背景介绍
domain:Contains two independent C-terminal transactivation domains, NTAD and CTAD, which function synergistically. Their transcriptional activity is repressed by an intervening inhibitory domain (ID).,function: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, 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. Binds to core DNA sequence 5'-[AG]CGTG-3' within the hypoxia response element (HRE) of target gene promoters. Activation requires recruitment of transcriptional coactivators such as CREBPB and EP300. Activity is enhanced by interaction with both, NCOA1 or NCOA2. Interaction with redox regulatory protein APEX seems to activate CTAD and potentiates activation by NCOA1 and CREBBP.,induction:Under reduced oxygen tension. Induced also by various receptor-mediated factors such as growth factors, cytokines, and circulatory factors such as PDGF, EGF FGF-2 FGF-2 IGF-2, TGF-1 beta, HGF, TNF alpha, IL-1 beta, angiotensin-2 and thrombin. However, this induction is less intense than that stimulated by hypoxia.,online information:Hypoxia inducible factor entry,PTM:In normoxia, is hydroxylated on Asn-803 by HIF1AN, thus abrogating interaction with CREBBP and EP300 and preventing transcriptional activation. This hydroxylation is inhibited by the Cu/Zn-chelator, Clioquinol.,PTM:In normoxia, is hydroxylated on Pro-402 and Pro-564 in the oxygen-dependent degradation domain (ODD) by EGLN1/PHD1 and EGLN2/PHD2. EGLN3/PHD3 has also been shown to hydroxylate Pro-564. 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.,PTM:Requires phosphorylation for DNA-binding.,PTM:S-nitrosylation of Cys-800 may be responsible for increased recruitment of p300 coactivator necessary for transcriptional activity of HIF-1 complex.,PTM:Sumoylated; by SUMO1 under hypoxia. Sumoylation is enhanced through interaction with RWDD3. Desumoylation by SENP1 leads to increased HIF1A stability and transriptional activity.,PTM:The iron and 2-oxoglutarate dependent 3-hydroxylation of asparagine is (S) stereospecific within HIF CTAD domains.,PTM:Ubiquitinated; in normoxia, following hydroxylation and interaction with VHL. Lys-532 appears to be the principal site of ubiquitination. Clioquinol, the Cu/Zn-chelator, inhibits ubiquitination through preventing hydroxylation at Asn-803.,similarity:Contains 1 basic helix-loop-helix (bHLH) domain.,similarity:Contains 1 PAC (PAS-associated C-terminal) domain.,similarity:Contains 2 PAS (PER-ARNT-SIM) domains.,subcellular location:Cytoplasmic in normoxia, nuclear translocation in response to hypoxia. Colocalizes with SUMO1 in the nucleus, under hypoxia.,subunit:Interacts with the HIF1A beta/ARNT subunit; heterodimerization is required for DNA binding. Interacts with COPS5; the interaction increases the transcriptional activity of HIF1A through increased stability (By similarity). Interacts with CREBBP and EP300 (via TAZ-type 1 domains). Interacts with NCOA1, NCOA2, APEX and HSP90. Interacts (hydroxylated within the ODD domain) with VHLL (via beta domain); the interaction, leads to polyubiquitination and subsequent HIF1A proteasomal degradation. During hypoxia, sumoylated HIF1A also binds VHL; the interaction promotes the ubiquitination of HIF1A. Interacts with SENP1; the interaction desumoylates HIF1A resulting in stabilization and activation of transcription. Interacts (Via the ODD domain) with ARD1A; the interaction appears not to acetylate HIF1A nor have any affect on protein stability, during hypoxia. Interacts with RWDD3; the interaction enhances HIF1A sumoylation. Interacts with TSGA10.,tissue specificity:Expressed in most tissues with highest levels in kidney and heart. Overexpressed in the majority of common human cancers and their metastases, due to the presence of intratumoral hypoxia and as a result of mutations in genes encoding oncoproteins and tumor suppressors.,
功能
cell morphogenesis,?cell morphogenesis involved in differentiation,?angiogenesis,?blood vessel development,?response to hypoxia,?ameboidal cell migration,?in utero embryonic development,?neural crest cell migration,?regulation of cytokine production,?positive regulation of cytokine production,?epithelial to mesenchymal transition,?placenta development,?embryonic placenta development,?regulation of endothelial cell proliferation,?positive regulation of endothelial cell proliferation,?vasculature development,?healing during inflammatory response,?connective tissue replacement during inflammatory response,?lactate metabolic process,?regulation of carbohydrate metabolic process,regulation of glycolysis,?transcription,?transcription, DNA-dependent,?regulation of transcription, DNA-dependent,regulation of transcription from RNA polymerase II promoter,?transcription from RNA polymerase II promoter,?cell motion,?defense response,?inflammatory response,?response to oxidative stress,?positive regulation of cell proliferation,?glycoprotein metabolic process,?mRNA transcription,?response to wounding,?embryonic development ending in birth or egg hatching,?positive regulation of biosynthetic process,?regulation of catabolic process,?positive regulation of catabolic process,?positive regulation of signal transduction,?positive regulation of macromolecule biosynthetic process,?regulation of vascular endothelial growth factor production,?positive regulation vascular endothelial growth factor production,?positive regulation of macromolecule metabolic process,?positive regulation of gene expression,?regulation of epithelial cell migration,?positive regulation of epithelial cell migration,?positive regulation of cell communication,?regulation of cellular carbohydrate metabolic process,?positive regulation of cellular carbohydrate metabolic process,?regulation of glucose metabolic process,?positive regulation of glucose metabolic process,?mesenchymal cell development,?neural crest cell development,?neural crest cell differentiation,?cell migration,cellular homeostasis,?hemoglobin metabolic process,?regulation of cell migration,?positive regulation of cell migration,regulation of vascular endothelial growth factor receptor signaling pathway,?positive regulation of vascular endothelial growth factor receptor signaling pathway,?positive regulation of cellular biosynthetic process,?regulation of cellular catabolic process,?positive regulation of cellular catabolic process,?regulation of hormone metabolic process,?positive regulation of hormone metabolic process,?oxygen homeostasis,?regulation of gene-specific transcription,?regulation of chemokine production,?positive regulation of chemokine production,?regulation of monooxygenase activity,?positive regulation of monooxygenase activity,?RNA biosynthetic process,?regulation of homeostatic process,?regulation of transforming growth factor-beta2 production,?collagen metabolic process,?cellular component morphogenesis,?gas homeostasis,?carbohydrate homeostasis,?cellular response to stress,?cellular response to oxidative stress,?regulation of locomotion,?positive regulation of locomotion,?wound healing,?regulation of cell proliferation,?hemoglobin biosynthetic process,?homeostatic process,?glucose homeostasis,?mRNA transcription from RNA polymerase II promoter,?chordate embryonic development,?positive regulation of catalytic activity,?positive regulation of gene-specific transcription,?regulation of generation of precursor metabolites and energy,?regulation of carbohydrate catabolic process,?regulation of cellular carbohydrate catabolic process,?regulation of transcription from RNA polymerase II promoter in response to stress,?regulation of transcription from RNA polymerase II promoter in response to oxidative stress,?regulation of transcription in response to stress,?positive regulation of molecular function,?multicellular organismal metabolic process,?multicellular organismal macromolecule metabolic process,?regulation of transcription,positive regulation of cell differentiation,?regulation of myeloid cell differentiation,?positive regulation of myeloid cell differentiation,?regulation of erythrocyte differentiation,?positive regulation of erythrocyte differentiation,?regulation of angiogenesis,?positive regulation of angiogenesis,?positive regulation of glycolysis,?positive regulation of transcription, DNA-dependent,?positive regulation of carbohydrate metabolic process,?positive regulation of nucleobase, nucleoside, nucleotide and nucleic acid metabolic process,?positive regulation of transcription,?positive regulation of transcription from RNA polymerase II promoter,?muscle maintenance,?regulation of hormone biosynthetic process,?positive regulation of hormone biosynthetic process,?blood vessel morphogenesis,?embryonic organ development,mesenchymal cell differentiation,?tissue remodeling,?cell motility,?chemical homeostasis,?regulation of nitric-oxide synthase activity,?positive regulation of nitric-oxide synthase activity,?positive regulation of developmental process,positive regulation of nitrogen compound metabolic process,?positive regulation of multicellular organismal process,regulation of RNA metabolic process,?positive regulation of RNA metabolic process,?regulation of cell motion,?positive regulation of cell motion,?regulation of oxidoreductase activity,?positive regulation of oxidoreductase activity,?elastin metabolic process,?localization of cell,?anatomical structure homeostasis,?mesenchyme development,?response to oxygen levels,
