ID HIF1A_HUMAN Reviewed; 826 AA. AC Q16665; C0LZJ3; Q53XP6; Q96PT9; Q9UPB1; DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot. DT 01-NOV-1996, sequence version 1. DT 27-MAR-2024, entry version 253. DE RecName: Full=Hypoxia-inducible factor 1-alpha {ECO:0000305}; DE Short=HIF-1-alpha {ECO:0000303|PubMed:7539918}; DE Short=HIF1-alpha {ECO:0000303|PubMed:7539918}; DE AltName: Full=ARNT-interacting protein; DE AltName: Full=Basic-helix-loop-helix-PAS protein MOP1 {ECO:0000303|PubMed:9079689}; DE AltName: Full=Class E basic helix-loop-helix protein 78; DE Short=bHLHe78; DE AltName: Full=Member of PAS protein 1 {ECO:0000303|PubMed:9079689}; DE AltName: Full=PAS domain-containing protein 8; GN Name=HIF1A {ECO:0000303|PubMed:7539918, ECO:0000312|HGNC:HGNC:4910}; GN Synonyms=BHLHE78, MOP1 {ECO:0000303|PubMed:9079689}, PASD8; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA], AND PROTEIN SEQUENCE OF 166-170; 259-289 AND RP 771-781. RX PubMed=7539918; DOI=10.1073/pnas.92.12.5510; RA Wang G.L., Jiang B.-H., Rue E.A., Semenza G.L.; RT "Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer RT regulated by cellular O2 tension."; RL Proc. Natl. Acad. Sci. U.S.A. 92:5510-5514(1995). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA]. RC TISSUE=Hepatoma; RX PubMed=9079689; DOI=10.1074/jbc.272.13.8581; RA Hogenesch J.B., Chan W.K., Jackiw V.H., Brown R.C., Gu Y.-Z., RA Pray-Grant M., Perdew G.H., Bradfield C.A.; RT "Characterization of a subset of the basic-helix-loop-helix-PAS superfamily RT that interacts with components of the dioxin signaling pathway."; RL J. Biol. Chem. 272:8581-8593(1997). RN [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM 1). RX PubMed=9782081; DOI=10.1006/geno.1998.5416; RA Iyer N.V., Leung S.W., Semenza G.L.; RT "The human hypoxia-inducible factor 1alpha gene: HIF1A structure and RT evolutionary conservation."; RL Genomics 52:159-165(1998). RN [4] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3), AND ALTERNATIVE SPLICING. RX PubMed=18638657; DOI=10.1016/j.humimm.2008.05.004; RA Lukashev D., Sitkovsky M.; RT "Preferential expression of the novel alternative isoform I.3 of hypoxia- RT inducible factor 1alpha in activated human T lymphocytes."; RL Hum. Immunol. 69:421-425(2008). RN [5] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA]. RA Rupert J.L., Hochachka P.W.; RT "HIF1a sequence in the Quechua, a high altitude population."; RL Submitted (NOV-1999) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RC TISSUE=Glial tumor; RA Sun B., Zhao H.R., Yu R.T., Ni M.S.H.; RL Submitted (SEP-2000) to the EMBL/GenBank/DDBJ databases. RN [7] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2). RC TISSUE=Liver; RA Tanaka S., Sugimachi K.; RT "Hypoxia-inducible factor-1 alpha variant isolated from human liver RT tissue."; RL Submitted (OCT-2001) to the EMBL/GenBank/DDBJ databases. RN [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., RA Phelan M., Farmer A.; RT "Cloning of human full-length CDSs in BD Creator(TM) system donor vector."; RL Submitted (AUG-2003) to the EMBL/GenBank/DDBJ databases. RN [9] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=12508121; DOI=10.1038/nature01348; RA Heilig R., Eckenberg R., Petit J.-L., Fonknechten N., Da Silva C., RA Cattolico L., Levy M., Barbe V., De Berardinis V., Ureta-Vidal A., RA Pelletier E., Vico V., Anthouard V., Rowen L., Madan A., Qin S., Sun H., RA Du H., Pepin K., Artiguenave F., Robert C., Cruaud C., Bruels T., RA Jaillon O., Friedlander L., Samson G., Brottier P., Cure S., Segurens B., RA Aniere F., Samain S., Crespeau H., Abbasi N., Aiach N., Boscus D., RA Dickhoff R., Dors M., Dubois I., Friedman C., Gouyvenoux M., James R., RA Madan A., Mairey-Estrada B., Mangenot S., Martins N., Menard M., Oztas S., RA Ratcliffe A., Shaffer T., Trask B., Vacherie B., Bellemere C., Belser C., RA Besnard-Gonnet M., Bartol-Mavel D., Boutard M., Briez-Silla S., RA Combette S., Dufosse-Laurent V., Ferron C., Lechaplais C., Louesse C., RA Muselet D., Magdelenat G., Pateau E., Petit E., Sirvain-Trukniewicz P., RA Trybou A., Vega-Czarny N., Bataille E., Bluet E., Bordelais I., Dubois M., RA Dumont C., Guerin T., Haffray S., Hammadi R., Muanga J., Pellouin V., RA Robert D., Wunderle E., Gauguet G., Roy A., Sainte-Marthe L., Verdier J., RA Verdier-Discala C., Hillier L.W., Fulton L., McPherson J., Matsuda F., RA Wilson R., Scarpelli C., Gyapay G., Wincker P., Saurin W., Quetier F., RA Waterston R., Hood L., Weissenbach J.; RT "The DNA sequence and analysis of human chromosome 14."; RL Nature 421:601-607(2003). RN [10] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Choriocarcinoma, and Placenta; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [11] RP IDENTIFICATION IN COMPLEX WITH EP300 AND CREBBP, AND INTERACTION WITH RP EP300. RX PubMed=8917528; DOI=10.1073/pnas.93.23.12969; RA Arany Z., Huang L.E., Eckner R., Bhattacharya S., Jiang C., Goldberg M.A., RA Bunn H.F., Livingston D.M.; RT "An essential role for p300/CBP in the cellular response to hypoxia."; RL Proc. Natl. Acad. Sci. U.S.A. 93:12969-12973(1996). RN [12] RP TRANSACTIVATION DOMAINS NTAD AND CTAD. RX PubMed=9235919; DOI=10.1074/jbc.272.31.19253; RA Jiang B.H., Zheng J.Z., Leung S.W., Roe R., Semenza G.L.; RT "Transactivation and inhibitory domains of hypoxia-inducible factor 1alpha. RT Modulation of transcriptional activity by oxygen tension."; RL J. Biol. Chem. 272:19253-19260(1997). RN [13] RP SUBCELLULAR LOCATION, AND MUTAGENESIS OF LYS-719. RX PubMed=9822602; DOI=10.1093/emboj/17.22.6573; RA Kallio P.J., Okamoto K., O'Brien S., Carrero P., Makino Y., Tanaka H., RA Poellinger L.; RT "Signal transduction in hypoxic cells: inducible nuclear translocation and RT recruitment of the CBP/p300 coactivator by the hypoxia-inducible factor- RT 1alpha."; RL EMBO J. 17:6573-6586(1998). RN [14] RP OXYGEN-DEPENDENT DEGRADATION DOMAIN. RX PubMed=9653127; DOI=10.1073/pnas.95.14.7987; RA Huang L.E., Gu J., Schau M., Bunn H.F.; RT "Regulation of hypoxia-inducible factor 1alpha is mediated by an O2- RT dependent degradation domain via the ubiquitin-proteasome pathway."; RL Proc. Natl. Acad. Sci. U.S.A. 95:7987-7992(1998). RN [15] RP FUNCTION, TRANSACTIVATION DOMAINS NTAD AND CTAD, INTERACTION WITH APEX1, RP AND MUTAGENESIS OF CYS-800. RX PubMed=10202154; DOI=10.1093/emboj/18.7.1905; RA Ema M., Hirota K., Mimura J., Abe H., Yodoi J., Sogawa K., Poellinger L., RA Fujii-Kuriyama Y.; RT "Molecular mechanisms of transcription activation by HLF and HIF1alpha in RT response to hypoxia: their stabilization and redox signal-induced RT interaction with CBP/p300."; RL EMBO J. 18:1905-1914(1999). RN [16] RP FUNCTION, DNA-BINDING, AND INTERACTION WITH EP300. RX PubMed=9887100; DOI=10.1101/gad.13.1.64; RA Bhattacharya S., Michels C.M., Leung M.K., Arany Z.P., Kung A.L., RA Livingston D.M.; RT "Functional role of p35srj, a novel p300/CBP binding protein, during RT transactivation by HIF-1."; RL Genes Dev. 13:64-75(1999). RN [17] RP INTERACTION WITH VHL. RX PubMed=11006129; DOI=10.1006/bbrc.2000.3451; RA Aso T., Yamazaki K., Aigaki T., Kitajima S.; RT "Drosophila von Hippel-Lindau tumor suppressor complex possesses E3 RT ubiquitin ligase activity."; RL Biochem. Biophys. Res. Commun. 276:355-361(2000). RN [18] RP INTERACTION WITH VHL AND ARNT, AND MUTAGENESIS OF LYS-532; LYS-538; LYS-547 RP AND LYS-719. RX PubMed=10944113; DOI=10.1093/emboj/19.16.4298; RA Tanimoto K., Makino Y., Pereira T., Poellinger L.; RT "Mechanism of regulation of the hypoxia-inducible factor-1 alpha by the von RT Hippel-Lindau tumor suppressor protein."; RL EMBO J. 19:4298-4309(2000). RN [19] RP FUNCTION, AND INTERACTION WITH NCOA1; NCOA2 AND APEX1. RX PubMed=10594042; DOI=10.1128/mcb.20.1.402-415.2000; RA Carrero P., Okamoto K., Coumailleau P., O'Brien S., Tanaka H., RA Poellinger L.; RT "Redox-regulated recruitment of the transcriptional coactivators CREB- RT binding protein and SRC-1 to hypoxia-inducible factor 1alpha."; RL Mol. Cell. Biol. 20:402-415(2000). RN [20] RP MUTAGENESIS OF SER-551 AND THR-552, AND UBIQUITINATION. RX PubMed=10758161; DOI=10.1073/pnas.080072497; RA Sutter C.H., Laughner E., Semenza G.L.; RT "Hypoxia-inducible factor 1alpha protein expression is controlled by RT oxygen-regulated ubiquitination that is disrupted by deletions and missense RT mutations."; RL Proc. Natl. Acad. Sci. U.S.A. 97:4748-4753(2000). RN [21] RP HYDROXYLATION AT PRO-402 AND PRO-564, UBIQUITINATION, INTERACTION WITH THE RP VHLE COMPLEX, FUNCTION, AND MUTAGENESIS OF PRO-394; LEU-397; LEU-400; RP PRO-402 AND PRO-564. RX PubMed=11566883; DOI=10.1093/emboj/20.18.5197; RA Masson N., Willam C., Maxwell P.H., Pugh C.W., Ratcliffe P.J.; RT "Independent function of two destruction domains in hypoxia-inducible RT factor-alpha chains activated by prolyl hydroxylation."; RL EMBO J. 20:5197-5206(2001). RN [22] RP INTERACTION WITH PSMA7. RX PubMed=11389899; DOI=10.1016/s0014-5793(01)02499-1; RA Cho S., Choi Y.J., Kim J.M., Jeong S.T., Kim J.H., Kim S.H., Ryu S.E.; RT "Binding and regulation of HIF-1alpha by a subunit of the proteasome RT complex, PSMA7."; RL FEBS Lett. 498:62-66(2001). RN [23] RP UBIQUITINATION, FUNCTION, AND HYDROXYLATION AT PRO-564. RX PubMed=11292861; DOI=10.1126/science.1059796; RA Jaakkola P., Mole D.R., Tian Y.-M., Wilson M.I., Gielbert J., Gaskell S.J., RA von Kriegsheim A., Hebestreit H.F., Mukherji M., Schofield C.J., RA Maxwell P.H., Pugh C.W., Ratcliffe P.J.; RT "Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by RT O2-regulated prolyl hydroxylation."; RL Science 292:468-472(2001). RN [24] RP INTERACTION WITH NAA10, AND ACETYLATION AT LYS-532. RX PubMed=12464182; DOI=10.1016/s0092-8674(02)01085-1; RA Jeong J.-W., Bae M.-K., Ahn M.-Y., Kim S.-H., Sohn T.-K., Bae M.-H., RA Yoo M.-A., Song E.-J., Lee K.-J., Kim K.-W.; RT "Regulation and destabilization of HIF-1alpha by ARD1-mediated RT acetylation."; RL Cell 111:709-720(2002). RN [25] RP HYDROXYLATION AT ASN-803, AND IDENTIFICATION BY MASS SPECTROMETRY. RX PubMed=12080085; DOI=10.1101/gad.991402; RA Lando D., Peet D.J., Gorman J.J., Whelan D.A., Whitelaw M.L., Bruick R.K.; RT "FIH-1 is an asparaginyl hydroxylase enzyme that regulates the RT transcriptional activity of hypoxia-inducible factor."; RL Genes Dev. 16:1466-1471(2002). RN [26] RP HYDROXYLATION AT PRO-564, AND IDENTIFICATION BY MASS SPECTROMETRY. RX PubMed=12351678; DOI=10.1073/pnas.192342099; RA Ivan M., Haberberger T., Gervasi D.C., Michelson K.S., Guenzler V., RA Kondo K., Yang H., Sorokina I., Conaway R.C., Conaway J.W., RA Kaelin W.G. Jr.; RT "Biochemical purification and pharmacological inhibition of a mammalian RT prolyl hydroxylase acting on hypoxia-inducible factor."; RL Proc. Natl. Acad. Sci. U.S.A. 99:13459-13464(2002). RN [27] RP S-NITROSYLATION AT CYS-800, AND MUTAGENESIS OF CYS-800. RX PubMed=12914934; DOI=10.1016/s0014-5793(03)00807-x; RA Yasinska I.M., Sumbayev V.V.; RT "S-nitrosation of Cys-800 of HIF-1alpha protein activates its interaction RT with p300 and stimulates its transcriptional activity."; RL FEBS Lett. 549:105-109(2003). RN [28] RP S-NITROSYLATION. RX PubMed=12560087; DOI=10.1016/s0014-5793(02)03887-5; RA Sumbayev V.V., Budde A., Zhou J., Bruene B.; RT "HIF-1 alpha protein as a target for S-nitrosation."; RL FEBS Lett. 535:106-112(2003). RN [29] RP INTERACTION WITH EP300, AND MUTAGENESIS OF LEU-795. RX PubMed=12778114; DOI=10.1038/nsb936; RA Freedman S.J., Sun Z.Y., Kung A.L., France D.S., Wagner G., Eck M.J.; RT "Structural basis for negative regulation of hypoxia-inducible factor- RT 1alpha by CITED2."; RL Nat. Struct. Biol. 10:504-512(2003). RN [30] RP SUMOYLATION AT LYS-391 AND LYS-477, FUNCTION, AND MUTAGENESIS OF LYS-389; RP LYS-391; LYS-392; LYS-442; LYS-460; LYS-477; LYS-532; LYS-538 AND LYS-547. RX PubMed=15465032; DOI=10.1016/j.bbrc.2004.09.068; RA Bae S.-H., Jeong J.-W., Park J.A., Kim S.-H., Bae M.-K., Choi S.-J., RA Kim K.-W.; RT "Sumoylation increases HIF-1alpha stability and its transcriptional RT activity."; RL Biochem. Biophys. Res. Commun. 324:394-400(2004). RN [31] RP INTERACTION WITH VHLL. RX PubMed=14757845; RA Qi H., Gervais M.L., Li W., DeCaprio J.A., Challis J.R.G., Ohh M.; RT "Molecular cloning and characterization of the von Hippel-Lindau-like RT protein."; RL Mol. Cancer Res. 2:43-52(2004). RN [32] RP UBIQUITINATION, DEUBIQUITINATION BY USP20, AND INTERACTION WITH USP20. RX PubMed=15776016; DOI=10.1038/sj.embor.7400377; RA Li Z., Wang D., Messing E.M., Wu G.; RT "VHL protein-interacting deubiquitinating enzyme 2 deubiquitinates and RT stabilizes HIF-1alpha."; RL EMBO Rep. 6:373-378(2005). RN [33] RP INTERACTION WITH NAA10, AND MUTAGENESIS OF LYS-532. RX PubMed=16288748; DOI=10.1016/j.febslet.2005.10.036; RA Arnesen T., Kong X., Evjenth R., Gromyko D., Varhaug J.E., Lin Z., Sang N., RA Caro J., Lillehaug J.R.; RT "Interaction between HIF-1 alpha (ODD) and hARD1 does not induce RT acetylation and destabilization of HIF-1 alpha."; RL FEBS Lett. 579:6428-6432(2005). RN [34] RP FUNCTION, INTERACTION WITH EP300 IN THE HIF1A/EP300/CREBBP COMPLEX, AND RP MUTAGENESIS OF ASN-803. RX PubMed=16543236; DOI=10.1074/jbc.m600456200; RA Fath D.M., Kong X., Liang D., Lin Z., Chou A., Jiang Y., Fang J., Caro J., RA Sang N.; RT "Histone deacetylase inhibitors repress the transactivation potential of RT hypoxia-inducible factors independently of direct acetylation of HIF- RT alpha."; RL J. Biol. Chem. 281:13612-13619(2006). RN [35] RP UBIQUITINATION, HYDROXYLATION, FUNCTION, INTERACTION WITH EP300, RP IDENTIFICATION BY MASS SPECTROMETRY, AND MUTAGENESIS OF ASN-803. RX PubMed=16973622; DOI=10.1074/jbc.m603913200; RA Choi S.M., Choi K.-O., Park Y.K., Cho H., Yang E.G., Park H.; RT "Clioquinol, a Cu(II)/Zn(II) chelator, inhibits both ubiquitination and RT asparagine hydroxylation of hypoxia-inducible factor-1alpha, leading to RT expression of vascular endothelial growth factor and erythropoietin in RT normoxic cells."; RL J. Biol. Chem. 281:34056-34063(2006). RN [36] RP SUMOYLATION AT LYS-391 AND LYS-477, FUNCTION, AND MUTAGENESIS OF LYS-377; RP LYS-391; LYS-477 AND LYS-532. RX PubMed=17610843; DOI=10.1016/j.bbrc.2007.06.103; RA Berta M.A., Mazure N., Hattab M., Pouyssegur J., Brahimi-Horn M.C.; RT "SUMOylation of hypoxia-inducible factor-1alpha reduces its transcriptional RT activity."; RL Biochem. Biophys. Res. Commun. 360:646-652(2007). RN [37] RP SUMOYLATION, AND INTERACTION WITH RWDD3. RX PubMed=17956732; DOI=10.1016/j.cell.2007.07.044; RA Carbia-Nagashima A., Gerez J., Perez-Castro C., Paez-Pereda M., RA Silberstein S., Stalla G.K., Holsboer F., Arzt E.; RT "RSUME, a small RWD-containing protein, enhances SUMO conjugation and RT stabilizes HIF-1alpha during hypoxia."; RL Cell 131:309-323(2007). RN [38] RP INTERACTION WITH RACK1. RX PubMed=17244529; DOI=10.1016/j.molcel.2007.01.001; RA Liu Y.V., Baek J.H., Zhang H., Diez R., Cole R.N., Semenza G.L.; RT "RACK1 competes with HSP90 for binding to HIF-1alpha and is required for RT O(2)-independent and HSP90 inhibitor-induced degradation of HIF-1alpha."; RL Mol. Cell 25:207-217(2007). RN [39] RP UBIQUITINATION AT LYS-532; LYS-538 AND LYS-547, INTERACTION WITH VHL, AND RP MUTAGENESIS OF PRO-402; LYS-532; LYS-538; LYS-547 AND PRO-564. RX PubMed=16862177; DOI=10.1038/sj.onc.1209818; RA Paltoglou S., Roberts B.J.; RT "HIF-1alpha and EPAS ubiquitination mediated by the VHL tumour suppressor RT involves flexibility in the ubiquitination mechanism, similar to other RING RT E3 ligases."; RL Oncogene 26:604-609(2007). RN [40] RP FUNCTION, AND INTERACTION WITH RORA. RX PubMed=18658046; DOI=10.1161/atvbaha.108.171546; RA Kim E.J., Yoo Y.G., Yang W.K., Lim Y.S., Na T.Y., Lee I.K., Lee M.O.; RT "Transcriptional activation of HIF-1 by RORalpha and its role in hypoxia RT signaling."; RL Arterioscler. Thromb. Vasc. Biol. 28:1796-1802(2008). RN [41] RP REVIEW ON REGULATION. RX PubMed=18809331; DOI=10.1016/j.tibs.2008.08.002; RA Yee Koh M., Spivak-Kroizman T.R., Powis G.; RT "HIF-1 regulation: not so easy come, easy go."; RL Trends Biochem. Sci. 33:526-534(2008). RN [42] RP INDUCTION BY HIPK2. RX PubMed=19046997; DOI=10.1016/j.bbamcr.2008.10.013; RA Nardinocchi L., Puca R., Guidolin D., Belloni A.S., Bossi G., Michiels C., RA Sacchi A., Onisto M., D'Orazi G.; RT "Transcriptional regulation of hypoxia-inducible factor 1alpha by HIPK2 RT suggests a novel mechanism to restrain tumor growth."; RL Biochim. Biophys. Acta 1793:368-377(2009). RN [43] RP FUNCTION IN MITOCHONDRIAL TRANSPORT. RX PubMed=19528298; DOI=10.1083/jcb.200811033; RA Li Y., Lim S., Hoffman D., Aspenstrom P., Federoff H.J., Rempe D.A.; RT "HUMMR, a hypoxia- and HIF-1alpha-inducible protein, alters mitochondrial RT distribution and transport."; RL J. Cell Biol. 185:1065-1081(2009). RN [44] RP FUNCTION. RX PubMed=20624928; DOI=10.1096/fj.10-159806; RA Gimm T., Wiese M., Teschemacher B., Deggerich A., Schodel J., Knaup K.X., RA Hackenbeck T., Hellerbrand C., Amann K., Wiesener M.S., Honing S., RA Eckardt K.U., Warnecke C.; RT "Hypoxia-inducible protein 2 is a novel lipid droplet protein and a RT specific target gene of hypoxia-inducible factor-1."; RL FASEB J. 24:4443-4458(2010). RN [45] RP PHOSPHORYLATION AT SER-551; THR-555; SER-576; SER-589 AND SER-657, AND RP MUTAGENESIS OF SER-576 AND SER-657. RX PubMed=20889502; DOI=10.1074/jbc.m110.160325; RA Xu D., Yao Y., Lu L., Costa M., Dai W.; RT "Plk3 functions as an essential component of the hypoxia regulatory pathway RT by direct phosphorylation of HIF-1alpha."; RL J. Biol. Chem. 285:38944-38950(2010). RN [46] RP PHOSPHORYLATION AT SER-247 BY CSNK1D/CK1, MUTAGENESIS OF SER-247, AND RP INTERACTION WITH ARNT. RX PubMed=20699359; DOI=10.1242/jcs.068122; RA Kalousi A., Mylonis I., Politou A.S., Chachami G., Paraskeva E., Simos G.; RT "Casein kinase 1 regulates human hypoxia-inducible factor HIF-1."; RL J. Cell Sci. 123:2976-2986(2010). RN [47] RP UBIQUITINATION. RX PubMed=22537386; DOI=10.1186/1741-7007-10-36; RA Bandau S., Knebel A., Gage Z.O., Wood N.T., Alexandru G.; RT "UBXN7 docks on neddylated cullin complexes using its UIM motif and causes RT HIF1alpha accumulation."; RL BMC Biol. 10:36-36(2012). RN [48] RP FUNCTION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, AND INDUCTION. RX PubMed=22009797; DOI=10.1530/erc-11-0211; RA Shan B., Gerez J., Haedo M., Fuertes M., Theodoropoulou M., Buchfelder M., RA Losa M., Stalla G.K., Arzt E., Renner U.; RT "RSUME is implicated in HIF-1-induced VEGF-A production in pituitary tumour RT cells."; RL Endocr. Relat. Cancer 19:13-27(2012). RN [49] RP INTERACTION WITH USP19. RX PubMed=22128162; DOI=10.1074/jbc.m111.305615; RA Altun M., Zhao B., Velasco K., Liu H., Hassink G., Paschke J., Pereira T., RA Lindsten K.; RT "Ubiquitin-specific protease 19 (USP19) regulates hypoxia-inducible factor RT 1alpha (HIF-1alpha) during hypoxia."; RL J. Biol. Chem. 287:1962-1969(2012). RN [50] RP INDUCTION. RX PubMed=22286099; DOI=10.1038/ncb2424; RA Foxler D.E., Bridge K.S., James V., Webb T.M., Mee M., Wong S.C., Feng Y., RA Constantin-Teodosiu D., Petursdottir T.E., Bjornsson J., Ingvarsson S., RA Ratcliffe P.J., Longmore G.D., Sharp T.V.; RT "The LIMD1 protein bridges an association between the prolyl hydroxylases RT and VHL to repress HIF-1 activity."; RL Nat. Cell Biol. 14:201-208(2012). RN [51] RP INTERACTION WITH DCUN1D1. RX PubMed=23401859; DOI=10.1128/mcb.01342-12; RA Heir P., Sufan R.I., Greer S.N., Poon B.P., Lee J.E., Ohh M.; RT "DCNL1 functions as a substrate sensor and activator of cullin 2-RING RT ligase."; RL Mol. Cell. Biol. 33:1621-1631(2013). RN [52] RP INTERACTION WITH RWDD3. RX PubMed=23469069; DOI=10.1371/journal.pone.0057795; RA Gerez J., Fuertes M., Tedesco L., Silberstein S., Sevlever G., RA Paez-Pereda M., Holsboer F., Turjanski A.G., Arzt E.; RT "In silico structural and functional characterization of the RSUME splice RT variants."; RL PLoS ONE 8:E57795-E57795(2013). RN [53] RP ACETYLATION AT LYS-709, DEACETYLATION AT LYS-709 BY SIRT2, HYDROXYLATION, RP INTERACTION WITH SIRT2 AND EGLN1, AND MUTAGENESIS OF PRO-402; PRO-564 AND RP LYS-709. RX PubMed=24681946; DOI=10.1038/onc.2014.76; RA Seo K.S., Park J.H., Heo J.Y., Jing K., Han J., Min K.N., Kim C., Koh G.Y., RA Lim K., Kang G.Y., Uee Lee J., Yim Y.H., Shong M., Kwak T.H., Kweon G.R.; RT "SIRT2 regulates tumour hypoxia response by promoting HIF-1alpha RT hydroxylation."; RL Oncogene 34:1354-1362(2015). RN [54] RP INTERACTION WITH HSP90AA1 AND HSP90AB1. RX PubMed=26517842; DOI=10.1371/journal.pone.0141786; RA Prince T.L., Kijima T., Tatokoro M., Lee S., Tsutsumi S., Yim K., Rivas C., RA Alarcon S., Schwartz H., Khamit-Kush K., Scroggins B.T., Beebe K., RA Trepel J.B., Neckers L.; RT "Client proteins and small molecule inhibitors display distinct binding RT preferences for constitutive and stress-induced HSP90 isoforms and their RT conformationally restricted mutants."; RL PLoS ONE 10:E0141786-E0141786(2015). RN [55] RP HYDROXYLATION PRO-564, UBIQUITINATION, AND INTERACTION WITH CBFA2T3 AND RP EGLN1. RX PubMed=25974097; DOI=10.1371/journal.pone.0123725; RA Kumar P., Gullberg U., Olsson I., Ajore R.; RT "Myeloid translocation gene-16 co-repressor promotes degradation of RT hypoxia-inducible factor 1."; RL PLoS ONE 10:E0123725-E0123725(2015). RN [56] RP DEUBIQUITINATION BY UCHL1, AND UBIQUITINATION BY VHL. RX PubMed=25615526; DOI=10.1038/ncomms7153; RA Goto Y., Zeng L., Yeom C.J., Zhu Y., Morinibu A., Shinomiya K., RA Kobayashi M., Hirota K., Itasaka S., Yoshimura M., Tanimoto K., Torii M., RA Sowa T., Menju T., Sonobe M., Kakeya H., Toi M., Date H., Hammond E.M., RA Hiraoka M., Harada H.; RT "UCHL1 provides diagnostic and antimetastatic strategies due to its RT deubiquitinating effect on HIF-1alpha."; RL Nat. Commun. 6:6153-6153(2015). RN [57] RP REGULATION BY IRON ION, AND HYDROXYLATION. RX PubMed=28296633; DOI=10.7554/elife.22693; RA Miles A.L., Burr S.P., Grice G.L., Nathan J.A.; RT "The vacuolar-ATPase complex and assembly factors, TMEM199 and CCDC115, RT control HIF1alpha prolyl hydroxylation by regulating cellular iron RT levels."; RL Elife 6:E22693-E22693(2017). RN [58] RP FUNCTION, GLYCOSYLATION AT ARG-18 (MICROBIAL INFECTION), AND MUTAGENESIS OF RP ARG-18. RX PubMed=30125331; DOI=10.1371/journal.ppat.1007259; RA Xu C., Liu X., Zha H., Fan S., Zhang D., Li S., Xiao W.; RT "A pathogen-derived effector modulates host glucose metabolism by arginine RT GlcNAcylation of HIF-1alpha protein."; RL PLoS Pathog. 14:e1007259-e1007259(2018). RN [59] RP FUNCTION (MICROBIAL INFECTION), AND ACTIVITY REGULATION. RX PubMed=32697943; DOI=10.1016/j.cmet.2020.07.007; RA Codo A.C., Davanzo G.G., Monteiro L.B., de Souza G.F., Muraro S.P., RA Virgilio-da-Silva J.V., Prodonoff J.S., Carregari V.C., RA de Biagi Junior C.A.O., Crunfli F., Jimenez Restrepo J.L., Vendramini P.H., RA Reis-de-Oliveira G., Bispo Dos Santos K., Toledo-Teixeira D.A., RA Parise P.L., Martini M.C., Marques R.E., Carmo H.R., Borin A., RA Coimbra L.D., Boldrini V.O., Brunetti N.S., Vieira A.S., Mansour E., RA Ulaf R.G., Bernardes A.F., Nunes T.A., Ribeiro L.C., Palma A.C., RA Agrela M.V., Moretti M.L., Sposito A.C., Pereira F.B., Velloso L.A., RA Vinolo M.A.R., Damasio A., Proenca-Modena J.L., Carvalho R.F., Mori M.A., RA Martins-de-Souza D., Nakaya H.I., Farias A.S., Moraes-Vieira P.M.; RT "Elevated Glucose Levels Favor SARS-CoV-2 Infection and Monocyte Response RT through a HIF-1alpha/Glycolysis-Dependent Axis."; RL Cell Metab. 0:0-0(2020). RN [60] RP 3D-STRUCTURE MODELING. RX PubMed=11089639; DOI=10.1080/07391102.2000.10506656; RA Michel G., Minet E., Ernest I., Roland I., Durant F., Remacle J., RA Michiels C.; RT "A model for the complex between the hypoxia-inducible factor-1 (HIF-1) and RT its consensus DNA sequence."; RL J. Biomol. Struct. Dyn. 18:169-179(2000). RN [61] RP X-RAY CRYSTALLOGRAPHY (2.15 ANGSTROMS) OF 775-826 IN COMPLEX WITH HIF1AN. RX PubMed=12446723; DOI=10.1074/jbc.c200644200; RA Elkins J.M., Hewitson K.S., McNeill L.A., Seibel J.F., Schlemminger I., RA Pugh C.W., Ratcliffe P.J., Schofield C.J.; RT "Structure of factor-inhibiting hypoxia-inducible factor (HIF) reveals RT mechanism of oxidative modification of HIF-1 alpha."; RL J. Biol. Chem. 278:1802-1806(2003). RN [62] RP STRUCTURE BY NMR OF 786-826 IN COMPLEX WITH 302-418 OF EP300. RX PubMed=11959990; DOI=10.1073/pnas.082117899; RA Freedman S.J., Sun Z.-Y.J., Poy F., Kung A.L., Livingston D.M., Wagner G., RA Eck M.J.; RT "Structural basis for recruitment of CBP/p300 by hypoxia-inducible factor-1 RT alpha."; RL Proc. Natl. Acad. Sci. U.S.A. 99:5367-5372(2002). RN [63] RP STRUCTURE BY NMR OF 776-826 IN COMPLEX WITH 345-439 OF CREBBP. RX PubMed=11959977; DOI=10.1073/pnas.082121399; RA Dames S.A., Martinez-Yamout M., De Guzman R.N., Dyson H.J., Wright P.E.; RT "Structural basis for Hif-1 alpha /CBP recognition in the cellular hypoxic RT response."; RL Proc. Natl. Acad. Sci. U.S.A. 99:5271-5276(2002). RN [64] RP X-RAY CRYSTALLOGRAPHY (1.85 ANGSTROMS) OF 556-575 IN COMPLEX WITH ELOB; RP ELOC AND 54-213 OF VHL. RX PubMed=12004076; DOI=10.1126/science.1073440; RA Min J.-H., Yang H., Ivan M., Gertler F., Kaelin W.G. Jr., Pavletich N.P.; RT "Structure of an HIF-1alpha-pVHL complex: hydroxyproline recognition in RT signaling."; RL Science 296:1886-1889(2002). RN [65] RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 549-582 IN COMPLEX WITH 17-112 OF RP ELOB; ELOC AND 52-213 OF VHL. RX PubMed=12050673; DOI=10.1038/nature00767; RA Hon W.-C., Wilson M.I., Harlos K., Claridge T.D.W., Schofield C.J., RA Pugh C.W., Maxwell P.H., Ratcliffe P.J., Stuart D.I., Jones E.Y.; RT "Structural basis for the recognition of hydroxyproline in HIF-1 alpha by RT pVHL."; RL Nature 417:975-978(2002). CC -!- FUNCTION: Functions as a master transcriptional regulator of the CC adaptive response to hypoxia (PubMed:11292861, PubMed:11566883, CC PubMed:15465032, PubMed:16973622, PubMed:17610843, PubMed:18658046, CC PubMed:20624928, PubMed:22009797, PubMed:9887100, PubMed:30125331). CC Under hypoxic conditions, activates the transcription of over 40 genes, CC including erythropoietin, glucose transporters, glycolytic enzymes, CC vascular endothelial growth factor, HILPDA, and other genes whose CC protein products increase oxygen delivery or facilitate metabolic CC adaptation to hypoxia (PubMed:11292861, PubMed:11566883, CC PubMed:15465032, PubMed:16973622, PubMed:17610843, PubMed:20624928, CC PubMed:22009797, PubMed:9887100, PubMed:30125331). Plays an essential CC role in embryonic vascularization, tumor angiogenesis and CC pathophysiology of ischemic disease (PubMed:22009797). Heterodimerizes CC with ARNT; heterodimer binds to core DNA sequence 5'-TACGTG-3' within CC the hypoxia response element (HRE) of target gene promoters (By CC similarity). Activation requires recruitment of transcriptional CC coactivators such as CREBBP and EP300 (PubMed:9887100, CC PubMed:16543236). Activity is enhanced by interaction with NCOA1 and/or CC NCOA2 (PubMed:10594042). Interaction with redox regulatory protein CC APEX1 seems to activate CTAD and potentiates activation by NCOA1 and CC CREBBP (PubMed:10202154, PubMed:10594042). Involved in the axonal CC distribution and transport of mitochondria in neurons during hypoxia CC (PubMed:19528298). {ECO:0000250|UniProtKB:Q61221, CC ECO:0000269|PubMed:10202154, ECO:0000269|PubMed:10594042, CC ECO:0000269|PubMed:11292861, ECO:0000269|PubMed:11566883, CC ECO:0000269|PubMed:15465032, ECO:0000269|PubMed:16543236, CC ECO:0000269|PubMed:16973622, ECO:0000269|PubMed:17610843, CC ECO:0000269|PubMed:18658046, ECO:0000269|PubMed:19528298, CC ECO:0000269|PubMed:20624928, ECO:0000269|PubMed:22009797, CC ECO:0000269|PubMed:30125331, ECO:0000269|PubMed:9887100}. CC -!- FUNCTION: (Microbial infection) Upon infection by human coronavirus CC SARS-CoV-2, is required for induction of glycolysis in monocytes and CC the consequent pro-inflammatory state (PubMed:32697943). In monocytes, CC induces expression of ACE2 and cytokines such as IL1B, TNF, IL6, and CC interferons (PubMed:32697943). Promotes human coronavirus SARS-CoV-2 CC replication and monocyte inflammatory response (PubMed:32697943). CC {ECO:0000269|PubMed:32697943}. CC -!- ACTIVITY REGULATION: Induced by reactive oxygen species (ROS). CC {ECO:0000269|PubMed:32697943}. CC -!- ACTIVITY REGULATION: (Microbial infection) In monocytes, human CC coronavirus SARS-CoV-2 increases HIF1A levels and activity which CC promotes a pro-inflammatory state. {ECO:0000269|PubMed:32697943}. CC -!- SUBUNIT: Interacts with the ARNT; forms a heterodimer that binds core CC DNA sequence 5'-TACGTG-3' within the hypoxia response element (HRE) of CC target gene promoters (PubMed:10944113, PubMed:20699359). Interacts CC with COPS5; the interaction increases the transcriptional activity of CC HIF1A through increased stability (By similarity). Interacts with EP300 CC (via TAZ-type 1 domains); the interaction is stimulated in response to CC hypoxia and inhibited by CITED2 (PubMed:8917528, PubMed:9887100, CC PubMed:12778114, PubMed:16543236, PubMed:16973622, PubMed:11959990). CC Interacts with CREBBP (via TAZ-type 1 domains) (PubMed:8917528, CC PubMed:11959977). Interacts with NCOA1, NCOA2, APEX1 and HSP90 CC (PubMed:10594042, PubMed:10202154). Interacts (hydroxylated within the CC ODD domain) with VHLL (via beta domain); the interaction, leads to CC polyubiquitination and subsequent HIF1A proteasomal degradation CC (PubMed:14757845). During hypoxia, sumoylated HIF1A also binds VHL; the CC interaction promotes the ubiquitination of HIF1A (PubMed:11006129, CC PubMed:10944113, PubMed:16862177, PubMed:12004076, PubMed:12050673). CC Interacts with SENP1; the interaction desumoylates HIF1A resulting in CC stabilization and activation of transcription (By similarity). CC Interacts (via the ODD domain) with NAA10; the interaction appears not CC to acetylate HIF1A nor have any affect on protein stability, during CC hypoxia (PubMed:12464182, PubMed:16288748). Interacts with RWDD3; the CC interaction enhances HIF1A sumoylation (PubMed:17956732, CC PubMed:23469069). Interacts with TSGA10 (By similarity). Interacts with CC HIF3A (By similarity). Interacts with RORA (via the DNA binding CC domain); the interaction enhances HIF1A transcription under hypoxia CC through increasing protein stability (PubMed:18658046). Interaction CC with PSMA7 inhibits the transactivation activity of HIF1A under both CC normoxic and hypoxia-mimicking conditions (PubMed:11389899). Interacts CC with USP20 (PubMed:15776016). Interacts with RACK1; promotes HIF1A CC ubiquitination and proteasome-mediated degradation (PubMed:17244529). CC Interacts (via N-terminus) with USP19 (PubMed:22128162). Interacts with CC SIRT2 (PubMed:24681946). Interacts (deacetylated form) with EGLN1 CC (PubMed:24681946). Interacts with CBFA2T3 (PubMed:25974097). Interacts CC with HSP90AA1 and HSP90AB1 (PubMed:26517842). Interacts with DCUN1D1; CC this interaction increases the interaction between VHL and DCUN1D1 CC (PubMed:23401859). Interacts with HIF1AN (PubMed:12446723). CC {ECO:0000250|UniProtKB:Q61221, ECO:0000269|PubMed:10202154, CC ECO:0000269|PubMed:10594042, ECO:0000269|PubMed:10944113, CC ECO:0000269|PubMed:11006129, ECO:0000269|PubMed:11389899, CC ECO:0000269|PubMed:11959977, ECO:0000269|PubMed:11959990, CC ECO:0000269|PubMed:12004076, ECO:0000269|PubMed:12050673, CC ECO:0000269|PubMed:12446723, ECO:0000269|PubMed:12464182, CC ECO:0000269|PubMed:12778114, ECO:0000269|PubMed:14757845, CC ECO:0000269|PubMed:15776016, ECO:0000269|PubMed:16288748, CC ECO:0000269|PubMed:16543236, ECO:0000269|PubMed:16862177, CC ECO:0000269|PubMed:16973622, ECO:0000269|PubMed:17244529, CC ECO:0000269|PubMed:17956732, ECO:0000269|PubMed:18658046, CC ECO:0000269|PubMed:20699359, ECO:0000269|PubMed:22128162, CC ECO:0000269|PubMed:23401859, ECO:0000269|PubMed:23469069, CC ECO:0000269|PubMed:24681946, ECO:0000269|PubMed:25974097, CC ECO:0000269|PubMed:26517842, ECO:0000269|PubMed:8917528, CC ECO:0000269|PubMed:9887100}. CC -!- INTERACTION: CC Q16665; P10275: AR; NbExp=2; IntAct=EBI-447269, EBI-608057; CC Q16665; P27540: ARNT; NbExp=12; IntAct=EBI-447269, EBI-80809; CC Q16665; P49407: ARRB1; NbExp=3; IntAct=EBI-447269, EBI-743313; CC Q16665; Q9C0J9: BHLHE41; NbExp=2; IntAct=EBI-447269, EBI-10988877; CC Q16665; O00257: CBX4; NbExp=15; IntAct=EBI-447269, EBI-722425; CC Q16665; Q92793: CREBBP; NbExp=2; IntAct=EBI-447269, EBI-81215; CC Q16665; P35222: CTNNB1; NbExp=4; IntAct=EBI-447269, EBI-491549; CC Q16665; Q96CJ1: EAF2; NbExp=3; IntAct=EBI-447269, EBI-1245604; CC Q16665; Q9GZT9: EGLN1; NbExp=4; IntAct=EBI-447269, EBI-1174818; CC Q16665; Q96KS0: EGLN2; NbExp=2; IntAct=EBI-447269, EBI-726614; CC Q16665; Q9H6Z9: EGLN3; NbExp=6; IntAct=EBI-447269, EBI-1175354; CC Q16665; Q09472: EP300; NbExp=20; IntAct=EBI-447269, EBI-447295; CC Q16665; P11474: ESRRA; NbExp=3; IntAct=EBI-447269, EBI-372412; CC Q16665; P49327: FASN; NbExp=4; IntAct=EBI-447269, EBI-356658; CC Q16665; P09467: FBP1; NbExp=5; IntAct=EBI-447269, EBI-712740; CC Q16665; Q8N461: FBXL16; NbExp=6; IntAct=EBI-447269, EBI-7208098; CC Q16665; P23771: GATA3; NbExp=3; IntAct=EBI-447269, EBI-6664760; CC Q16665; Q9NWT6: HIF1AN; NbExp=12; IntAct=EBI-447269, EBI-745632; CC Q16665; Q9Y2N7-4: HIF3A; NbExp=2; IntAct=EBI-447269, EBI-38258397; CC Q16665; Q92831: KAT2B; NbExp=2; IntAct=EBI-447269, EBI-477430; CC Q16665; Q13330: MTA1; NbExp=6; IntAct=EBI-447269, EBI-714236; CC Q16665; P46531: NOTCH1; NbExp=2; IntAct=EBI-447269, EBI-636374; CC Q16665; Q13438: OS9; NbExp=9; IntAct=EBI-447269, EBI-725454; CC Q16665; Q8N2W9: PIAS4; NbExp=3; IntAct=EBI-447269, EBI-473160; CC Q16665; P14618-1: PKM; NbExp=7; IntAct=EBI-447269, EBI-4304679; CC Q16665; P25789: PSMA4; NbExp=4; IntAct=EBI-447269, EBI-359310; CC Q16665; Q9UHD8-1: SEPTIN9; NbExp=4; IntAct=EBI-447269, EBI-851558; CC Q16665; P84022: SMAD3; NbExp=6; IntAct=EBI-447269, EBI-347161; CC Q16665; P08047: SP1; NbExp=3; IntAct=EBI-447269, EBI-298336; CC Q16665; P63165: SUMO1; NbExp=4; IntAct=EBI-447269, EBI-80140; CC Q16665; O94888: UBXN7; NbExp=3; IntAct=EBI-447269, EBI-1993627; CC Q16665; P40818: USP8; NbExp=2; IntAct=EBI-447269, EBI-1050865; CC Q16665; P40337: VHL; NbExp=19; IntAct=EBI-447269, EBI-301246; CC Q16665; P17861: XBP1; NbExp=3; IntAct=EBI-447269, EBI-6942961; CC Q16665; Q99PV5: Bhlhe41; Xeno; NbExp=3; IntAct=EBI-447269, EBI-6143801; CC Q16665; Q5RIX9: e2f7; Xeno; NbExp=2; IntAct=EBI-447269, EBI-8030618; CC Q16665; Q6S7F2: E2f7; Xeno; NbExp=3; IntAct=EBI-447269, EBI-8030813; CC Q16665; Q61539: Esrrb; Xeno; NbExp=2; IntAct=EBI-447269, EBI-2312731; CC Q16665; Q8BIF2: Rbfox3; Xeno; NbExp=2; IntAct=EBI-447269, EBI-4567146; CC Q16665; P51450-2: Rorc; Xeno; NbExp=2; IntAct=EBI-447269, EBI-4422078; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:9822602}. Nucleus CC {ECO:0000269|PubMed:22009797, ECO:0000269|PubMed:9822602}. Nucleus CC speckle {ECO:0000250|UniProtKB:Q61221}. Note=Colocalizes with HIF3A in CC the nucleus and speckles (By similarity). Cytoplasmic in normoxia, CC nuclear translocation in response to hypoxia (PubMed:9822602). CC {ECO:0000250|UniProtKB:Q61221, ECO:0000269|PubMed:9822602}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=1; CC IsoId=Q16665-1; Sequence=Displayed; CC Name=2; CC IsoId=Q16665-2; Sequence=VSP_047335, VSP_007738; CC Name=3; Synonyms=I.3; CC IsoId=Q16665-3; Sequence=VSP_044942; CC -!- TISSUE SPECIFICITY: Expressed in most tissues with highest levels in CC kidney and heart. Overexpressed in the majority of common human cancers CC and their metastases, due to the presence of intratumoral hypoxia and CC as a result of mutations in genes encoding oncoproteins and tumor CC suppressors. A higher level expression seen in pituitary tumors as CC compared to the pituitary gland. {ECO:0000269|PubMed:22009797}. CC -!- INDUCTION: Under reduced oxygen tension. Induced also by various CC receptor-mediated factors such as growth factors, cytokines, and CC circulatory factors such as PDGF, EGF, FGF2, IGF2, TGFB1, HGF, TNF, CC IL1B/interleukin-1 beta, angiotensin-2 and thrombin. However, this CC induction is less intense than that stimulated by hypoxia. Repressed by CC HIPK2 and LIMD1. {ECO:0000269|PubMed:19046997, CC ECO:0000269|PubMed:22009797, ECO:0000269|PubMed:22286099}. CC -!- DOMAIN: Contains two independent C-terminal transactivation domains, CC NTAD and CTAD, which function synergistically. Their transcriptional CC activity is repressed by an intervening inhibitory domain (ID). CC {ECO:0000269|PubMed:10202154, ECO:0000269|PubMed:9235919}. CC -!- PTM: S-nitrosylation of Cys-800 may be responsible for increased CC recruitment of p300 coactivator necessary for transcriptional activity CC of HIF-1 complex. {ECO:0000269|PubMed:12560087, CC ECO:0000269|PubMed:12914934}. CC -!- PTM: Requires phosphorylation for DNA-binding. Phosphorylation at Ser- CC 247 by CSNK1D/CK1 represses kinase activity and impairs ARNT binding CC (PubMed:20699359, PubMed:20889502). Phosphorylation by GSK3-beta and CC PLK3 promote degradation by the proteasome (By similarity). CC {ECO:0000250|UniProtKB:Q61221, ECO:0000269|PubMed:20699359, CC ECO:0000269|PubMed:20889502}. CC -!- PTM: Sumoylated; with SUMO1 under hypoxia (PubMed:15465032, CC PubMed:15776016, PubMed:17610843). Sumoylation is enhanced through CC interaction with RWDD3 (PubMed:17956732). Both sumoylation and CC desumoylation seem to be involved in the regulation of its stability CC during hypoxia (PubMed:15465032, PubMed:15776016, PubMed:17610843). CC Sumoylation can promote either its stabilization or its VHL-dependent CC degradation by promoting hydroxyproline-independent HIF1A-VHL complex CC binding, thus leading to HIF1A ubiquitination and proteasomal CC degradation (PubMed:15465032, PubMed:15776016, PubMed:17610843). CC Desumoylation by SENP1 increases its stability amd transcriptional CC activity (By similarity). There is a disaccord between various CC publications on the effect of sumoylation and desumoylation on its CC stability and transcriptional activity (Probable). CC {ECO:0000250|UniProtKB:Q61221, ECO:0000269|PubMed:15465032, CC ECO:0000269|PubMed:15776016, ECO:0000269|PubMed:17610843, CC ECO:0000269|PubMed:17956732, ECO:0000305}. CC -!- PTM: Acetylation of Lys-532 by ARD1 increases interaction with VHL and CC stimulates subsequent proteasomal degradation (PubMed:12464182). CC Deacetylation of Lys-709 by SIRT2 increases its interaction with and CC hydroxylation by EGLN1 thereby inactivating HIF1A activity by inducing CC its proteasomal degradation (PubMed:24681946). CC {ECO:0000269|PubMed:12464182, ECO:0000269|PubMed:24681946}. CC -!- PTM: Polyubiquitinated; in normoxia, following hydroxylation and CC interaction with VHL. Lys-532 appears to be the principal site of CC ubiquitination. Clioquinol, the Cu/Zn-chelator, inhibits ubiquitination CC through preventing hydroxylation at Asn-803. Ubiquitinated by E3 ligase CC VHL (PubMed:25615526). Deubiquitinated by UCHL1 (PubMed:25615526). CC {ECO:0000269|PubMed:12080085, ECO:0000269|PubMed:15776016, CC ECO:0000269|PubMed:16862177, ECO:0000269|PubMed:22537386, CC ECO:0000269|PubMed:25615526, ECO:0000269|PubMed:25974097}. CC -!- PTM: In normoxia, is hydroxylated on Pro-402 and Pro-564 in the oxygen- CC dependent degradation domain (ODD) by EGLN1/PHD2 and EGLN2/PHD1 CC (PubMed:11292861, PubMed:11566883, PubMed:12351678, PubMed:15776016, CC PubMed:25974097). EGLN3/PHD3 has also been shown to hydroxylate Pro-564 CC (PubMed:11292861, PubMed:11566883, PubMed:12351678, PubMed:15776016, CC PubMed:25974097). The hydroxylated prolines promote interaction with CC VHL, initiating rapid ubiquitination and subsequent proteasomal CC degradation (PubMed:11292861, PubMed:11566883, PubMed:12351678, CC PubMed:15776016, PubMed:25974097). Deubiquitinated by USP20 CC (PubMed:11292861, PubMed:11566883, PubMed:12351678, PubMed:15776016, CC PubMed:25974097). Under hypoxia, proline hydroxylation is impaired and CC ubiquitination is attenuated, resulting in stabilization CC (PubMed:11292861, PubMed:11566883, PubMed:12351678, PubMed:15776016, CC PubMed:25974097). In normoxia, is hydroxylated on Asn-803 by HIF1AN, CC thus abrogating interaction with CREBBP and EP300 and preventing CC transcriptional activation (PubMed:12080085). This hydroxylation is CC inhibited by the Cu/Zn-chelator, Clioquinol (PubMed:12080085). CC Repressed by iron ion, via Fe(2+) prolyl hydroxylase (PHD) enzymes- CC mediated hydroxylation and subsequent proteasomal degradation CC (PubMed:28296633). {ECO:0000269|PubMed:11292861, CC ECO:0000269|PubMed:11566883, ECO:0000269|PubMed:12080085, CC ECO:0000269|PubMed:12351678, ECO:0000269|PubMed:15776016, CC ECO:0000269|PubMed:25974097, ECO:0000269|PubMed:28296633}. CC -!- PTM: The iron and 2-oxoglutarate dependent 3-hydroxylation of CC asparagine is (S) stereospecific within HIF CTAD domains. CC {ECO:0000269|PubMed:12080085}. CC -!- PTM: (Microbial infection) Glycosylated at Arg-18 by enteropathogenic CC E.coli protein NleB1: arginine GlcNAcylation enhances transcription CC factor activity and impairs glucose metabolism. CC {ECO:0000269|PubMed:30125331}. CC -!- MISCELLANEOUS: [Isoform 3]: Up-regulated in peripheral T-lymphocytes CC after T-cell receptor stimulation. Highest expression in peripheral CC blood leukocytes and thymus. {ECO:0000305}. CC -!- WEB RESOURCE: Name=Wikipedia; Note=Hypoxia inducible factor entry; CC URL="https://en.wikipedia.org/wiki/Hypoxia_inducible_factor"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; U22431; AAC50152.1; -; mRNA. DR EMBL; U29165; AAC51210.1; -; mRNA. DR EMBL; AF050127; AAC68568.1; -; Genomic_DNA. DR EMBL; AF050115; AAC68568.1; JOINED; Genomic_DNA. DR EMBL; AF050116; AAC68568.1; JOINED; Genomic_DNA. DR EMBL; AF050117; AAC68568.1; JOINED; Genomic_DNA. DR EMBL; AF050118; AAC68568.1; JOINED; Genomic_DNA. DR EMBL; AF050119; AAC68568.1; JOINED; Genomic_DNA. DR EMBL; AF050120; AAC68568.1; JOINED; Genomic_DNA. DR EMBL; AF050121; AAC68568.1; JOINED; Genomic_DNA. DR EMBL; AF050122; AAC68568.1; JOINED; Genomic_DNA. DR EMBL; AF050123; AAC68568.1; JOINED; Genomic_DNA. DR EMBL; AF050124; AAC68568.1; JOINED; Genomic_DNA. DR EMBL; AF050125; AAC68568.1; JOINED; Genomic_DNA. DR EMBL; AF050126; AAC68568.1; JOINED; Genomic_DNA. DR EMBL; FJ790247; ACN88547.1; -; mRNA. DR EMBL; AF207601; AAF20139.1; -; mRNA. DR EMBL; AF207602; AAF20140.1; -; mRNA. DR EMBL; AF208487; AAF20149.1; -; Genomic_DNA. DR EMBL; AF304431; AAG43026.1; -; mRNA. DR EMBL; AB073325; BAB70608.1; -; mRNA. DR EMBL; BT009776; AAP88778.1; -; mRNA. DR EMBL; AL137129; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC012527; AAH12527.1; -; mRNA. DR CCDS; CCDS9753.1; -. [Q16665-1] DR CCDS; CCDS9754.1; -. [Q16665-2] DR PIR; I38972; I38972. DR RefSeq; NP_001230013.1; NM_001243084.1. [Q16665-3] DR RefSeq; NP_001521.1; NM_001530.3. [Q16665-1] DR RefSeq; NP_851397.1; NM_181054.2. [Q16665-2] DR PDB; 1H2K; X-ray; 2.15 A; S=786-826. DR PDB; 1H2L; X-ray; 2.25 A; S=786-826. DR PDB; 1H2M; X-ray; 2.50 A; S=775-826. DR PDB; 1L3E; NMR; -; A=786-826. DR PDB; 1L8C; NMR; -; B=776-826. DR PDB; 1LM8; X-ray; 1.85 A; H=556-575. DR PDB; 1LQB; X-ray; 2.00 A; D=549-582. DR PDB; 2ILM; X-ray; 2.30 A; S=786-826. DR PDB; 3HQR; X-ray; 2.00 A; S=558-574. DR PDB; 3HQU; X-ray; 2.30 A; S=558-574. DR PDB; 4AJY; X-ray; 1.73 A; H=559-577. DR PDB; 4H6J; X-ray; 1.52 A; A=238-348. DR PDB; 5JWP; X-ray; 2.10 A; B=788-806. DR PDB; 5L9B; X-ray; 1.95 A; C/D=556-574. DR PDB; 5L9V; X-ray; 1.83 A; C/D=395-411. DR PDB; 5LA9; X-ray; 2.81 A; C/D=395-411. DR PDB; 5LAS; X-ray; 2.10 A; C/D=395-411. DR PDB; 6GFX; X-ray; 1.83 A; D=560-577. DR PDB; 6GMR; X-ray; 1.75 A; H=560-577. DR PDB; 6YW3; X-ray; 2.28 A; S=556-574. DR PDB; 7LVS; X-ray; 2.02 A; F=796-826. DR PDB; 7QGS; X-ray; 2.00 A; B=794-826. DR PDB; 8HE0; X-ray; 1.80 A; B=717-757. DR PDB; 8HE3; X-ray; 1.90 A; B=749-757. DR PDBsum; 1H2K; -. DR PDBsum; 1H2L; -. DR PDBsum; 1H2M; -. DR PDBsum; 1L3E; -. DR PDBsum; 1L8C; -. DR PDBsum; 1LM8; -. DR PDBsum; 1LQB; -. DR PDBsum; 2ILM; -. DR PDBsum; 3HQR; -. DR PDBsum; 3HQU; -. DR PDBsum; 4AJY; -. DR PDBsum; 4H6J; -. DR PDBsum; 5JWP; -. DR PDBsum; 5L9B; -. DR PDBsum; 5L9V; -. DR PDBsum; 5LA9; -. DR PDBsum; 5LAS; -. DR PDBsum; 6GFX; -. DR PDBsum; 6GMR; -. DR PDBsum; 6YW3; -. DR PDBsum; 7LVS; -. DR PDBsum; 7QGS; -. DR PDBsum; 8HE0; -. DR PDBsum; 8HE3; -. DR AlphaFoldDB; Q16665; -. DR SMR; Q16665; -. DR BioGRID; 109338; 435. DR ComplexPortal; CPX-7381; Hypoxia-inducible transcription factor complex, HIF1. DR CORUM; Q16665; -. DR DIP; DIP-29722N; -. DR ELM; Q16665; -. DR IntAct; Q16665; 109. DR MINT; Q16665; -. DR STRING; 9606.ENSP00000437955; -. DR BindingDB; Q16665; -. DR ChEMBL; CHEMBL4261; -. DR DrugBank; DB02342; 2-Methoxyestradiol. DR DrugBank; DB01136; Carvedilol. DR DrugBank; DB05959; ENMD-1198. DR DrugBank; DB08687; FG-2216. DR DrugBank; DB01275; Hydralazine. DR DrugBank; DB06082; PX-478. DR DrugBank; DB12255; Vadadustat. DR DrugCentral; Q16665; -. DR GlyCosmos; Q16665; 1 site, No reported glycans. DR GlyGen; Q16665; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; Q16665; -. DR PhosphoSitePlus; Q16665; -. DR BioMuta; HIF1A; -. DR DMDM; 2498017; -. DR jPOST; Q16665; -. DR MassIVE; Q16665; -. DR MaxQB; Q16665; -. DR PaxDb; 9606-ENSP00000437955; -. DR PeptideAtlas; Q16665; -. DR ProteomicsDB; 61021; -. [Q16665-1] DR ProteomicsDB; 61022; -. [Q16665-2] DR ProteomicsDB; 7584; -. DR ABCD; Q16665; 16 sequenced antibodies. DR Antibodypedia; 84; 2532 antibodies from 53 providers. DR DNASU; 3091; -. DR Ensembl; ENST00000323441.10; ENSP00000323326.6; ENSG00000100644.17. [Q16665-2] DR Ensembl; ENST00000337138.9; ENSP00000338018.4; ENSG00000100644.17. [Q16665-1] DR Ensembl; ENST00000539097.2; ENSP00000437955.1; ENSG00000100644.17. [Q16665-3] DR GeneID; 3091; -. DR KEGG; hsa:3091; -. DR MANE-Select; ENST00000337138.9; ENSP00000338018.4; NM_001530.4; NP_001521.1. DR UCSC; uc001xfq.3; human. [Q16665-1] DR AGR; HGNC:4910; -. DR CTD; 3091; -. DR DisGeNET; 3091; -. DR GeneCards; HIF1A; -. DR HGNC; HGNC:4910; HIF1A. DR HPA; ENSG00000100644; Tissue enhanced (bone). DR MIM; 603348; gene. DR neXtProt; NX_Q16665; -. DR OpenTargets; ENSG00000100644; -. DR PharmGKB; PA29283; -. DR VEuPathDB; HostDB:ENSG00000100644; -. DR eggNOG; KOG3558; Eukaryota. DR GeneTree; ENSGT00940000156774; -. DR InParanoid; Q16665; -. DR OMA; NSPSDYC; -. DR OrthoDB; 5396877at2759; -. DR PhylomeDB; Q16665; -. DR TreeFam; TF317772; -. DR PathwayCommons; Q16665; -. DR Reactome; R-HSA-1234158; Regulation of gene expression by Hypoxia-inducible Factor. DR Reactome; R-HSA-1234174; Cellular response to hypoxia. DR Reactome; R-HSA-1234176; Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha. DR Reactome; R-HSA-2122947; NOTCH1 Intracellular Domain Regulates Transcription. DR Reactome; R-HSA-400253; Circadian Clock. DR Reactome; R-HSA-5689880; Ub-specific processing proteases. DR Reactome; R-HSA-6785807; Interleukin-4 and Interleukin-13 signaling. DR Reactome; R-HSA-8849473; PTK6 Expression. DR Reactome; R-HSA-8857538; PTK6 promotes HIF1A stabilization. DR Reactome; R-HSA-8951664; Neddylation. DR Reactome; R-HSA-9701898; STAT3 nuclear events downstream of ALK signaling. DR SignaLink; Q16665; -. DR SIGNOR; Q16665; -. DR BioGRID-ORCS; 3091; 15 hits in 1194 CRISPR screens. DR ChiTaRS; HIF1A; human. DR EvolutionaryTrace; Q16665; -. DR GeneWiki; HIF1A; -. DR GenomeRNAi; 3091; -. DR Pharos; Q16665; Tchem. DR PRO; PR:Q16665; -. DR Proteomes; UP000005640; Chromosome 14. DR RNAct; Q16665; Protein. DR Bgee; ENSG00000100644; Expressed in pancreatic ductal cell and 206 other cell types or tissues. DR ExpressionAtlas; Q16665; baseline and differential. DR GO; GO:1904115; C:axon cytoplasm; IEA:GOC. DR GO; GO:0000785; C:chromatin; IDA:ARUK-UCL. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0005829; C:cytosol; IDA:UniProtKB. DR GO; GO:0000791; C:euchromatin; IEA:Ensembl. DR GO; GO:0031514; C:motile cilium; IEA:Ensembl. DR GO; GO:0016604; C:nuclear body; IDA:HPA. DR GO; GO:0016607; C:nuclear speck; ISS:UniProtKB. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0032991; C:protein-containing complex; IMP:CAFA. DR GO; GO:0090575; C:RNA polymerase II transcription regulator complex; IDA:BHF-UCL. DR GO; GO:0000987; F:cis-regulatory region sequence-specific DNA binding; IMP:BHF-UCL. DR GO; GO:0001216; F:DNA-binding transcription activator activity; IMP:BHF-UCL. DR GO; GO:0001228; F:DNA-binding transcription activator activity, RNA polymerase II-specific; IDA:ARUK-UCL. DR GO; GO:0003700; F:DNA-binding transcription factor activity; IDA:UniProtKB. DR GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; IDA:BHF-UCL. DR GO; GO:0001217; F:DNA-binding transcription repressor activity; IMP:BHF-UCL. DR GO; GO:0070888; F:E-box binding; IEA:Ensembl. DR GO; GO:0019899; F:enzyme binding; IPI:UniProtKB. DR GO; GO:0042826; F:histone deacetylase binding; IEA:Ensembl. DR GO; GO:0051879; F:Hsp90 protein binding; IDA:BHF-UCL. DR GO; GO:0016922; F:nuclear receptor binding; IPI:UniProtKB. DR GO; GO:0002039; F:p53 binding; IDA:DisProt. DR GO; GO:0019904; F:protein domain specific binding; IPI:CAFA. DR GO; GO:0046982; F:protein heterodimerization activity; IPI:UniProtKB. DR GO; GO:0019901; F:protein kinase binding; IPI:UniProtKB. DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IMP:BHF-UCL. DR GO; GO:0000977; F:RNA polymerase II transcription regulatory region sequence-specific DNA binding; IDA:ARUK-UCL. DR GO; GO:0061629; F:RNA polymerase II-specific DNA-binding transcription factor binding; IPI:BHF-UCL. DR GO; GO:0001223; F:transcription coactivator binding; IPI:UniProtKB. DR GO; GO:0140537; F:transcription regulator activator activity; IPI:DisProt. DR GO; GO:0031625; F:ubiquitin protein ligase binding; IPI:UniProtKB. DR GO; GO:0001525; P:angiogenesis; IEA:Ensembl. DR GO; GO:0019896; P:axonal transport of mitochondrion; IMP:UniProtKB. DR GO; GO:0001922; P:B-1 B cell homeostasis; IEA:Ensembl. DR GO; GO:0030282; P:bone mineralization; IEA:Ensembl. DR GO; GO:0003208; P:cardiac ventricle morphogenesis; IEA:Ensembl. DR GO; GO:0071456; P:cellular response to hypoxia; IDA:UniProtKB. DR GO; GO:0071347; P:cellular response to interleukin-1; IEP:BHF-UCL. DR GO; GO:0034599; P:cellular response to oxidative stress; IDA:BHF-UCL. DR GO; GO:0098586; P:cellular response to virus; IDA:UniProtKB. DR GO; GO:0021987; P:cerebral cortex development; IEA:Ensembl. DR GO; GO:0002062; P:chondrocyte differentiation; IEA:Ensembl. DR GO; GO:0032963; P:collagen metabolic process; ISS:BHF-UCL. DR GO; GO:0002248; P:connective tissue replacement involved in inflammatory response wound healing; ISS:BHF-UCL. DR GO; GO:0048546; P:digestive tract morphogenesis; IEA:Ensembl. DR GO; GO:0071542; P:dopaminergic neuron differentiation; IEA:Ensembl. DR GO; GO:0051541; P:elastin metabolic process; ISS:BHF-UCL. DR GO; GO:0035162; P:embryonic hemopoiesis; IEA:Ensembl. DR GO; GO:0001892; P:embryonic placenta development; IEA:Ensembl. DR GO; GO:0061030; P:epithelial cell differentiation involved in mammary gland alveolus development; IEA:Ensembl. DR GO; GO:0001837; P:epithelial to mesenchymal transition; ISS:BHF-UCL. DR GO; GO:0002071; P:glandular epithelial cell maturation; IEA:Ensembl. DR GO; GO:0001947; P:heart looping; IEA:Ensembl. DR GO; GO:0042541; P:hemoglobin biosynthetic process; IEA:Ensembl. DR GO; GO:0097411; P:hypoxia-inducible factor-1alpha signaling pathway; IEA:Ensembl. DR GO; GO:0035773; P:insulin secretion involved in cellular response to glucose stimulus; IEA:Ensembl. DR GO; GO:0060574; P:intestinal epithelial cell maturation; IEA:Ensembl. DR GO; GO:0001678; P:intracellular glucose homeostasis; IDA:UniProtKB. DR GO; GO:0006879; P:intracellular iron ion homeostasis; IEA:Ensembl. DR GO; GO:0032364; P:intracellular oxygen homeostasis; IDA:HGNC-UCL. DR GO; GO:0061072; P:iris morphogenesis; IEA:Ensembl. DR GO; GO:0006089; P:lactate metabolic process; IEA:Ensembl. DR GO; GO:0007595; P:lactation; IEA:Ensembl. DR GO; GO:0097152; P:mesenchymal cell apoptotic process; IEA:Ensembl. DR GO; GO:0046716; P:muscle cell cellular homeostasis; IEA:Ensembl. DR GO; GO:0030502; P:negative regulation of bone mineralization; IEA:Ensembl. DR GO; GO:0010629; P:negative regulation of gene expression; IMP:BHF-UCL. DR GO; GO:0045926; P:negative regulation of growth; IEA:Ensembl. DR GO; GO:2001054; P:negative regulation of mesenchymal cell apoptotic process; IEA:Ensembl. DR GO; GO:1902894; P:negative regulation of miRNA transcription; IMP:BHF-UCL. DR GO; GO:1903377; P:negative regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway; IDA:ParkinsonsUK-UCL. DR GO; GO:2000378; P:negative regulation of reactive oxygen species metabolic process; IEA:Ensembl. DR GO; GO:0070244; P:negative regulation of thymocyte apoptotic process; IEA:Ensembl. DR GO; GO:0032007; P:negative regulation of TOR signaling; IEA:Ensembl. DR GO; GO:0001755; P:neural crest cell migration; IEA:Ensembl. DR GO; GO:0021502; P:neural fold elevation formation; IEA:Ensembl. DR GO; GO:0007405; P:neuroblast proliferation; IEA:Ensembl. DR GO; GO:0051402; P:neuron apoptotic process; IEA:Ensembl. DR GO; GO:0003151; P:outflow tract morphogenesis; IEA:Ensembl. DR GO; GO:0045766; P:positive regulation of angiogenesis; IMP:UniProtKB. DR GO; GO:0043536; P:positive regulation of blood vessel endothelial cell migration; IMP:BHF-UCL. DR GO; GO:0032722; P:positive regulation of chemokine production; TAS:BHF-UCL. DR GO; GO:0070101; P:positive regulation of chemokine-mediated signaling pathway; IDA:BHF-UCL. DR GO; GO:1900017; P:positive regulation of cytokine production involved in inflammatory response; IDA:UniProtKB. DR GO; GO:0045893; P:positive regulation of DNA-templated transcription; IDA:UniProtKB. DR GO; GO:0001938; P:positive regulation of endothelial cell proliferation; IC:BHF-UCL. DR GO; GO:0010634; P:positive regulation of epithelial cell migration; ISS:BHF-UCL. DR GO; GO:0045648; P:positive regulation of erythrocyte differentiation; IC:BHF-UCL. DR GO; GO:0010628; P:positive regulation of gene expression; IDA:CAFA. DR GO; GO:0045821; P:positive regulation of glycolytic process; IC:BHF-UCL. DR GO; GO:0046886; P:positive regulation of hormone biosynthetic process; IDA:BHF-UCL. DR GO; GO:0035774; P:positive regulation of insulin secretion involved in cellular response to glucose stimulus; IEA:Ensembl. DR GO; GO:1902895; P:positive regulation of miRNA transcription; IDA:ARUK-UCL. DR GO; GO:1901526; P:positive regulation of mitophagy; IEA:Ensembl. DR GO; GO:0002052; P:positive regulation of neuroblast proliferation; IEA:Ensembl. DR GO; GO:0051000; P:positive regulation of nitric-oxide synthase activity; TAS:BHF-UCL. DR GO; GO:2000273; P:positive regulation of signaling receptor activity; IMP:BHF-UCL. DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:UniProtKB. DR GO; GO:0010575; P:positive regulation of vascular endothelial growth factor production; IDA:BHF-UCL. DR GO; GO:0030949; P:positive regulation of vascular endothelial growth factor receptor signaling pathway; IC:BHF-UCL. DR GO; GO:1903715; P:regulation of aerobic respiration; IEA:Ensembl. DR GO; GO:0006355; P:regulation of DNA-templated transcription; IDA:UniProtKB. DR GO; GO:0010468; P:regulation of gene expression; IDA:UniProtKB. DR GO; GO:0006110; P:regulation of glycolytic process; IDA:UniProtKB. DR GO; GO:2000434; P:regulation of protein neddylation; IMP:UniProtKB. DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IBA:GO_Central. DR GO; GO:0032909; P:regulation of transforming growth factor beta2 production; IMP:BHF-UCL. DR GO; GO:0001666; P:response to hypoxia; IDA:UniProtKB. DR GO; GO:0010039; P:response to iron ion; IEP:UniProtKB. DR GO; GO:0014850; P:response to muscle activity; IEA:Ensembl. DR GO; GO:0000302; P:response to reactive oxygen species; IDA:UniProtKB. DR GO; GO:0061298; P:retina vasculature development in camera-type eye; IEA:Ensembl. DR GO; GO:0007165; P:signal transduction; IMP:BHF-UCL. DR GO; GO:0031929; P:TOR signaling; IEA:Ensembl. DR GO; GO:0010573; P:vascular endothelial growth factor production; IDA:BHF-UCL. DR GO; GO:0008542; P:visual learning; IEA:Ensembl. DR CDD; cd19727; bHLH-PAS_HIF1a_PASD8; 1. DR CDD; cd00130; PAS; 2. DR DisProt; DP00262; -. DR Gene3D; 4.10.280.10; Helix-loop-helix DNA-binding domain; 1. DR Gene3D; 3.30.450.20; PAS domain; 2. DR IDEAL; IID00085; -. DR InterPro; IPR011598; bHLH_dom. DR InterPro; IPR001321; HIF-1_alpha. DR InterPro; IPR014887; HIF-1_CTAD. DR InterPro; IPR021537; HIF_alpha-like. DR InterPro; IPR036638; HLH_DNA-bd_sf. DR InterPro; IPR001610; PAC. DR InterPro; IPR000014; PAS. DR InterPro; IPR035965; PAS-like_dom_sf. DR InterPro; IPR013767; PAS_fold. DR InterPro; IPR013655; PAS_fold_3. DR NCBIfam; TIGR00229; sensory_box; 2. DR PANTHER; PTHR23043; HYPOXIA-INDUCIBLE FACTOR 1 ALPHA; 1. DR PANTHER; PTHR23043:SF7; HYPOXIA-INDUCIBLE FACTOR 1-ALPHA; 1. DR Pfam; PF11413; HIF-1; 1. DR Pfam; PF08778; HIF-1a_CTAD; 1. DR Pfam; PF00989; PAS; 1. DR Pfam; PF08447; PAS_3; 1. DR PRINTS; PR01080; HYPOXIAIF1A. DR SMART; SM00353; HLH; 1. DR SMART; SM00086; PAC; 1. DR SMART; SM00091; PAS; 2. DR SUPFAM; SSF47459; HLH, helix-loop-helix DNA-binding domain; 1. DR SUPFAM; SSF55785; PYP-like sensor domain (PAS domain); 2. DR PROSITE; PS50888; BHLH; 1. DR PROSITE; PS50112; PAS; 2. DR Genevisible; Q16665; HS. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; Activator; Alternative splicing; Cytoplasm; KW Direct protein sequencing; DNA-binding; Glycoprotein; KW Host-virus interaction; Hydroxylation; Isopeptide bond; Nucleus; KW Phosphoprotein; Reference proteome; Repeat; S-nitrosylation; Transcription; KW Transcription regulation; Ubl conjugation. FT CHAIN 1..826 FT /note="Hypoxia-inducible factor 1-alpha" FT /id="PRO_0000127220" FT DOMAIN 17..70 FT /note="bHLH" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00981" FT DOMAIN 85..158 FT /note="PAS 1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00140" FT DOMAIN 228..298 FT /note="PAS 2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00140" FT DOMAIN 302..345 FT /note="PAC" FT REGION 1..401 FT /note="Interaction with TSGA10" FT /evidence="ECO:0000250|UniProtKB:Q61221" FT REGION 1..30 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 21..30 FT /note="DNA-binding" FT /evidence="ECO:0000250|UniProtKB:Q61221" FT REGION 170..191 FT /note="Required for heterodimer formation with ARNT" FT /evidence="ECO:0000250|UniProtKB:Q61221" FT REGION 380..417 FT /note="N-terminal VHL recognition site" FT REGION 401..603 FT /note="ODD" FT /evidence="ECO:0000303|PubMed:16288748" FT REGION 494..520 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 531..575 FT /note="NTAD" FT /evidence="ECO:0000303|PubMed:10202154, FT ECO:0000303|PubMed:9235919" FT REGION 556..572 FT /note="C-terminal VHL recognition site" FT REGION 576..785 FT /note="ID" FT REGION 642..688 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 786..826 FT /note="CTAD" FT /evidence="ECO:0000303|PubMed:10202154, FT ECO:0000303|PubMed:9235919" FT MOTIF 718..721 FT /note="Nuclear localization signal" FT /evidence="ECO:0000255" FT COMPBIAS 494..516 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 645..670 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOD_RES 247 FT /note="Phosphoserine; by CK1" FT /evidence="ECO:0000269|PubMed:20699359" FT MOD_RES 402 FT /note="4-hydroxyproline" FT /evidence="ECO:0000269|PubMed:11566883" FT MOD_RES 532 FT /note="N6-acetyllysine" FT /evidence="ECO:0000269|PubMed:24681946" FT MOD_RES 551 FT /note="Phosphoserine; by GSK3-beta" FT /evidence="ECO:0000269|PubMed:20889502" FT MOD_RES 555 FT /note="Phosphothreonine; by GSK3-beta" FT /evidence="ECO:0000269|PubMed:20889502" FT MOD_RES 564 FT /note="4-hydroxyproline" FT /evidence="ECO:0000269|PubMed:11292861, FT ECO:0000269|PubMed:11566883, ECO:0000269|PubMed:12351678, FT ECO:0000269|PubMed:25974097" FT MOD_RES 576 FT /note="Phosphoserine; by PLK3" FT /evidence="ECO:0000269|PubMed:20889502" FT MOD_RES 589 FT /note="Phosphoserine; by GSK3-beta" FT /evidence="ECO:0000269|PubMed:20889502" FT MOD_RES 657 FT /note="Phosphoserine; by PLK3" FT /evidence="ECO:0000269|PubMed:20889502" FT MOD_RES 709 FT /note="N6-acetyllysine" FT /evidence="ECO:0000269|PubMed:24681946" FT MOD_RES 800 FT /note="S-nitrosocysteine" FT /evidence="ECO:0000305|PubMed:12914934" FT MOD_RES 803 FT /note="(3S)-3-hydroxyasparagine" FT /evidence="ECO:0000269|PubMed:12080085" FT CARBOHYD 18 FT /note="(Microbial infection) N-beta-linked (GlcNAc) FT arginine" FT /evidence="ECO:0000269|PubMed:30125331" FT CROSSLNK 391 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in SUMO)" FT /evidence="ECO:0000269|PubMed:15465032, FT ECO:0000269|PubMed:17610843" FT CROSSLNK 477 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in SUMO)" FT /evidence="ECO:0000269|PubMed:15465032, FT ECO:0000269|PubMed:17610843" FT CROSSLNK 532 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000305|PubMed:16862177" FT CROSSLNK 538 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000305|PubMed:16862177" FT CROSSLNK 547 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000305|PubMed:16862177" FT VAR_SEQ 1..12 FT /note="MEGAGGANDKKK -> MSSQCRSLENKFVFLKEGLGNSKPEELEEIRIENGR FT (in isoform 3)" FT /evidence="ECO:0000303|PubMed:18638657" FT /id="VSP_044942" FT VAR_SEQ 735 FT /note="G -> I (in isoform 2)" FT /evidence="ECO:0000303|Ref.7" FT /id="VSP_047335" FT VAR_SEQ 736..826 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|Ref.7" FT /id="VSP_007738" FT VARIANT 582 FT /note="P -> S (in dbSNP:rs11549465)" FT /id="VAR_049541" FT VARIANT 588 FT /note="A -> T (in dbSNP:rs11549467)" FT /id="VAR_049542" FT VARIANT 796 FT /note="T -> A (in dbSNP:rs1802821)" FT /id="VAR_015854" FT MUTAGEN 18 FT /note="R->K: Strongly reduced GlcNAcylation by E.coli FT NleB1." FT /evidence="ECO:0000269|PubMed:30125331" FT MUTAGEN 247 FT /note="S->A: Constitutive kinase activity." FT /evidence="ECO:0000269|PubMed:20699359" FT MUTAGEN 247 FT /note="S->D: Impaired kinase activity." FT /evidence="ECO:0000269|PubMed:20699359" FT MUTAGEN 377 FT /note="K->R: No change in HIF1A protein turnover rate but FT increased transcriptional activity; when associated with FT R-391; R-477 and R-532." FT /evidence="ECO:0000269|PubMed:17610843" FT MUTAGEN 389 FT /note="K->R: No change in sumoylation." FT /evidence="ECO:0000269|PubMed:15465032" FT MUTAGEN 391 FT /note="K->R: Abolishes 1 sumoylation. Abolishes 1 FT sumoylation; when associated with R-532. Abolishes 2 FT sumoylations; when associated with R-477. No change in FT HIF1A protein turnover rate but increased transcriptional FT activity; when associated with R-377; R-477 and R-532." FT /evidence="ECO:0000269|PubMed:15465032, FT ECO:0000269|PubMed:17610843" FT MUTAGEN 392 FT /note="K->R: No change in sumoylation." FT /evidence="ECO:0000269|PubMed:15465032" FT MUTAGEN 394 FT /note="P->A: No change in VHLE3-dependent ubiquitination." FT /evidence="ECO:0000269|PubMed:11566883" FT MUTAGEN 397 FT /note="L->A: Abolishes VHLE3-dependent ubiquitination; when FT associated with A-400." FT /evidence="ECO:0000269|PubMed:11566883" FT MUTAGEN 400 FT /note="L->A: Abolishes VHLE3-dependent ubiquitination; when FT associated with A-397." FT /evidence="ECO:0000269|PubMed:11566883" FT MUTAGEN 402 FT /note="P->A: Abolishes in VHLE3-dependent ubiquitination, FT abolishes oxygen-dependent regulation of VP16, partially FT reduced VHLE target site ubiquitination and no interaction FT with VHL. No VHLE target site ubiquitination; when FT associated with G-564. Increases HIF1A instability and FT reduces HIF1A-induced target gene transcriptional FT activation; when associated with A-564." FT /evidence="ECO:0000269|PubMed:11566883, FT ECO:0000269|PubMed:16862177, ECO:0000269|PubMed:24681946" FT MUTAGEN 442 FT /note="K->R: No change in sumoylation." FT /evidence="ECO:0000269|PubMed:15465032" FT MUTAGEN 460 FT /note="K->R: No change in sumoylation nor in ARD1-mediated FT acetylation." FT /evidence="ECO:0000269|PubMed:15465032" FT MUTAGEN 477 FT /note="K->R: Abolishes 1 sumoylation. Abolishes 2 FT sumoylations; when associated with R-391. No change in FT HIF1A protein turnover rate but increased transcriptional FT activity; when associated with R-377; R-391 and R-532." FT /evidence="ECO:0000269|PubMed:15465032, FT ECO:0000269|PubMed:17610843" FT MUTAGEN 532 FT /note="K->R: Reduced ubiquitination. No change in FT sumoylation nor on interaction with NAA10. No change in FT HIF1A protein turnover rate but increased transcriptional FT activity; when associated with R-377; R-391 and R-477. FT Complete loss of ubiquitination, but no change in VHL FT binding; when associated with K-538 and K-547." FT /evidence="ECO:0000269|PubMed:10944113, FT ECO:0000269|PubMed:15465032, ECO:0000269|PubMed:16288748, FT ECO:0000269|PubMed:16862177, ECO:0000269|PubMed:17610843" FT MUTAGEN 538 FT /note="K->R: No change in sumoylation, but reduced FT ubiquitination. Complete loss of ubiquitination, but no FT change in VHL binding; when associated with K-532 and FT K-547." FT /evidence="ECO:0000269|PubMed:10944113, FT ECO:0000269|PubMed:15465032, ECO:0000269|PubMed:16862177" FT MUTAGEN 547 FT /note="K->R: No change in sumoylation, but reduced FT ubiquitination. Complete loss of ubiquitination, but no FT change in VHL binding; when associated with K-532 and FT K-538." FT /evidence="ECO:0000269|PubMed:10944113, FT ECO:0000269|PubMed:15465032, ECO:0000269|PubMed:16862177" FT MUTAGEN 551 FT /note="S->G: Constitutive expression under nonhypoxic FT conditions by decreasing ubiquitination." FT /evidence="ECO:0000269|PubMed:10758161" FT MUTAGEN 552 FT /note="T->A: Constitutive expression under nonhypoxic FT conditions by decreasing ubiquitination." FT /evidence="ECO:0000269|PubMed:10758161" FT MUTAGEN 564 FT /note="P->A: Increases HIF1A instability and reduces FT HIF1A-induced target gene transcriptional activation; when FT associated with A-402." FT /evidence="ECO:0000269|PubMed:11566883, FT ECO:0000269|PubMed:16862177, ECO:0000269|PubMed:24681946" FT MUTAGEN 564 FT /note="P->G: No change in VHL-dependent ubiquitination. FT Partially reduced VHLE target site ubiquitination. No VHLE FT target site ubiquitination; when associated with A-402." FT /evidence="ECO:0000269|PubMed:11566883, FT ECO:0000269|PubMed:16862177, ECO:0000269|PubMed:24681946" FT MUTAGEN 576 FT /note="S->A: Induces stabilization of the protein." FT /evidence="ECO:0000269|PubMed:20889502" FT MUTAGEN 657 FT /note="S->A: Induces stabilization of the protein." FT /evidence="ECO:0000269|PubMed:20889502" FT MUTAGEN 709 FT /note="K->R: Abolishes SIRT2-mediated deacetylation, FT increases HIF1A instability and reduces HIF1A-induced FT target gene transcriptional activation. Increases FT interaction with EGLN1." FT /evidence="ECO:0000269|PubMed:24681946" FT MUTAGEN 719 FT /note="K->T: Dramatic reduction of accumulation in the FT nucleus in response to hypoxia." FT /evidence="ECO:0000269|PubMed:10944113, FT ECO:0000269|PubMed:9822602" FT MUTAGEN 795 FT /note="L->A: Inhibits interaction with EP300 and FT transactivation activity." FT /evidence="ECO:0000269|PubMed:12778114" FT MUTAGEN 800 FT /note="C->A: Blocks increase in transcriptional activation FT caused by nitrosylation." FT /evidence="ECO:0000269|PubMed:10202154, FT ECO:0000269|PubMed:12914934" FT MUTAGEN 800 FT /note="C->S: Abolishes hypoxia-inducible transcriptional FT activation of ctaD." FT /evidence="ECO:0000269|PubMed:10202154, FT ECO:0000269|PubMed:12914934" FT MUTAGEN 803 FT /note="N->A: Recruits CREBBP. No enhancement of CREBBP by FT Clioquinol in the presence of FIH1. No change in nuclear FT location nor on repression of transcriptional activity in FT the presence of histone deacetylase inhibitor." FT /evidence="ECO:0000269|PubMed:16543236, FT ECO:0000269|PubMed:16973622" FT CONFLICT 572 FT /note="F -> L (in Ref. 3; AAC68568)" FT /evidence="ECO:0000305" FT STRAND 241..246 FT /evidence="ECO:0007829|PDB:4H6J" FT STRAND 251..255 FT /evidence="ECO:0007829|PDB:4H6J" FT HELIX 258..263 FT /evidence="ECO:0007829|PDB:4H6J" FT HELIX 267..270 FT /evidence="ECO:0007829|PDB:4H6J" FT HELIX 275..277 FT /evidence="ECO:0007829|PDB:4H6J" FT TURN 281..283 FT /evidence="ECO:0007829|PDB:4H6J" FT HELIX 284..297 FT /evidence="ECO:0007829|PDB:4H6J" FT STRAND 298..301 FT /evidence="ECO:0007829|PDB:4H6J" FT STRAND 305..308 FT /evidence="ECO:0007829|PDB:4H6J" FT STRAND 310..325 FT /evidence="ECO:0007829|PDB:4H6J" FT TURN 327..329 FT /evidence="ECO:0007829|PDB:4H6J" FT STRAND 332..341 FT /evidence="ECO:0007829|PDB:4H6J" FT HELIX 397..400 FT /evidence="ECO:0007829|PDB:5L9V" FT STRAND 408..410 FT /evidence="ECO:0007829|PDB:5LA9" FT HELIX 559..562 FT /evidence="ECO:0007829|PDB:5L9B" FT TURN 779..783 FT /evidence="ECO:0007829|PDB:1L8C" FT HELIX 784..787 FT /evidence="ECO:0007829|PDB:1L8C" FT STRAND 789..792 FT /evidence="ECO:0007829|PDB:1L8C" FT HELIX 797..803 FT /evidence="ECO:0007829|PDB:7QGS" FT HELIX 809..811 FT /evidence="ECO:0007829|PDB:7LVS" FT HELIX 817..821 FT /evidence="ECO:0007829|PDB:7QGS" FT TURN 822..824 FT /evidence="ECO:0007829|PDB:7QGS" SQ SEQUENCE 826 AA; 92670 MW; ABD4F7DAA135BE2D CRC64; MEGAGGANDK KKISSERRKE KSRDAARSRR SKESEVFYEL AHQLPLPHNV SSHLDKASVM RLTISYLRVR KLLDAGDLDI EDDMKAQMNC FYLKALDGFV MVLTDDGDMI YISDNVNKYM GLTQFELTGH SVFDFTHPCD HEEMREMLTH RNGLVKKGKE QNTQRSFFLR MKCTLTSRGR TMNIKSATWK VLHCTGHIHV YDTNSNQPQC GYKKPPMTCL VLICEPIPHP SNIEIPLDSK TFLSRHSLDM KFSYCDERIT ELMGYEPEEL LGRSIYEYYH ALDSDHLTKT HHDMFTKGQV TTGQYRMLAK RGGYVWVETQ ATVIYNTKNS QPQCIVCVNY VVSGIIQHDL IFSLQQTECV LKPVESSDMK MTQLFTKVES EDTSSLFDKL KKEPDALTLL APAAGDTIIS LDFGSNDTET DDQQLEEVPL YNDVMLPSPN EKLQNINLAM SPLPTAETPK PLRSSADPAL NQEVALKLEP NPESLELSFT MPQIQDQTPS PSDGSTRQSS PEPNSPSEYC FYVDSDMVNE FKLELVEKLF AEDTEAKNPF STQDTDLDLE MLAPYIPMDD DFQLRSFDQL SPLESSSASP ESASPQSTVT VFQQTQIQEP TANATTTTAT TDELKTVTKD RMEDIKILIA SPSPTHIHKE TTSATSSPYR DTQSRTASPN RAGKGVIEQT EKSHPRSPNV LSVALSQRTT VPEEELNPKI LALQNAQRKR KMEHDGSLFQ AVGIGTLLQQ PDDHAATTSL SWKRVKGCKS SEQNGMEQKT IILIPSDLAC RLLGQSMDES GLPQLTSYDC EVNAPIQGSR NLLQGEELLR ALDQVN //