Regulation of hypoxia-inducible factor 1α is mediated by an O2-dependent degradation domain via the ubiquitin-proteasome pathway

摘要: Hypoxia induces a group of physiologically important genes such as erythropoietin and vascular endothelial growth factor. These are transcriptionally up-regulated by hypoxia-inducible factor 1 (HIF-1), global regulator that belongs to the basic helix-loop-helix PAS family. Although HIF-1 is heterodimer composed α β subunits, its activity primarily determined hypoxia-induced stabilization HIF-1α, which otherwise rapidly degraded in oxygenated cells. We report identification an oxygen-dependent degradation (ODD) domain within HIF-1α controls ubiquitin-proteasome pathway. The ODD consists ≈200 amino acid residues, located central region HIF-1α. Because portions independently confer deletion this entire required give rise stable capable heterodimerization, DNA-binding, transactivation absence hypoxic signaling. Conversely, alone confers instability when fused protein, Gal4. Hence, plays pivotal role for regulating thereby may provide means controlling gene expression changes oxygen tension.