Transcript von Hippel

von Hippel-Lindau
Syndrome (VHL)
Justin Melton
von Hippel-Lindau Syndrome
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Multi-system disorder characterized by
abnormal growth of blood vessels
VHL the gene
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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
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Inheritance
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.
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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.
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Sources
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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=b
v.View..ShowSection&rid=gnd.section.143
http://www.clinicaltrials.gov
Questions?