ID:HIF1A_HUMAN DESCRIPTION: RecName: Full=Hypoxia-inducible factor 1-alpha; Short=HIF-1-alpha; Short=HIF1-alpha; AltName: Full=ARNT-interacting protein; AltName: Full=Basic-helix-loop-helix-PAS protein MOP1; AltName: Full=Class E basic helix-loop-helix protein 78; Short=bHLHe78; AltName: Full=Member of PAS protein 1; AltName: Full=PAS domain-containing protein 8; 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, 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. 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. Involved in the axonal distribution and transport of mitochondria in neurons during 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 EP300 (via TAZ-type 1 domains); the interaction is stimulated in response to hypoxia and inhibited by CITED2. Interacts with CREBBP (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 (By similarity). Interacts with RORA (via the DNA binding domain); the interaction enhances HIF1A transcription under hypoxia through increasing protein stability. Interaction with PSMA7 inhibits the transactivation activity of HIF1A under both normoxic and hypoxia- mimicking conditions. Interacts with USP20. Interacts with GNB2L1/RACK1; promotes HIF1A ubiquitination and proteasome- mediated degradation. Interacts (via N-terminus) with USP19. INTERACTION: P10275:AR; NbExp=2; IntAct=EBI-447269, EBI-608057; P27540:ARNT; NbExp=7; IntAct=EBI-447269, EBI-80809; P49407:ARRB1; NbExp=3; IntAct=EBI-447269, EBI-743313; Q09472:EP300; NbExp=5; IntAct=EBI-447269, EBI-447295; Q9NWT6:HIF1AN; NbExp=3; IntAct=EBI-447269, EBI-745632; Q92831:KAT2B; NbExp=2; IntAct=EBI-447269, EBI-477430; Q13438:OS9; NbExp=9; IntAct=EBI-447269, EBI-1174342; Q8N2W9:PIAS4; NbExp=3; IntAct=EBI-447269, EBI-473160; P14618-1:PKM; NbExp=7; IntAct=EBI-447269, EBI-4304679; Q8BIF2:Rbfox3 (xeno); NbExp=2; IntAct=EBI-447269, EBI-4567146; P51450-2:Rorc (xeno); NbExp=2; IntAct=EBI-447269, EBI-4422078; Q9UHD8-1:SEPT9; NbExp=4; IntAct=EBI-447269, EBI-851558; P63165:SUMO1; NbExp=2; IntAct=EBI-447269, EBI-80140; O94888:UBXN7; NbExp=3; IntAct=EBI-447269, EBI-1993627; P40337:VHL; NbExp=6; IntAct=EBI-447269, EBI-301246; SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Note=Cytoplasmic in normoxia, nuclear translocation in response to hypoxia. Colocalizes with SUMO1 in the nucleus, under hypoxia. 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. INDUCTION: Under reduced oxygen tension. Induced also by various receptor-mediated factors such as growth factors, cytokines, and circulatory factors such as PDGF, EGF, FGF2, IGF2, TGFB1, HGF, TNF, IL1B/interleukin-1 beta, angiotensin-2 and thrombin. However, this induction is less intense than that stimulated by hypoxia. Repressed by HIPK2 and LIMD1. 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). 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. Deubiquitinated by USP20. Under hypoxia, proline hydroxylation is impaired and ubiquitination is attenuated, resulting in stabilization. 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: S-nitrosylation of Cys-800 may be responsible for increased recruitment of p300 coactivator necessary for transcriptional activity of HIF-1 complex. PTM: Requires phosphorylation for DNA-binding. Phosphorylation at Ser-247 by CSNK1D/CK1 represses kinase activity and impairs ARNT binding. Phosphorylation by GSK3-beta and PLK3 promote degradation by the proteasome. PTM: Sumoylated; with SUMO1 under hypoxia. Sumoylation is enhanced through interaction with RWDD3. Desumoylation by SENP1 leads to increased HIF1A stability and transriptional activity (By similarity). 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. PTM: The iron and 2-oxoglutarate dependent 3-hydroxylation of asparagine is (S) stereospecific within HIF CTAD domains. SIMILARITY: Contains 1 bHLH (basic helix-loop-helix) domain. SIMILARITY: Contains 1 PAC (PAS-associated C-terminal) domain. SIMILARITY: Contains 2 PAS (PER-ARNT-SIM) domains. WEB RESOURCE: Name=Wikipedia; Note=Hypoxia inducible factor entry; URL="http://en.wikipedia.org/wiki/Hypoxia_inducible_factor";
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
ModBase Predicted Comparative 3D Structure on Q16665
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Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
Gene Ontology (GO) Annotations with Structured Vocabulary
Molecular Function: GO:0000981 RNA polymerase II transcription factor activity, sequence-specific DNA binding GO:0000989 transcription factor activity, transcription factor binding GO:0001076 transcription factor activity, RNA polymerase II transcription factor binding GO:0001077 transcriptional activator activity, RNA polymerase II core promoter proximal region sequence-specific binding GO:0001228 transcriptional activator activity, RNA polymerase II transcription regulatory region sequence-specific binding GO:0002039 p53 binding GO:0003677 DNA binding GO:0003700 transcription factor activity, sequence-specific DNA binding GO:0003705 transcription factor activity, RNA polymerase II distal enhancer sequence-specific binding GO:0005515 protein binding GO:0008134 transcription factor binding GO:0019899 enzyme binding GO:0019901 protein kinase binding GO:0019904 protein domain specific binding GO:0031625 ubiquitin protein ligase binding GO:0035035 histone acetyltransferase binding GO:0035257 nuclear hormone receptor binding GO:0042826 histone deacetylase binding GO:0043565 sequence-specific DNA binding GO:0046982 protein heterodimerization activity GO:0046983 protein dimerization activity GO:0051879 Hsp90 protein binding GO:0070888 E-box binding
Biological Process: GO:0001525 angiogenesis GO:0001568 blood vessel development GO:0001666 response to hypoxia GO:0001755 neural crest cell migration GO:0001837 epithelial to mesenchymal transition GO:0001892 embryonic placenta development GO:0001922 B-1 B cell homeostasis GO:0001938 positive regulation of endothelial cell proliferation GO:0001944 vasculature development GO:0001947 heart looping GO:0002052 positive regulation of neuroblast proliferation GO:0002248 connective tissue replacement involved in inflammatory response wound healing GO:0003151 outflow tract morphogenesis GO:0003208 cardiac ventricle morphogenesis GO:0006089 lactate metabolic process GO:0006110 regulation of glycolytic process GO:0006351 transcription, DNA-templated GO:0006355 regulation of transcription, DNA-templated GO:0006366 transcription from RNA polymerase II promoter GO:0006879 cellular iron ion homeostasis GO:0007165 signal transduction GO:0007595 lactation GO:0008542 visual learning GO:0010039 response to iron ion GO:0010468 regulation of gene expression GO:0010508 positive regulation of autophagy GO:0010573 vascular endothelial growth factor production GO:0010575 positive regulation of vascular endothelial growth factor production GO:0010628 positive regulation of gene expression GO:0010629 negative regulation of gene expression GO:0010634 positive regulation of epithelial cell migration GO:0010870 positive regulation of receptor biosynthetic process GO:0014850 response to muscle activity GO:0016239 positive regulation of macroautophagy GO:0016579 protein deubiquitination GO:0019221 cytokine-mediated signaling pathway GO:0019896 axonal transport of mitochondrion GO:0021502 neural fold elevation formation GO:0021987 cerebral cortex development GO:0030154 cell differentiation GO:0030279 negative regulation of ossification GO:0030502 negative regulation of bone mineralization GO:0030949 positive regulation of vascular endothelial growth factor receptor signaling pathway GO:0032007 negative regulation of TOR signaling GO:0032364 oxygen homeostasis GO:0032722 positive regulation of chemokine production GO:0032909 regulation of transforming growth factor beta2 production GO:0032963 collagen metabolic process GO:0035162 embryonic hemopoiesis GO:0035774 positive regulation of insulin secretion involved in cellular response to glucose stimulus GO:0042127 regulation of cell proliferation GO:0042541 hemoglobin biosynthetic process GO:0042593 glucose homeostasis GO:0042789 mRNA transcription from RNA polymerase II promoter GO:0043066 negative regulation of apoptotic process GO:0043524 negative regulation of neuron apoptotic process GO:0043536 positive regulation of blood vessel endothelial cell migration GO:0043619 regulation of transcription from RNA polymerase II promoter in response to oxidative stress GO:0043687 post-translational protein modification GO:0045648 positive regulation of erythrocyte differentiation GO:0045766 positive regulation of angiogenesis GO:0045821 positive regulation of glycolytic process GO:0045893 positive regulation of transcription, DNA-templated GO:0045926 negative regulation of growth GO:0045944 positive regulation of transcription from RNA polymerase II promoter GO:0046716 muscle cell cellular homeostasis GO:0046886 positive regulation of hormone biosynthetic process GO:0048514 blood vessel morphogenesis GO:0048546 digestive tract morphogenesis GO:0048593 camera-type eye morphogenesis GO:0050790 regulation of catalytic activity GO:0051000 positive regulation of nitric-oxide synthase activity GO:0051216 cartilage development GO:0051541 elastin metabolic process GO:0060574 intestinal epithelial cell maturation GO:0061030 epithelial cell differentiation involved in mammary gland alveolus development GO:0061072 iris morphogenesis GO:0061298 retina vasculature development in camera-type eye GO:0061418 regulation of transcription from RNA polymerase II promoter in response to hypoxia GO:0061419 positive regulation of transcription from RNA polymerase II promoter in response to hypoxia GO:0070101 positive regulation of chemokine-mediated signaling pathway GO:0070243 regulation of thymocyte apoptotic process GO:0070244 negative regulation of thymocyte apoptotic process GO:0071347 cellular response to interleukin-1 GO:0071456 cellular response to hypoxia GO:0071542 dopaminergic neuron differentiation GO:0097411 hypoxia-inducible factor-1alpha signaling pathway GO:1902895 positive regulation of pri-miRNA transcription from RNA polymerase II promoter GO:1903377 negative regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway GO:1903599 positive regulation of mitophagy GO:1903715 regulation of aerobic respiration GO:2000378 negative regulation of reactive oxygen species metabolic process GO:2001054 negative regulation of mesenchymal cell apoptotic process
AK296876 - Homo sapiens cDNA FLJ54364 complete cds, highly similar to Hypoxia-inducible factor 1 alpha. AK304436 - Homo sapiens cDNA FLJ57096 complete cds, highly similar to Hypoxia-inducible factor 1 alpha. AK299551 - Homo sapiens cDNA FLJ59406 complete cds, highly similar to Hypoxia-inducible factor 1 alpha. AK304315 - Homo sapiens cDNA FLJ55752 complete cds, highly similar to Hypoxia-inducible factor 1 alpha. FW408286 - NUCLEIC ACID COMPOUNDS FOR INHIBITING HIF1A GENE EXPRESSION AND USES THEREOF. FW408287 - NUCLEIC ACID COMPOUNDS FOR INHIBITING HIF1A GENE EXPRESSION AND USES THEREOF. JD272560 - Sequence 253584 from Patent EP1572962. BX648795 - Homo sapiens mRNA; cDNA DKFZp686O09143 (from clone DKFZp686O09143). U29165 - Human MOP1 mRNA, complete cds. BC012527 - Homo sapiens hypoxia inducible factor 1, alpha subunit (basic helix-loop-helix transcription factor), mRNA (cDNA clone MGC:10483 IMAGE:3842146), complete cds. AK312397 - Homo sapiens cDNA, FLJ92729, highly similar to Homo sapiens hypoxia-inducible factor 1, alpha subunit (basic helix-loop-helix transcription factor) (HIF1A), mRNA. JD133153 - Sequence 114177 from Patent EP1572962. AB733094 - Homo sapiens HIF-1A mRNA for hypoxia-inducible factor1alpha, complete cds. AB073325 - Homo sapiens HIF1A mRNA for hypoxia-inducible factor 1 alpha variant, complete cds. U22431 - Human hypoxia-inducible factor 1 alpha (HIF-1 alpha) mRNA, complete cds. AB500182 - Homo sapiens HIF1A mRNA for hypoxia-inducible factor 1, alpha subunit, variant K12NR, complete cds. AF207601 - Homo sapiens cell-line GM11201 hypoxia-inducible factor 1 alpha (HIF1A) mRNA, complete cds. AF207602 - Homo sapiens cell-line GM11197 hypoxia-inducible factor 1 alpha (HIF1A) mRNA, complete cds. AB385144 - Synthetic construct DNA, clone: pF1KB5648, Homo sapiens HIF1A gene for hypoxia-inducible factor 1 alpha, complete cds, without stop codon, in Flexi system. KJ896971 - Synthetic construct Homo sapiens clone ccsbBroadEn_06365 HIF1A gene, encodes complete protein. KR710293 - Synthetic construct Homo sapiens clone CCSBHm_00011107 HIF1A (HIF1A) mRNA, encodes complete protein. KR710294 - Synthetic construct Homo sapiens clone CCSBHm_00011108 HIF1A (HIF1A) mRNA, encodes complete protein. BT009776 - Homo sapiens hypoxia-inducible factor 1, alpha subunit (basic helix-loop-helix transcription factor) mRNA, complete cds. AF304431 - Homo sapiens hypoxia-inducible factor 1 alpha subunit (HIF1A) mRNA, complete cds. FJ790247 - Homo sapiens hypoxia-inducible factor 1 alpha isoform I.3 (HIF1A) mRNA, complete cds. LZ221033 - WO 2017163391-A/9: Method of evaluating or selecting androgen receptor regulator specific to sebaceous gland in skin or hair follicle. LZ221031 - WO 2017163391-A/7: Method of evaluating or selecting androgen receptor regulator specific to sebaceous gland in skin or hair follicle. DQ975378 - Homo sapiens hypoxia-inducible factor 1 alpha subunit transcript variant 3-like (HIF1A) mRNA, partial sequence, alternatively spliced. X72726 - H.sapiens tunp mRNA for transformation upregulated nuclear protein, exon D. JD490881 - Sequence 471905 from Patent EP1572962. JD400349 - Sequence 381373 from Patent EP1572962. JD062765 - Sequence 43789 from Patent EP1572962. AJ227916 - Homo sapiens partial mRNA; ID LG141-7A. JD349463 - Sequence 330487 from Patent EP1572962. JD549407 - Sequence 530431 from Patent EP1572962. JD083405 - Sequence 64429 from Patent EP1572962. MP119867 - Sequence 10 from Patent EP3444356. MP119865 - Sequence 8 from Patent EP3444356.
Biochemical and Signaling Pathways
BioCarta from NCI Cancer Genome Anatomy Project h_p53hypoxiaPathway - Hypoxia and p53 in the Cardiovascular system h_eponfkbPathway - Erythropoietin mediated neuroprotection through NF-kB h_vegfPathway - VEGF, Hypoxia, and Angiogenesis h_hifPathway - Hypoxia-Inducible Factor in the Cardiovascular System
Reactome (by CSHL, EBI, and GO)
Protein Q16665 (Reactome details) participates in the following event(s):
R-HSA-1234177 Cytosolic PHD2,3 hydroxylates proline residues on HIF1A R-HSA-8857583 LINC01139 promotes phosphorylation of HIF1A by PTK6 and LRRK2 R-HSA-1234181 Nuclear PHD1,3 hydroxylates proline residues on HIF1A R-HSA-1912396 NICD1 binds HIF1A R-NUL-2065560 mNICD1 binds HIF1A R-HSA-1234164 Cytosolic hydroxylation of asparagine residue in HIF alpha R-HSA-6781797 USP19 binds HIF1A,BIRC2,BIRC3 R-HSA-1234169 Nuclear VHL:EloB,C:CUL2:RBX1 binds hydroxyprolyl-HIF-alpha R-HSA-1234183 Cytosolic VHL:EloB,C:CUL2:RBX1 binds hydroxyprolyl-HIF-alpha R-HSA-8956103 VHL:EloB,C:NEDD8-CUL2:RBX1 complex binds hydroxyprolyl-HIF-alpha R-HSA-1234171 HIF-alpha binds ARNT (HIF1-beta) forming HIF-alpha:ARNT R-HSA-8848812 HIF1A,EPAS1 bind PTK6 gene R-HSA-1234172 Nuclear VBC complex ubiquitinylates HIF-alpha R-HSA-1234163 Cytosolic VBC complex ubiquitinylates hydroxyprolyl-HIF-alpha R-HSA-8956106 VHL:EloB,C:NEDD8-CUL2:RBX1 complex ubiquitinylates HIF-alpha R-HSA-1234176 Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha R-HSA-8857538 PTK6 promotes HIF1A stabilization R-HSA-2122947 NOTCH1 Intracellular Domain Regulates Transcription R-HSA-1234162 Oxygen-dependent asparagine hydroxylation of Hypoxia-inducible Factor Alpha R-HSA-1234158 Regulation of gene expression by Hypoxia-inducible Factor R-HSA-5689880 Ub-specific processing proteases R-HSA-1234174 Regulation of Hypoxia-inducible Factor (HIF) by oxygen R-HSA-8848021 Signaling by PTK6 R-HSA-8951664 Neddylation R-HSA-6785807 Interleukin-4 and 13 signaling R-HSA-8849473 PTK6 Expression R-HSA-1980143 Signaling by NOTCH1 R-HSA-5688426 Deubiquitination R-HSA-2262749 Cellular response to hypoxia R-HSA-9006927 Signaling by Non-Receptor Tyrosine Kinases R-HSA-597592 Post-translational protein modification R-HSA-449147 Signaling by Interleukins R-HSA-157118 Signaling by NOTCH R-HSA-2262752 Cellular responses to stress R-HSA-162582 Signal Transduction R-HSA-392499 Metabolism of proteins R-HSA-1280215 Cytokine Signaling in Immune system R-HSA-8953897 Cellular responses to external stimuli R-HSA-168256 Immune System
US Server
Sequence and Links to Tools and Databases 
Common Gene Haplotype Alleles 
