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Hypoxia-induced pathway. In normoxia, the subunit alpha of HIFα is hydroxylated before binding to the pVHL complex and is degraded through the proteasome. During hypoxia, HIF hydroxylation is inhibited, resulting in accumulation of unhydroxylated HIF, which no longer binds to pVHL. HIF1α is therefore stabilised by dimerisation with HIF1β and translocates to the nucleus. Complexes HIF1α and HIF1β bind to hypoxia-inducible gene promoters, including the main genes implicated in angiogenesis. There is an analogy in the consequence between hypoxia and VHL gene loss. HIF1αβ: Hypoxia-inducible factor; pVHL: von Hippel-Lindau protein; pVHL multiprotein complex: pVHL + cullin 2 + elongins B,C + ubiquitin ligase complex components; VEGF: vascular endothelial growth factor; PDGF: platelet-derived growth factor; TGFβ: transforming growth factor.
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