Hypoxia inducible factor-alpha binding and ubiquitylation by the von Hippel-Lindau tumor suppressor protein.

摘要: The von Hippel-Lindau tumor suppressor protein (pVHL) has emerged as a key factor in cellular responses to oxygen availability, being required for the oxygen-dependent proteolysis of alpha subunits hypoxia inducible factor-1 (HIF). Mutations VHL cause hereditary cancer syndrome associated with dysregulated angiogenesis, and up-regulation genes. Here we investigate mechanisms underlying these processes show that extracts from VHL-deficient renal carcinoma cells have defect HIF-alpha ubiquitylation activity which is complemented by exogenous pVHL. This was specific among range substrates tested. Furthermore, were only pVHL-associated proteasomal identified comparison metabolically labeled anti-pVHL immunoprecipitates proteosomally inhibited normal cells. Analysis pVHL/HIF-alpha interactions defined short sequences conserved residues within internal transactivation domains molecules sufficient recognition In contrast, while full-length pVHL p19 variant interact HIF-alpha, association abrogated further N-terminal C-terminal truncations. interaction also disrupted tumor-associated mutations beta-domain loss defective regulation, defining mechanism generate constitutively hypoxic pattern gene expression promoting angiogenesis. findings indicate regulates acting component ubiquitin ligase complex, support model its beta domain interacts subunits.