von Hippel-Lindau von Hippel-Lindau Syndrome (VHL)Syndrome (VHL)

Justin MeltonJustin Melton

von Hippel-Lindau Syndromevon Hippel-Lindau Syndrome

Multi-system disorder characterized by Multi-system disorder characterized by abnormal growth of blood vesselsabnormal growth of blood vessels

VHL the geneVHL the gene Tumor suppressor geneTumor suppressor gene Inherited in an Autosomal Dominant Inherited in an Autosomal Dominant

fashionfashion Mapped to chromosome 3p25-26 Mapped to chromosome 3p25-26

using genetic linkage analysisusing genetic linkage analysis Has 3 exons encoding 4.7 kb mRNAHas 3 exons encoding 4.7 kb mRNA Highly conserved sequence in Highly conserved sequence in

rodents and primatesrodents and primates Homologs in C. elegans and Homologs in C. elegans and

DrosphilaDrosphila

pVHL the proteinpVHL the protein

213 amino acid protein213 amino acid proteinHas 2 main binding or Has 2 main binding or

active sites (alpha and active sites (alpha and beta)beta)

Alpha site binds to an E3 Alpha site binds to an E3 ligaseligase

Beta site binds to HIF-1α Beta site binds to HIF-1α – a transcription factor– a transcription factor

InheritanceInheritance

Review:

Normal VHL FunctionNormal VHL Function

Normal fuction important? Uh… Normal fuction important? Uh… YEAH!YEAH!

HIF transcription factorHIF transcription factor

Knockout MiceKnockout Mice

Vhl-/- mice die in utero at day 10.5-12.5.Vhl-/- mice die in utero at day 10.5-12.5.Vhl+/- are phenotypically normal and show Vhl+/- are phenotypically normal and show

no signs of disease until up to 15 months.no signs of disease until up to 15 months.

So what if we lose it in humans?So what if we lose it in humans?

Mutations Cont.Mutations Cont.

VHL in CancerVHL in Cancer

FutureFuture

Treatments?Treatments?

Usual cancer treatments: chemotherapy, Usual cancer treatments: chemotherapy, cryotherapy, radiation and surgery.cryotherapy, radiation and surgery.

Hundreds of clinical trials currently taking Hundreds of clinical trials currently taking place involving VHL in some fashion.place involving VHL in some fashion.

Some target VHL specifically while others Some target VHL specifically while others target downstream events, such as TGFtarget downstream events, such as TGFββ transcription.transcription.

SourcesSources http://www.vhl.orghttp://www.vhl.org Kim, William and Kaelin, William Jr. “The von Kim, William and Kaelin, William Jr. “The von

Hippel-Lindau tumor suppressor protein: new Hippel-Lindau tumor suppressor protein: new insights into oxygen sensing and cancer.” insights into oxygen sensing and cancer.” Current Opinion 2003 13: pp55-60.Current Opinion 2003 13: pp55-60.

Richards, Frances. “Molecular Pathology of von Richards, Frances. “Molecular Pathology of von Hippel-Lindau disease and the VHL tumor Hippel-Lindau disease and the VHL tumor suppressor gene.” Exp. Rev. Mol. Med. 19 suppressor gene.” Exp. Rev. Mol. Med. 19 March 2001.March 2001.

http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bhttp://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowSection&rid=gnd.section.143v.View..ShowSection&rid=gnd.section.143

http://http://www.clinicaltrials.govwww.clinicaltrials.gov

Questions?Questions?