VHL Von Hippel-Lindau syndrome

VHLVon 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

• Products are involved in angiogenesis, erythropoiesis, energy metabolism, glucose transport

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

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)

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

• 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

• Treatment– Surgery to remove tumors, especially before they

get big enough to cause serious problems– Focused radiation for cancerous growths

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

Retinal hemangioblastoma

Cerebellar hemangioblastoma

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

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