von Hippel-Lindau Syndrome (VHL)

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Presentation transcript:

von Hippel-Lindau Syndrome (VHL) Justin Melton

von Hippel-Lindau Syndrome Multi-system disorder characterized by abnormal growth of blood vessels

VHL the gene Tumor suppressor gene Inherited in an Autosomal Dominant fashion Mapped to chromosome 3p25-26 using genetic linkage analysis Has 3 exons encoding 4.7 kb mRNA Highly conserved sequence in rodents and primates Homologs in C. elegans and Drosphila

pVHL the protein 213 amino acid protein Has 2 main binding or active sites (alpha and beta) Alpha site binds to an E3 ligase Beta site binds to HIF-1α – a transcription factor

Inheritance

Review:

Normal VHL Function

Normal fuction important? Uh… YEAH!

HIF transcription factor

Knockout Mice Vhl-/- mice die in utero at day 10.5-12.5. Vhl+/- are phenotypically normal and show no signs of disease until up to 15 months.

So what if we lose it in humans?

Mutations Cont.

VHL in Cancer

Future

Treatments? Usual cancer treatments: chemotherapy, cryotherapy, radiation and surgery. Hundreds of clinical trials currently taking place involving VHL in some fashion. Some target VHL specifically while others target downstream events, such as TGFβ transcription.

Sources http://www.vhl.org Kim, William and Kaelin, William Jr. “The von Hippel-Lindau tumor suppressor protein: new insights into oxygen sensing and cancer.” Current Opinion 2003 13: pp55-60. Richards, Frances. “Molecular Pathology of von Hippel-Lindau disease and the VHL tumor suppressor gene.” Exp. Rev. Mol. Med. 19 March 2001. http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowSection&rid=gnd.section.143 http://www.clinicaltrials.gov

Questions?