2. The Function of VHL and pVHL Protein VHL is a tumor suppressor gene on chromosome 3 Helps to regulate and destroy the alpha subunit of hypoxia-inducible factor or HIF-1 HIF-1 is a transcription factor that has a myriad of target genes Products are involved in angiogenesis, erythropoiesis, energy metabolism, glucose transport

3. Different Results in Different Conditions Normoxia pVHL helps to degrade the alpha subunit of HIF-1 HIF-1α unit is created and degraded very rapidly in “futile cycle” So full HIF-1 transcription factor remains inactive Hypoxia HIF-1α does not occur, so its levels increase Can now combine with HIF- 1β to form full HIF-1 Target genes are promoted and proteins synthesized These proteins help cell survive condition Esp proteins that attract new vessels

4. Results of Activation of HIF-1 Important in Angiogenic Response Induces genes encoding: – Vascular Endothelial Growth Factor (VEGF) – Platelet-Derived Growth Factor (PDGF) – Transforming Growth Factor-α (TGF-α)

5. The Disease 1/36,000 individuals Usually appears in young adulthood Autosomal dominant 20% of the time the altered gene is new mutation  uninherited 2 copies needed for tumor and cyst formation – Caused by knockout of function – Leads to over recruitment of vessels  creation of tumors

7. Prognosis – Untreated can result in blindness or permanent brain damage – With treatment and early detection better off – Usually a 50 year life-span – Death usually occurs due to complications with kidney cancer and pheochromocytoma

8. Treatment – Surgery to remove tumors, especially before they get big enough to cause serious problems – Focused radiation for cancerous growths

9. Variety of Disease Results Mainly kidney cancer known as clear-cell Renal Cell Carcinoma or ccRCC – Main cause of disease related death (70%) Less frequently cancers in – Pancreas – Adernal gland – testes Hemangioblastomas – In CNS – Usually non-cancerous, but issue with where they develop  pressure on spinal cord, eyes, brain

10. Retinal hemangioblastoma

11. Cerebellar hemangioblastoma

12. Model Organisms Mouse, drosphilia, C. Elegens, and Zebrafish have all been studied Generally, models have shown that VHL is important in angiogenesis Double mutants are lethal embryonically

16. References Davis, S. & Uwaydat, S. (n.d.). Diagnosis and treatment of von hippel– lindau syndrome. Retrieved from http://www.aao.org/publications/eyenet/201005/pearls.cfm http://www.aao.org/publications/eyenet/201005/pearls.cfm Hsu, Y. (2012). Complex cellular functions of the von hippel–lindau tumor suppressor gene: insights from model organisms. Oncogene, 31, 2247- 2257. National Library of Medicine. (2011, November 14). Genetics home reference. Retrieved from http://ghr.nlm.nih.gov/condition/von-hippel- lindau-syndrome Stanford medicine cancer institute. (2013). Retrieved from http://cancer.stanford.edu/information/geneticsAndCancer/types/vhl.htm l Weinberg, R. A. (2007). The biology of cancer. New York: Garland Pub. William G. Kaelin Jr. (2010, october 26). National institute of neurological disorders and stroke. Retrieved from http://www.ninds.nih.gov/disorders/von_hippel_lindau http://www.ninds.nih.gov/disorders/von_hippel_lindau