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>