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VHL Von Hippel-Lindau syndrome

VHL Von Hippel-Lindau syndrome. 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

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VHL Von Hippel-Lindau syndrome

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  1. VHL Von Hippel-Lindau syndrome

  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 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 • 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

  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

  6. 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

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

  8. 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

  9. Retinal hemangioblastoma

  10. Cerebellar hemangioblastoma

  11. 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

  12. 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 • 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.html • 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

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