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 HIF1β 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, 22472257.
• National Library of Medicine. (2011, November 14). Genetics home
reference. Retrieved from http://ghr.nlm.nih.gov/condition/von-hippellindau-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