| Enzyme Function |
FUNCTION: Functions as a master transcriptional regulator of the adaptive response to hypoxia (PubMed:15225651, PubMed:17981124, PubMed:22009797). 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 (PubMed:15225651, PubMed:17981124, PubMed:22009797). Plays an essential role in embryonic vascularization, tumor angiogenesis and pathophysiology of ischemic disease (PubMed:22009797). Heterodimerizes with ARNT; heterodimer binds to core DNA sequence 5'-TACGTG-3' within the hypoxia response element (HRE) of target gene promoters (PubMed:26245371). Activation requires recruitment of transcriptional coactivators such as CREBBP and EP300. Activity is enhanced by interaction with NCOA1 and/or NCOA2. Interaction with redox regulatory protein APEX1 seems to activate CTAD and potentiates activation by NCOA1 and CREBBP. Involved in the axonal distribution and transport of mitochondria in neurons during hypoxia (By similarity). {ECO:0000250|UniProtKB:Q16665, ECO:0000269|PubMed:15225651, ECO:0000269|PubMed:17981124, ECO:0000269|PubMed:22009797, ECO:0000269|PubMed:26245371}. |
| Post Translational Modification |
PTM: S-nitrosylation of Cys-810 may be responsible for increased recruitment of p300 coactivator necessary for transcriptional activity of HIF-1 complex. {ECO:0000250|UniProtKB:Q16665}.; PTM: Requires phosphorylation for DNA-binding. Phosphorylation at Ser-247 by CSNK1D/CK1 represses kinase activity and impairs ARNT binding (By similarity). Phosphorylation by GSK3-beta and PLK3 promote degradation by the proteasome (PubMed:20889502). {ECO:0000250|UniProtKB:Q16665, ECO:0000269|PubMed:20889502}.; PTM: Sumoylated; with SUMO1 under hypoxia (PubMed:15225651, PubMed:17981124). Sumoylation is enhanced through interaction with RWDD3 (By similarity). Both sumoylation and desumoylation seem to be involved in the regulation of its stability during hypoxia (PubMed:15225651, PubMed:17981124). Sumoylation can promote either its stabilization or its VHL-dependent degradation by promoting hydroxyproline-independent HIF1A-VHL complex binding, thus leading to HIF1A ubiquitination and proteasomal degradation (By similarity). Desumoylation by SENP1 increases its stability amd transcriptional activity (PubMed:17981124). There is a disaccord between various publications on the effect of sumoylation and desumoylation on its stability and transcriptional activity (Probable). {ECO:0000250|UniProtKB:Q16665, ECO:0000269|PubMed:15225651, ECO:0000269|PubMed:17981124, ECO:0000305}.; PTM: Acetylation of Lys-545 by ARD1 increases interaction with VHL and stimulates subsequent proteasomal degradation (By similarity). Deacetylation of Lys-719 by SIRT2 increases its interaction with and hydroxylation by EGLN1 thereby inactivating HIF1A activity by inducing its proteasomal degradation (By similarity). {ECO:0000250|UniProtKB:Q16665}.; PTM: Ubiquitinated; in normoxia, following hydroxylation and interaction with VHL. Lys-545 appears to be the principal site of ubiquitination. Clioquinol, the Cu/Zn-chelator, inhibits ubiquitination through preventing hydroxylation at Asn-813 (By similarity). {ECO:0000250|UniProtKB:Q16665}.; PTM: The iron and 2-oxoglutarate dependent 3-hydroxylation of asparagine is (S) stereospecific within HIF CTAD domains. {ECO:0000250|UniProtKB:Q16665}.; PTM: In normoxia, is hydroxylated on Pro-402 and Pro-577 in the oxygen-dependent degradation domain (ODD) by EGLN1/PHD2 and EGLN2/PHD1. EGLN3/PHD3 has also been shown to hydroxylate Pro-577. The hydroxylated prolines promote interaction with VHL, initiating rapid ubiquitination and subsequent proteasomal degradation. Deubiquitinated by USP20. Under hypoxia, proline hydroxylation is impaired and ubiquitination is attenuated, resulting in stabilization (By similarity). In normoxia, is hydroxylated on Asn-813 by HIF1AN, thus abrogating interaction with CREBBP and EP300 and preventing transcriptional activation. Repressed by iron ion, via Fe(2+) prolyl hydroxylase (PHD) enzymes-mediated hydroxylation and subsequent proteasomal degradation. {ECO:0000250|UniProtKB:Q16665}. |