Functions as a master transcriptional regulator of the adaptive response to hypoxia. Under hypoxic conditions, activates the transcription of over 40 genes, including erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor, HILPDA, and other genes whose protein products increase oxygen delivery or facilitate metabolic adaptation to hypoxia. Plays an essential role in embryonic vascularization, tumor angiogenesis and pathophysiology of ischemic disease. Induced by reactive oxygen species (ROS). Efficient DNA binding requires heterodimerization of an alpha and a beta/ARNT subunit. Cytoplasmic in normoxia, nuclear translocation in response to hypoxia. Contains two independent C-terminal transactivation domains, NTAD and CTAD, which function synergistically. Their transcriptional activity is repressed by an intervening inhibitory domain (ID) (By similarity). In normoxia, is hydroxylated on Pro-426 and Pro-559. The hydroxylated prolines promote interaction with VHL, initiating rapid ubiquitination and subsequent proteasomal degradation. Under hypoxia, proline hydroxylation is impaired and ubiquitination is attenuated, resulting in stabilization (By similarity). In normoxia, is hydroxylated on Asn-743, thus abrogating interaction with CREBBP and EP300 and preventing transcriptional activation. The iron and 2-oxoglutarate dependent 3-hydroxylation of asparagine is (S) stereospecific within HIF CTAD domains.