):3173-85

Bennett V, Baines AJ. Spectrin and ankyrin-based pathways: metazoan inventions for integrating cells into tissues. Physiol Rev. 2001 Jul;81(3):1353-92

Bergsten E, Uutela M, Li X, Pietras K, Ostman A, Heldin CH, Alitalo K, Eriksson U. PDGF-D is a specific, protease-activated ligand for the PDGF beta-receptor. Nat Cell Biol. 2001 May;3(5):512-6

Gallagher G, Horsman DE, Tsang P, Forrest DL. Fusion of PRKG2 and SPTBN1 to the platelet-derived growth factor receptor beta gene (PDGFRB) in imatinib-responsive atypical myeloproliferative disorders. Cancer Genet Cytogenet. 2008 Feb;181(1):46-51


Huret JL. t(2;5)(p21;q33). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3):320.

Solid Tumour Section Review




Head and Neck: Ear: Endolymphatic Sac Tumor (ELST) Rodney C Diaz

Department of Otolaryngology-Head and Neck Surgery, University of California Davis Medical Center,

Sacramento, California 95817, USA (RCD)


Online updated version: http://AtlasGeneticsOncology.org/Tumors/EndolymphaticSacTumID5096.html DOI: 10.4267/2042/44722


Identity

Alias

Low Grade Papillary Adenocarcinoma of the

Endolymphatic Sac, Papillary Adenoma of the

Endolymphatic Sac.

Note

Endolymphatic sac tumors (ELSTs) are rare tumors of

the petrous temporal bone. Classified as mastoid

papillary tumors of unknown origin, these tumors were

synthesized into a new, distinct clinico-pathological

entity by Heffner in 1989. Initially described as a low

grade papillary adenocarcinoma, their histologic

appearance and apparent lack of metastatic potential

has since persuaded most practitioners to reclassify

them as papillary adenomas. ELSTs can arise

sporadically or in association with von Hippel-Lindau

(VHL) disease.

Classification

Note

The differential diagnosis for ELSTs includes all

intrinsic temporal bone neoplasms (most commonly

paraganglioma) as well as metastatic papillary thyroid

carcinoma, metastatic renal cell carcinoma, and choroid

plexus papilloma, the latter three of which are similar

in appearance to ELSTs histologically.


Disease

Endolymphatic sac tumors are rare. As a recognized,

distinct entity, ELSTs are relatively new.

The first reported case of a tumor arising from the

endolymphatic sac was discovered during

decompression of the endolymphatic sac for presumed

unilateral Ménière's Disease in 1984.

Although benign, ELSTs can be locally destructive.

They present with hearing loss, tinnitus, facial nerve

weakness or paralysis, vertigo, and can be lethal. CT

imaging demonstrates erosion of the posterior petrous

temporal bone with occasional intratumoral

calcification. MRI tumor signal is isointense to brain

and demonstrates gadolinium enhancement and

heterogeneous signal intensity from intratumoral

calcification and vascularity.

Etiology

The synthesis of sporadic temporal bone papillary

tumors into a distinct clinicopathological entity was

proposed in 1989 by Heffner, with the anatomic origin

of these tumors being the endolymphatic sac.

Knowledge of this tumor has grown, expedited in part

by its association with VHL disease, yet many aspects

are still poorly understood.

Head and Neck: Ear: Endolymphatic Sac Tumor (ELST) Diaz RC


MRI T1 weighted axial images of the brain at the level of the endolymphatic sac and internal auditory canal. The top view without gadolinium contrast shows moderate expansion of the endolymphatic sac and duct on the right. The bottom view with gadolinium contrast shows contrast enhancement of the endolymphatic sac on the right.

CT axial image of the temporal bones at the level of the endolymphatic sac and internal auditory canals. The vestibular aqueduct on the right is markedly widened directly behind the internal auditory canal and vestibule, in contrast to the appearance of the vestibular aqueduct on the left, which is thin and nondescript. The bony erosion and widening of the vestibular aqueduct on the right is highly suggestive of a neoplastic or otherwise destructive process within the endolymphatic sac, consistent with an ELST.



Initially described as a low grade papillary

adenocarcinoma, the histologic appearance and

apparent lack of metastatic potential of these tumors

has convinced some to reclassify them as benign

papillary adenomatous tumors. The high overall

survival following surgical resection, despite locally

aggressive behavior, is likely due to the underlying

benign histology of the tumor.

Epidemiology

Over 175 case reports of ELSTs have now been

reported in the literature. The majority of these are

single case reports of a practice group or university.

As the majority of these case reports do not disclose the

population size of their patient base, it is difficult to

assess the true incidence of these tumors. ELSTs tend

to afflict women more than men with an overall female

to male ratio of 2:1 in a review of the literature.

Clinics

The most common presenting complaints were aural,

with hearing loss occurring in neary every reported

patient, followed by tinnitus, aural fullness, and

imbalance. The symptoms of pulsatile tinnitus, otalgia,

otorrhea, vertigo, and facial paresis were also present in

some patients. Cranial neuropathies were also

diagnosed either at the time of presentation or

following treatment. The most commonly involved

nerve was the facial nerve, with preoperative facial

paresis or paralysis in 43% of patients. In patients with

larger tumors or in those who delayed presentation for

decades after onset of initial symptoms, multiple

cranial neuropathies were present including trigeminal,

glossopharyngeal, and vagal nerves.

From a statistical standpoint, a vascular tumor eroding

the temporal bone and cranial base is likely to be a

paraganglioma, and likely a glomus jugulare

tumor. Large glomus tumors as well as large ELSTs

can both present as pink or purple masses encroaching

on the middle ear and external auditory canal. Glomus

tumors exhibit a characteristic "salt and pepper" tumor

appearance on MRI, but this heterogeneity in signal

reflects the vascularity of such tumors and is not

pathognomonic. The heterogeneity in signal seen in

large ELSTs - arising from hypervascularity as well as

intra-tumoral hemorrhage and/or calcification - can

often mimic glomus tumors in this respect. This is not

necessarily problematic, as management would proceed

similarly for either histologic type of tumor: pre-

operative embolization followed by total tumor

resection via the appropriate lateral skull base

approach.

Pathology

ELSTs are highly vascular and are comprised of

papillary cystic structures lined with a simple cuboidal

or columnar epithelium. Siderophages and cholesterol

clefts are seen, as are clear, vacuolated cells. Nuclear

pleomorphism is not pronounced, and mitoses are rare.

Immunohistochemistry and special staining may aid in

differentiation of papillary tumors of question-able

origin. ELSTs usually stain positive for cytokeratin,

vimentin, and epithelial membrane antigen, as well as

stain on Periodic acid-Schiff (diastase sensitive). Some

papers have also reported sensitivity to glial fibrillary

acid protein; however, most authors have had poor

tumor reactivity to glial fibrillary acid protein. Papillary

thyroid metastasis to the temporal bone may be

differentiated by positive reaction to thyroglobulin

immunohisto-chemistry.

Transthyretin has been shown to exhibit differential

expression in choroid plexus papillomas with little to

no expression in ELSTs.

MRI T1 weighted images of the brain, showing a very large ELST of the left temporal bone, in axial view on the left and coronal view on the right. There has been complete erosion of the petrous temporal bone by the tumor, with significant brainstem and cerebellar compression.



Histological appearance of ELST. HE stain, low power magnification, demonstrating the characteristic papillary cystic architecture of these tumors.

Treatment

Surgical resection is the primary modality of treatement

for ELSTs. Despite the benign histologic nature of

these tumors, complete resection appears crucial for

ensuring success. Total tumor resection is clearly the

treatment of choice, as only one patient with reported

complete resection had subsequent recurrence.

Although the most common presenting symptom was

sensorineural hearing loss, many patients, particularly

those with VHL disease, present with small ELSTs and

consequently present with serviceable hearing. VHL

patients are unique in that all undergo active

surveillance and cranial imaging for hemangioblastoma

as part of their VHL disease management.

Subsequently, ELSTs in these patients are frequently

diagnosed early, with relatively little delay between

onset of audio-vestibular symptoms and identification

of tumor. This significantly affected surgical decision

making, as 32% of patients underwent hearing

conservation procedures while 68% underwent hearing

ablative procedures. In patients with excellent

preoperative hearing and a small ELST, such a hearing

conservation approach may be warranted. However, the

completeness of tumor resection should not be

compromised for the sake of hearing conservation. Half

of patients undergoing hearing conservation approaches

with subtotal resection followed by adjuvant radiation

therapy had regrowth of tumor.

In some tumors, total resection cannot be achieved

without risk of catastrophic loss of function or death,

and in these patients subtotal resection may be

warranted. Patients who have subtotal resection may

benefit from postoperative radiotherapy, but there still

remains a roughly 50% risk of tumor regrowth and

therefore close surveillance is warranted as re-resection

may be necessary. Stereotactic radiotherapy has shown

no increased benefit above standard fractionated

radiotherapy in survival or recurrence rates, and



subtotal resection followed by stereotactic radiotherapy

has uniformly resulted in tumor regrowth. There are no

reported cases of radiation therapy and/or stereotactic

radiotherapy used as the primary modality of treatment

for ELSTs.

Evolution

There are currently no reported cases of spontaneous

metastatic dissemination of ELSTs in the literature.

Recently however, two reports have surfaced

describing metastatic disease following subtotal

resection. The first was a reported case of ELST drop

metastasis with dissemination onto the ipsilateral

cerebellar convexity beyond the original tumor site in a

patient who had undergone previous subtotal resection

and radiotherapy. A second case of drop metastasis of

ELST involved the spine, manifesting after multiple

subtotal resections and three courses of stereotactic

radiosurgery.

These seminal reports serve to illustrate the importance

of complete tumor removal on initial resection in order

to minimize both recurrence and metastatic seeding.

The oncologic principle of complete tumor extirpation

on primary resection is certainly applicable to ELSTs,

despite their benign histology and absence of

spontaneous metastasis.

Prognosis

Overall survival characteristics for all reported cases of

ELSTs are: 74% no evidence of disease, 20% alive

with disease, and 4% died of disease, for the reporting

periods.

ELSTs are histologically benign yet sometimes

destructive, highly aggressive lesions. They show

excellent response to primary surgical resection, with

or without adjuvant radiotherapy. Complete tumor

removal on initial resection is crucial. Hearing

preservation should not take precedence over complete

tumor removal, as adjuvant radiotherapy does not

ensure against tumor recurrence, which can be

devastating and lethal. In addition, drop metastases

following subtotal tumor resection have now been

reported. In patients with VHL disease, regularly

scheduled audiometry and surveillance MRI are vital to

early detection of ELSTs, which can optimize the

opportunity for hearing preservation without

compromising tumor control.

Genetics

Note

The current literature suggests that approximately one

third of all ELSTs are associated with VHL disease.

VHL disease is an autosomal dominant familial cancer

syndrome. VHL disease affects approximately 1 in

39,000 people. It encompasses a variety of neoplasia

both benign and malignant including renal cell

carcinomas, central nervous system

hemangioblastomas, retinal hemangioblas-tomas,

pheochromocytomas, and cysts of the kidneys,

pancreas, and epididymis.

The gene responsible for VHL disease is a tumor

suppressor and it has been mapped to chromosome

3p25. The VHL gene product pVHL forms a multi-

protein complex that contains elongin B, elongin C,

Cul-2, and Rbx1.

The pVHL complex has a role in oxygen sensing. The

VHL gene regulates vascular endothelial growth factor

VEGF, and inactivation of the gene promotes VEGF

overexpression and angiogenesis. In addition, its loss of

function mutation can increase expression of hypoxia-

inducible factor HIF1, stimulating angiogenesis and

tumorigenesis. In VHL disease, it is believed that

tumors arise when both an inherited germline mutation

and a loss-of-function mutation of the wild-type VHL

gene are present.

In addition, it has been shown that somatic mutations to

the VHL gene locus at 3p25/26 are detected even in

cases of sporadic ELSTs, that is, in non-VHL patients.

Genetic sequencing analysis of the 3p25 VHL gene

locus in both sporadic and VHL-associated ELSTs

demonstrates nucleotide substitution as well as

deletion/frameshift errors.

Even though temporal bone lesions were described in

patients by Lindau in 1926, the association of these

tumors with VHL disease was not made until recently.

This clinical association has been confirmed at the

molecular level with mutations in the VHL gene

identified in endolymphatic sac tumors in VHL

patients. Approximately 10% of patients with VHL

disease have ELSTs, and approximately 30% of VHL

patients with ELSTs have bilateral tumors. This

variable phenotypic expression may be a reflection of

VHL gene function secondary to the type of mutation

present.

Indeed, VHL disease has been found to have

phenotypic expression consistent within members of a

family, thus implying a singular, conserved mutation

within affected families. VHL disease is categorized

into two familial types, with type 1 being without

pheochromocytomas and type 2 being with

pheochromocytomas. There is further subclassification

of type 2 into type 2a, low risk for developing renal cell

carcinoma, and type 2b, high risk for developing renal

cell carcinoma. Clinical presentation type correlates

with genetic mutation type: type 1 families usually

have deletion or truncation mutations, whereas type 2

families usually have missense mutations.

If a family history of VHL disease exists, or if the

diagnosis of VHL disease is made in the absence of an

ELST, then early routine audiologic screening can

allow for early tumor detection and the possibility of

hearing preservation surgery should ELST develop.

Positive identification of tumor on MRI with

gadolinium is necessary prior to surgery: to date,



surgical exploration in VHL patients with

audiovestibular symptoms but without MRI abnor-

mallities has not been documented and is not

recommended.


VHL

Location

3p25.3

DNA / RNA

The VHL gene is a tumor suppressor gene mapped to

chromosome 3p25/26.

Protein

The VHL gene product, pVHL, forms a multi-protein

complex that contains elongin B, elongin C, Cul-2, and

Rbx1.

References Schindler RA. Histopathology of the human endolymphatic sac. Am J Otol. 1981 Oct;3(2):139-43

Hassard AD, Boudreau SF, Cron CC. Adenoma of the endolymphatic sac. J Otolaryngol. 1984 Aug;13(4):213-6

Heffner DK. Low-grade adenocarcinoma of probable endolymphatic sac origin A clinicopathologic study of 20 cases. Cancer. 1989 Dec 1;64(11):2292-302

Latif F, Tory K, Gnarra J, Yao M, Duh FM, Orcutt ML, Stackhouse T, Kuzmin I, Modi W, Geil L. Identification of the von Hippel-Lindau disease tumor suppressor gene. Science. 1993 May 28;260(5112):1317-20

Lo WW, Applegate LJ, Carberry JN, Solti-Bohman LG, House JW, Brackmann DE, Waluch V, Li JC. Endolymphatic sac tumors: radiologic appearance. Radiology. 1993 Oct;189(1):199-204

Chen F, Kishida T, Yao M, Hustad T, Glavac D, Dean M, Gnarra JR, Orcutt ML, Duh FM, Glenn G. Germline mutations in the von Hippel-Lindau disease tumor suppressor gene: correlations with phenotype. Hum Mutat. 1995;5(1):66-75

Megerian CA, McKenna MJ, Nuss RC, Maniglia AJ, Ojemann RG, Pilch BZ, Nadol JB Jr. Endolymphatic sac tumors: histopathologic confirmation, clinical characterization, and implication in von Hippel-Lindau disease. Laryngoscope. 1995 Aug;105(8 Pt 1):801-8

Manski TJ, Heffner DK, Glenn GM, Patronas NJ, Pikus AT, Katz D, Lebovics R, Sledjeski K, Choyke PL, Zbar B, Linehan WM, Oldfield EH. Endolymphatic sac tumors. A source of morbid hearing loss in von Hippel-Lindau disease. JAMA. 1997 May 14;277(18):1461-6

Vortmeyer AO, Choo D, Pack SD, Oldfield E, Zhuang Z. von Hippel-Lindau disease gene alterations associated with

endolymphatic sac tumor. J Natl Cancer Inst. 1997 Jul 2;89(13):970-2

Noujaim SE, Pattekar MA, Cacciarelli A, Sanders WP, Wang AM. Paraganglioma of the temporal bone: role of magnetic resonance imaging versus computed tomography. Top Magn Reson Imaging. 2000 Apr;11(2):108-22

Vortmeyer AO, Huang SC, Koch CA, Governale L, Dickerman RD, McKeever PE, Oldfield EH, Zhuang Z. Somatic von Hippel-Lindau gene mutations detected in sporadic endolymphatic sac tumors. Cancer Res. 2000 Nov 1;60(21):5963-5

Hamazaki S, Yoshida M, Yao M, Nagashima Y, Taguchi K, Nakashima H, Okada S. Mutation of von Hippel-Lindau tumor suppressor gene in a sporadic endolymphatic sac tumor. Hum Pathol. 2001 Nov;32(11):1272-6

Ferreira MA, Feiz-Erfan I, Zabramski JM, Spetzler RF, Coons SW, Preul MC. Endolymphatic sac tumor: unique features of two cases and review of the literature. Acta Neurochir (Wien). 2002 Oct;144(10):1047-53

Megerian CA, Haynes DS, Poe DS, Choo DI, Keriakas TJ, Glasscock ME 3rd. Hearing preservation surgery for small endolymphatic sac tumors in patients with von Hippel-Lindau syndrome. Otol Neurotol. 2002 May;23(3):378-87

Bambakidis NC, Megerian CA, Ratcheson RA. Differential grading of endolymphatic sac tumor extension by virtue of von Hippel-Lindau disease status. Otol Neurotol. 2004 Sep;25(5):773-81

Kim WY, Kaelin WG. Role of VHL gene mutation in human cancer. J Clin Oncol. 2004 Dec 15;22(24):4991-5004

Lonser RR, Kim HJ, Butman JA, Vortmeyer AO, Choo DI, Oldfield EH. Tumors of the endolymphatic sac in von Hippel-Lindau disease. N Engl J Med. 2004 Jun 10;350(24):2481-6

Kim HJ, Butman JA, Brewer C, Zalewski C, Vortmeyer AO, Glenn G, Oldfield EH, Lonser RR. Tumors of the endolymphatic sac in patients with von Hippel-Lindau disease: implications for their natural history, diagnosis, and treatment. J Neurosurg. 2005 Mar;102(3):503-12

Patel NP, Wiggins RH 3rd, Shelton C. The radiologic diagnosis of endolymphatic sac tumors. Laryngoscope. 2006 Jan;116(1):40-6

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Solid Tumour Section Mini Review




Lymphangioleiomyoma Connie G Glasgow, Angelo M Taveira-DaSilva, Joel Moss

Translational Medicine Branch, NHLBI, NIH, Building 10, Room 6D05, MSC 1590, Bethesda, Maryland

20892-1590, USA (CGG, AMTD, JM)


Online updated version: http://AtlasGeneticsOncology.org/Tumors/LymphangioleiomyomaID5868.html DOI: 10.4267/2042/44723


Classification

Note

Lymphangioleiomyoma is a benign neoplasm of

lymphatic vessels characterized as a PEComa

(perivascular epithelioid cell tumour), involving the

proliferation of epithelioid cells, with mutations in the

tuberous sclerosis complex (TSC) genes TSC1 and

TSC2.


Note

Lymphangioleiomyomas are commonly associated with

lymphangioleiomyomatosis (LAM), a multi-system

disorder primarily affecting women of child-bearing

age. Initial presentation of LAM may

result from pulmonary or extrapulmonary lesions.

Pulmonary LAM is characterized by thin-walled cysts,

which are diffused throughout the lungs. Patients with

these lesions experience deterioration of lung function

that can lead to oxygen depen-dency, lung

transplantation or death. Extrapul-monary LAM

involves the axial lymphatics of the abdomen and

thorax (lymphangioleiomyomas, adenopathy), and

abdominal organs, especially the kidneys

(angiomyolipomas).

Abdomino-pelvic lymphangioleiomyomas may present

with abdominal pain as an acute abdomen, with a

neuropathy or with abdominal bloating. Thoraco-

abdominal lymphadenopathy and lymph-

angioleiomyomas, along with chylothorax (Figure 1) or

ascites may suggest the presence of a malignant

lymphoproliferative disease.

Figure 1: Large left chylous pleural effusion (white arrow) in a patient with LAM.

Lymphangioleiomyoma Glasgow CG, et al.


Figure 2 A, B, C, D, and E. Histological characterization of extrapulmonary LAM. LAM cells form fascicles separated by lymphatic channels (A). (HE, original magnification x 100) An example of LAM cells arranged in trabecular bundles and irregular papillary patterns (B). (H&E, original magnification x 250) Image representing morphological heterogeneity of LAM cells; large epithelioid LAM cells (asterik) and smaller, round to oval cells (arrows) (C). (H&E, original magnification x 1,000) Positive reactivity of LAM cells to HMB-45 (D). (immunoperoxidase with hematoxylin counterstain, original magnification x 400) Positive reactivity of LAM cells to SMMHC (E). (original magnification x 400). (from Matsui et al., Hum Pathol. 2000 October;31(10):1242-1248).



Etiology

LAM results from proliferation of an abnormal cell,

termed the LAM cell. LAM occurs in 30-40% of

patients with tuberous sclerosis complex, an autosomal

dominant disorder associated with mutations in the

TSC1 or TSC2 genes. Sporadic LAM is caused

presumably by cells with mutations of the TSC2 gene.

Lymphatic involvement (including

lymphangioleiomyomas) occurs less frequently in

patients with LAM/TSC, than in patients with sporadic

LAM.

Epidemiology

Lymphangioleiomyomas are present in about 16-21%

of patients with LAM.

Pathology

Histological examination of the cells lining the walls of

the extrapulmonary lesions reveal common

characteristics with pulmonary LAM cells, abnormal

smooth muscle-like cells with a mixture of epithelioid

and splindle-shaped morphologies. Cells react with

HMB-45, a monoclonal antibody against gp100 (a

premelanosomal marker), and with antibodies against

SMMHC, a smooth muscle-cell marker. Unlike the

nodular collections of the pulmonary LAM cells, the

extrapulmonary cells usually form fascicles or papillary

patterns. Both types of lesions contain slit-like

lymphatic channels (Figure 2A, B, C, D, and E).

Radiologic Imaging: Retroperitoneal lymphangio-

leiomyomas have a distinctive radiologic appearance

(Figures 3-7), and diurnal variation in size of the tumor

masses can be demonstrated by ultrasonography or

computed tomography scans (Figure 8).

Lymphangioleiomyomas are well characterized by

either ultrasonography or computed tomography

scanning, appearing as well-circumscribed lobular, thin

or thick-walled masses without evidence of necrosis or

hemorrhage. Masses greater than 3 cm in diameter are

usually cystic in appearance and many contain fluid,

presumably chyle. Lesions as large as 20 cm in

diameter have been observed. In patients with LAM,

the lesions most often occur in the retroperitoneal

region.

Treatment

There is no effective treatment for lymphangio-

leiomyomas. The lesions are usually asymptomatic,

however, ascites, peripheral edema, and compres-sion

of the bladder, bowel, pelvic veins and other viscera by

large lymphangioleiomyomata may cause severe

symptomatology, including pain, obstipation, urinary

frequency, and peripheral edema. Although surgery is

sometimes contemplated to ameliorate symptoms

caused by visceral compression, it is contraindicated,

as, in our experience; it may lead to persistent

lymphatic

leakage and intractable chylothorax and ascites.

Chylous effusions including pleural effusions are

particularly difficult to treat. Repeated thora-centeses

lead to malnutrition and may result in infectious

complications. Low fat diet with medium-chain

triglycerides and therapeutic thora-centesis should be

attempted initially. However, most patients require

pleurodesis, which may be effective if the rate of chyle

generation can be reduced. Patients should be placed on

a fat-free parenteral nutrition regimen prior to, during,

and after surgery. It is essential that good lung

expansion be obtained to ensure complete apposition of

the visceral and parietal pleura to avoid residual pleural

pockets. After a successful pleurodesis, a low fat diet

with mid-chain trigly-cerides is recommended. A

peritoneal-venous shunt may be considered for most

severe cases when the ascites is disabling and is

causing mechanical/ nutritional problems, but little

experience with this therapeutic modality in LAM is

reported. Treatment with octreotide may be considered

for those patients with disabling ascites and large

lymph-angioleiomyomata. Previous studies with

somato-statin and octreotide in other clinical settings

(e.g., traumatic damage to the lymphatics, yellow nail

syndrome) have shown a successful reduction in

chylous effusions, chyluria, ascites, and peripheral

lymphedema.

Sirolimus: The TSC1 and TSC2 genes encode

respectively, hamartin and tuberin. Although Hamartin

and tuberin may have individual functions, they are

also known to interact in a cytosolic complex.

Hamartin may play a role in the reorganization of the

actin cytoskeleton. Tuberin has roles in pathways

controlling cell growth and proliferation. It is a

negative regulator of cell cycle progression, and loss of

tuberin function shortens the G1 phase of the cell cycle.

Tuberin binds p27KIP1, a cyclin-dependent kinase

inhibitor, thereby preventing its degradation and

leading to inhibition of the cell cycle. Tuberin also

integrates signals from growth factors and energy

stores through its interaction with mTOR (mammalian

target of rapamycin). Tuberin has Rheb GAP (Ras

homolog enriched in brain GTPase-activating protein)

activity, which converts active Rheb-GTP to inactive

Rheb-GDP. Rheb regulates mTOR, a serine/threonine

kinase that phosphorylates at least two substrates: 4E-

BP1, allowing cap-dependent translation, and S6K1,

leading to translation of 5' TOP (terminal

oligopyrimidine tract)-containing RNAs.

Phosphorylation of tuberin by Akt, which is activated

by growth factors, leads to inhibition of tuberin,

resulting in cell growth and proliferation.

Phosphorylation of tuberin by AMPK (AMP-activated

kinase) activates tuberin and further promotes

inhibition of cell growth in conditions of energy

deprivation.



Figure 3. Mediastinal lymphangioleiomyoma (white arrow), located posteriorly to the descending thoracic aorta. A: aorta. Figure 4. Mediastinal lymphangioleiomyomas (white arrow), located posteriorly to the trachea. Figure 5. Large retroperitoneal lymphangioleiomyoma (white arrow) surrounding the aorta and inferior vena cava. A: aorta; IVC: inferior vena cava. Figure 6A and B. Black arrows point to large pelvic lymphangioleiomyoma (A). A complex lymphangioleiomyoma is shown marked by circle on panel B. Figure 7A, B and C. Evidence of bladder and bowel compression caused by the tumors. B: bladder.



Figure 8A, B, C and D. Diurnal variation of lymphangioleiomyomas. Abdominal ultrasound shows that the size of a lymphangioleiomyoma is greater in the evening (panel B) that in the morning (panel A). Abdominal CT scan showing also diurnal variation in tumor size from morning (panel C) to evening (panel D).

Sirolimus, an inmmunosuppressive agent, inacti-vates

mTOR. Sirolimus has been shown to induce apoptosis

of tumors in rodents and decrease the size of renal

angiomyolipomas in patients with lymph-

angioleiomyomatosis or TSC. Further, sirolimus was

effective in decreasing the size of chylous effusions and

lymphangioleiomyomas in one patient with LAM and

improved chylous effusions in another patient who

underwent lung trans-plantation.

Evolution

Lymphangioleiomyomas are thought to occur due to

the proliferation of LAM cells in lymphatic vessels,

causing obstruction and dilatation of the vessels leading

to collection of chylous material in cyst-like structures.

The cysts, when overdistended, may rupture resulting

in chylous ascites. Lymphangioleiomyomas can exhibit

diurnal variation, (visualized by CT or sonography)

with lesions increasing in size during the day. This

phenomenon can be an aid in a differential diagnosis of

a probable lymphangioleiomyoma with thick walls and

no fluid, from other mass lesions such as a lymphoma

or a sarcoma.

Prognosis

Lymphatic involvement (defined by the presence of

adenopathy and/or lymphangioleiomyomas) in patients

with LAM, is correlated with more severe lung disease

assessed by computed tomography scans.


Note

Serum levels of VEGF-D, a lymphangiogenic growth

factor, are higher in patients with LAM than those in

healthy volunteers. In addition, serum levels of VEGF-

D in patients with LAM who have

lymphangioleiomyomas and adenopathy are higher

than in patients without lymphangioleiomyomas. LAM

lung nodules demonstrate immunoreactivity for VEGF-

D. Because of these findings and reported observations

of LAM cell clusters in lymphatic channels, it has been

hypothesized that LAM-associated lymphangiogenesis,

driven by VEGF-D, may account for the dissemination

of LAM cells through the shedding of LAM cell

clusters into the lymphatic system.

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Avila NA, Kelly JA, Chu SC, Dwyer AJ, Moss J. Lymphangioleiomyomatosis: abdominopelvic CT and US findings. Radiology. 2000 Jul;216(1):147-53

Ferrans VJ, Yu ZX, Nelson WK, Valencia JC, Tatsuguchi A, Avila NA, Riemenschn W, Matsui K, Travis WD, Moss J. Lymphangioleiomyomatosis (LAM): a review of clinical and morphological features. J Nippon Med Sch. 2000 Oct;67(5):311-29

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Matsui K, Tatsuguchi A, Valencia J, Yu Z, Bechtle J, Beasley MB, Avila N, Travis WD, Moss J, Ferrans VJ. Extrapulmonary lymphangioleiomyomatosis (LAM): clinicopathologic features in 22 cases. Hum Pathol. 2000 Oct;31(10):1242-8

Avila NA, Bechtle J, Dwyer AJ, Ferrans VJ, Moss J. Lymphangioleiomyomatosis: CT of diurnal variation of lymphangioleiomyomas. Radiology. 2001 Nov;221(2):415-21

Kelly J, Moss J. Lymphangioleiomyomatosis. Am J Med Sci. 2001 Jan;321(1):17-25

Moss J, Avila NA, Barnes PM, Litzenberger RA, Bechtle J, Brooks PG, Hedin CJ, Hunsberger S, Kristof AS. Prevalence and clinical characteristics of lymphangioleiomyomatosis (LAM) in patients with tuberous sclerosis complex. Am J Respir Crit Care Med. 2001 Aug 15;164(4):669-71

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Crooks DM, Pacheco-Rodriguez G, DeCastro RM, McCoy JP Jr, Wang JA, Kumaki F, Darling T, Moss J. Molecular and genetic analysis of disseminated neoplastic cells in lymphangioleiomyomatosis. Proc Natl Acad Sci U S A. 2004 Dec 14;101(50):17462-7

Kumasaka T, Seyama K, Mitani K, Sato T, Souma S, Kondo T, Hayashi S, Minami M, Uekusa T, Fukuchi Y, Suda K. Lymphangiogenesis in lymphangioleiomyomatosis: its implication in the progression of lymphangioleiomyomatosis. Am J Surg Pathol. 2004 Aug;28(8):1007-16

Makrilakis K, Pavlatos S, Giannikopoulos G, Toubanakis C, Katsilambros N. Successful octreotide treatment of chylous pleural effusion and lymphedema in the yellow nail syndrome. Ann Intern Med. 2004 Aug 3;141(3):246-7

Ooi GC, Khong PL, Chan GC, Chan KN, Chan KL, Lam W, Ng I, Ha SY. Magnetic resonance screening of iron status in transfusion-dependent beta-thalassaemia patients. Br J Haematol. 2004 Feb;124(3):385-90

Avila NA, Dwyer AJ, Murphy-Johnson DV, Brooks P, Moss J. Sonography of lymphangioleiomyoma in lymphangioleiomyomatosis: demonstration of diurnal variation in lesion size. AJR Am J Roentgenol. 2005 Feb;184(2):459-64

Kumasaka T, Seyama K, Mitani K, Souma S, Kashiwagi S, Hebisawa A, Sato T, Kubo H, Gomi K, Shibuya K, Fukuchi Y, Suda K. Lymphangiogenesis-mediated shedding of LAM cell clusters as a mechanism for dissemination in lymphangioleiomyomatosis. Am J Surg Pathol. 2005 Oct;29(10):1356-66

Almoosa KF, McCormack FX, Sahn SA. Pleural disease in lymphangioleiomyomatosis. Clin Chest Med. 2006 Jun;27(2):355-68

Avila NA, Dwyer AJ, Rabel A, DeCastro RM, Moss J. CT of pleural abnormalities in lymphangioleiomyomatosis and comparison of pleural findings after different types of pleurodesis. AJR Am J Roentgenol. 2006 Apr;186(4):1007-12

Ryu JH, Moss J, Beck GJ, Lee JC, Brown KK, Chapman JT, Finlay GA, Olson EJ, Ruoss SJ, Maurer JR, Raffin TA, Peavy HH, McCarthy K, Taveira-Dasilva A, McCormack FX, Avila NA, Decastro RM, Jacobs SS, Stylianou M, Fanburg BL. The NHLBI lymphangioleiomyomatosis registry: characteristics of 230 patients at enrollment. Am J Respir Crit Care Med. 2006 Jan 1;173(1):105-11

Seyama K, Kumasaka T, Souma S, Sato T, Kurihara M, Mitani K, Tominaga S, Fukuchi Y. Vascular endothelial growth factor-D is increased in serum of patients with lymphangioleiomyomatosis. Lymphat Res Biol. 2006;4(3):143-52

Taveira-DaSilva AM, Steagall WK, Moss J. Lymphangioleiomyomatosis. Cancer Control. 2006 Oct;13(4):276-85

Avila NA, Dwyer AJ, Rabel A, Moss J. Sporadic lymphangioleiomyomatosis and tuberous sclerosis complex with lymphangioleiomyomatosis: comparison of CT features. Radiology. 2007 Jan;242(1):277-85

Taillé C, Debray MP, Crestani B. Sirolimus treatment for pulmonary lymphangioleiomyomatosis. Ann Intern Med. 2007 May 1;146(9):687-8

Bissler JJ, McCormack FX, Young LR, Elwing JM, Chuck G, Leonard JM, Schmithorst VJ, Laor T, Brody AS, Bean J, Salisbury S, Franz DN. Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis. N Engl J Med. 2008 Jan 10;358(2):140-51

Davies DM, Johnson SR, Tattersfield AE, Kingswood JC, Cox JA, McCartney DL, Doyle T, Elmslie F, Saggar A, de Vries PJ, Sampson JR. Sirolimus therapy in tuberous sclerosis or sporadic lymphangioleiomyomatosis. N Engl J Med. 2008 Jan 10;358(2):200-3

Glasgow CG, Avila NA, Lin JP, Stylianou MP, Moss J.. Related Articles: Serum VEGF-D levels in patients with



lymphangioleiomyomatosis (LAM) reflect lymphatic involvement. Accepted by Chest for publication October 8, 2008. in press.

Glasgow CG, Taveira-Dasilva AM, Darling TN, Moss J. Lymphatic involvement in lymphangioleiomyomatosis. Ann N Y Acad Sci. 2008;1131:206-14

Ohara T, Oto T, Miyoshi K, Tao H, Yamane M, Toyooka S, Okazaki M, Date H, Sano Y. Sirolimus ameliorated post lung transplant chylothorax in lymphangioleiomyomatosis. Ann Thorac Surg. 2008 Dec;86(6):e7-8

Weiss SW, Goldblum JR.. Enzinger and Weiss's Soft Tissue Tumors. Fourth edition; Mosby, Inc. (Elsevier) publisher 2008.


Glasgow CG, Taveira-DaSilva AM, Moss J. Lymphangioleiomyoma. Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3):327-333.



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