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VHL & von Hippel-Lindau syndrome. By: Michelle Ostrowski. http://www.highlighthealth.com/wp-content/uploads/2007/09/ubiquitination.png. DEGRADATION VIA UBIQUITINATION. http://www.crombes.hr/ifmbe-news/ifmbe-news.iee.org/ifmbe-news/nov2004/images/nobelfig02.gif. - PowerPoint PPT Presentation
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VHL &
VON HIPPEL-LINDAU SYNDROME
By: Michelle Ostrowski
http://www.highlighthealth.com/wp-content/uploads/2007/09/ubiquitination.png
http://www.crombes.hr/ifmbe-news/ifmbe-news.iee.org/ifmbe-news/nov2004/images/nobelfig02.gif
DEGRADATION VIA UBIQUITINATION
http://www.hindawi.com/floats/720840/figures/720840.fig.001.jpg
VHL = E3 component
http://www.hindawi.com/floats/720840/figures/720840.fig.001.jpg
E3 Ubiquitin Ligase Complex
+Substrate
EFFECTS OF OXYGEN LEVELS
http://www.nature.com/nm/journal/v11/n9/images/nm0905-925-F1.jpg
Enzyme:Proline hydroxylase
Downstream:EPOVEGFPDGFTGF-α
(angiogenesis & erythropoeisis)
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
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
http://onctalk.com/wp-content/uploads/2008/01/hallmarks-of-ca.jpg
WHAT ACTUALLY HAPPENS IN THE ORGANISM???
http://www.bugmanrochester.com/pest_mice.jpg
http://www.hesca.org/past_meetings/dallas/images/bio59.jpg
VHL -/- mice die as embryos day 10.5- 12.5 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
http://www.pnas.org/content/94/17/9102.full
ROLE IN HUMAN CANCERS
SPORADIC CASES: FAMILIAL CASES:
http://www.vhl.org/gifs/0ba3soma.gif
http://www.vhl.org/gifs/0ba4gona.gif
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
Retinal Angiomat
a
Cerebellar Hemangioblastom
a
http://hmg.oxfordjournals.org/content/vol10/issue7/images/large/DDE08901.jpeg
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)
http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=608537
BIBLIOGRAPHY http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=608537 http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=193300 Weinberg, Robert A. The Biology of Cancer. New York: Garland
Science, Taylor & Francis Group, LLC, 2007. (241-246, 225) Gnarra, James R. Defective placental vasculogenesis causes
embryonic lethality in VHL-deficient mice.
PNAS August 19, 1997 vol. 94 no. 17 9102-9107
http://www.pnas.org/content/94/17/9102.full 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, 5067-5074.
<http://www.nature.com/onc/journal/v20/n36/pdf/1204602a.pdf>