1. VHL & von Hippel-Lindau syndrome
By: Michelle Ostrowski

2. DEGRADATION VIA UBIQUITINATION
DEGRADATION VIA UBIQUITINATION

3.
VHL = E3 component

4. E3 Ubiquitin Ligase Complex+
Substrate

5. Effects of Oxygen Levels
Enzyme:
Proline hydroxylase
Downstream:
EPO
VEGF
PDGF
TGF-α
(angiogenesis & erythropoeisis)

6. VHL NON-FUNCTIONAL??? Oxygen levels have no effect
VHL cannot bind HIF-1α
HIF-1 α is not degraded, binds to HIF-1β
HIF initiates transcription of downstream genes
Angiogenesis and erythropoeisis stimulated

7. HOW DOES THIS RELATE TO CANCER?
Loss of regulation
Angiogenesis = growth of blood vessels
Erythropoeisis = stimulates production
of RBCs
Tumors need extra nutrients & an increased blood supply to grow

8. What Actually Happens in the ORGANISM???
VHL -/- mice die as embryos
day
lack of placental vasculogenesis
VHL +/- mice phenotypically normal
15+ months w/o spontaneous
Targeted inactivation of
specific tissues???
- similar clinical features as
those seen in humans…
good model organism

9. ROLE IN HUMAN CANCERS FAMILIAL CASES: SPORADIC CASES:

10. Von Hippel-Lindau syndrome
Incidence of 1 in 35,000
Autosomal dominant
VHL tumor suppressor
Type 1, 2A, 2B, 2C
Estimated penetrance
of 80-90% by 65 yrs
Cerebellar
Hemangioblastoma
Retinal Angiomata

11. WHY DO TUMORS TEND TO DEVELOP IN CERTAIN LOCATIONS MORE FREQUENTLY THAN IN OTHERS?
VHL expressed throughout the body
(development + adulthood)
Expression higher in specific tissues
(Brain, urogenital system, spinal cord, sensory ganglia, eyes, bronchial epithelium)

12. Bibliography http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=608537
Weinberg, Robert A. The Biology of Cancer. New York: Garland Science, Taylor & Francis Group, LLC, ( , 225)
Gnarra, James R. Defective placental vasculogenesis causes embryonic lethality in VHL-deficient mice.
PNAS August 19, 1997 vol. 94 no
Franke, Gerlind. Alu-Alu Recombination Underlies the Vast Majority of Large VHL Germline Deletions: Molecular Characterization and Genotype-Phenotype Correlations in VHL Patients. Human Mutation, Vol. 30, No 0, 1-11, 2009
Clifford, Steven C. The pVHL-associated SCF ubiquitin ligase complex: Molecular genetic analysis of elongin B and C, Rbx1 and HIF-1a in renal cell carcinoma. Oncogene (2001) 20,
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