Flashcards in Von Hippel- Lindau Deck (8)
What are the most common manifestations of von Hippel-Lindau?
-Hemangioblastoma (tumor of CNS originating from vascular system
- Renal cell carcinoma
- pheochromocytoma (rare tumor of adrenal gland)
- Multiple tumors in single organ
How can VHL be applied to other diseases?
help researchers to better understand carcinogenesis
ex) recently developed biologically targeted agents for renal cell carcinoma are based on pathophysiology of VHL mutation
- VEGFR tyrosine kinase inhibitors (sunitinib & sorafenib)
Are VHL mutations always associated with inherited VHL disease?
- sporadic mutations- inactivation of both VHL genes- present in 60-70% of cases of renal cell carcinoma
Where is the VHL mutation located?
short arm of chormosome 3
What is the normal function of VHL?
- part of multiprotein complex that tags proteins for degredation by proteasome- > binds with substrate and recruits it to the complex
- normally controls HIF
What is HIF?
Heterodimeric transcription factor
- oxygen dependent (controlled by alpha subunit -beta is constituitievely expressed)
How is HUF affected by VHL mutations?
control of alpha subunit is lost -> binds to the promoter of "hypoxix inducible genes" (i.e. vascular endothelial growth factor (VEGF) & platelet derived growth factor (PDGF)) => uncontrolled growth!