PathwayStep7269 PathwayStep7262 PathwayStep7249 Oxygen-dependent Asparagine Hydroxylation of Hypoxia-inducible Factor Alpha Regulation of Hypoxia-inducible Factor (HIF) by Oxygen Authored: May, B, 2011-03-09 Edited: May, B, 2011-03-09 GENE ONTOLOGYGO:0061418 In the presence of oxygen members of the transcription factor family HIF-alpha, comprising HIF1A, HIF2A (EPAS1), and HIF3A, are hydroxylated on proline residues by PHD1 (EGLN2), PHD2 (EGLN1), and PHD3 (EGLN3) and on asparagine residues by HIF1AN (FIH) (reviewed in Pouyssegur et al. 2006, Semenza 2007, Kaelin and Ratcliffe 2008, Nizet and Johnson 2009, Brahimi-Horn and Pouyssegur 2009, Majmundar et al. 2010, Loenarz and Schofield 2011). Both types of reaction require molecular oxygen as a substrate and it is probable that at least some HIF-alpha molecules carry both hydroxylated asparagine and hydroxylated proline (Tian et al. 2011).<br>Hydroxylated asparagine interferes with the ability of HIF-alpha to interact with p300 and CBP while hydroxylated proline facilitates the interaction of HIF-alpha with the E3 ubiquitin ligase VHL, causing ubiquitination and proteolysis of HIF-alpha. Hypoxia inhibits both types of hydroxylation, resulting in the stabilization of HIF-alpha, which then enters the nucleus, binds HIF-beta, and recruits p300 and CBP to activate target genes such as EPO and VEGF. Pubmed16724055 Pubmed17916722 Pubmed18498744 Pubmed19339544 Pubmed19704417 Pubmed20728359 Pubmed20965423 Pubmed21335549 Reactome Database ID Release 431234174 Reactome, http://www.reactome.org ReactomeREACT_120815 Reviewed: Rantanen, Krista, 2012-05-19 Regulation of Gene Expression by Hypoxia-inducible Factor Oxygen-dependent Proline Hydroxylation of Hypoxia-inducible Factor Alpha