c-MycA Biological Paradox

Ashton Butler

Table of Contents

Introduction to c-MycNormal role in the cellRelation to cancerBurkitt’s lymphoma

Introduction

Oncogene Found on Chromosome 8 Member of Myc protein family

Includes N-myc and L-myc Basic helix-loop-helix leucine zipper (bHLH/LZ)

transcription factors

bHLH/LZ Transcription Factor Structure

Normal Function c-Myc activated through dimerization with

Max leads to transcription of target genes

E-box

bHLH-LZ domain

http://myc-cancer-gene.org/documents/MycReview.pdf

bHLH/LZ Transcription Factor Structure

bHLH-LZ domain

Mad-max dimer represses transcription

Normal Roles Myc has 600+ identified

gene targets www.myc-cancer-

gene.org

Main functions: Cell proliferation Apoptosis

Hanahan and Weinberg, Cell 100:57-70 (2000)

Determining Normal Roles: Mouse Models Homozygous null mutant mice

lethal between 9.5 and 10.5 days of gestation indicates role in cell proliferation

Over-expressed mutant mice lethal 10 days-8 weeks after birth indicates role in apoptosis

http://biology.plosjournals.org/perlserv/?request=getdocument&doi=10.1371%2Fjournal.pbio.0020332

Function: Cell Proliferation Stimulates G1-S transition

Growth Factors actat the Restriction Point

c-Myc lowc-

Myc high

Function: Regulation of Apoptosis Over-expression in normal cells sensitizes the cell

to a variety of apoptotic triggers

Function: A Paradox Ability to induce proliferation while at the same time being

able to sensitize a cell to apoptosis is a “fail-safe” mechanism

c-Myc and Cancer: back to the mouse model

Double mutant adult mice tumorigenesis

Insertion of c-myc near various genetic enhancers tumorigenesis

in a variety of tissues

http://http://biology.plosjournals.org/biology.plosjournals.org/perlserv/?perlserv/?request=getdocument&doi=10request=getdocument&doi=10.1371%2Fjournal.pbio.0020332.1371%2Fjournal.pbio.0020332

c-Myc and Cancer Model: Unregulated c-Myc creates genetic

instability

G1-S checkpoint

c-Myc and Cancer

Over-expressed in 70% of all human cancers Translocated in 90% of all Burkitt’s lymphoma

cases 90% of gynecological cancers 80% of breast cancers 70% of colon cancers

Contributes to more than 70,000 cancer deaths annually in the U.S.

c-Myc and Cancer: Burkitt’s Lymphoma c-Myc was first discovered in lymphoma patients Reciprocal translocation from chromosome 8 to

chromosome 14

http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowSection&rid=gnd.section.92

http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/B/BurkittLymphoma.html

c-Myc and Cancer: Burkitt’s Lymphoma Rare but extremely aggressive cancer Predominantly affects children in Southern Africa Solid tumor of B lymphocytes High tendency to spread to CNS, bone marrow,

other blood elements

http://www.brown.edu/Courses/Digital_Path/systemic_path/female/burkitt.htmlhttp://tmcr.usuhs.mil/tmcr/chapter41/clinical.htm

Summary of c-Myc

Transcription factor Paradox: Functions in cell proliferation and

apoptosis Mouse model

Knockout: lethal (lack of cell proliferation) Over-expressed: lethal (apoptosis)

Oncogene Cancer: over-expression coupled with other

mutations (i.e. tumor suppressors) leads to tumorigenesis in a variety of tissues

References Cited Beer S, Zetterberg A, Ihrie RA, et al:Developmental Context Determines Latency of

MYC-Induced Tumorigenesis. PLoS Biology 2004, 2(11):e332. Burkitt lymphoma. Genes and Disease. http://www.ncbi.nlm.nih.gov/books/bv .fcgi?call

=bv.View..ShowSection&rid=gnd.section.92 Burkitt’s lymphoma. 27 Aug. 2004. http://users.rcn.com/jkimball.ma.ultranet/ Biology

Pages/B/BurkittLymphoma.html Cosel H: Scientists discover role for c-myc gene in tumor angiogenesis. Innovations

Report 1 Jan. 2002. http://www.innovations-report.com/ specials/ printa.php?id=13299. Gardner L, Lee L, Dang C: The c-Myc Oncogenic Transcription factor. http://myc-

cancer-gene.org/documents/ MycReview.pdf Pelengaris S, Rudolph B, Littlewood T: Action of Myc in vivo- proliferation and

apoptosis. Current Opinion in Genetics and Development 2000, 10:100-105. Nilsson JA, Cleveland JL: Myc pathways provoking cell suicide and cancer. Oncogene

2003, 22:9007-9021. Weinberg, R: The Biology of Cancer. 2007. Werner L, Leon J, Eilers M: Contributions of Myc to tumorigenesis. Biochimica et

Biophysica Acta 2001, 1602:61-71. Wyce M: Myc activates metastasis gene. Medical News Today 14 Sept. 2005.

http://www.medicalnewstoday.com/medicalnews. php?newsid=30583.