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 02-OCT-2024, entry version 256.
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:30125331, PubMed:9887100).
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:30125331, PubMed:9887100). 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:16543236,
CC PubMed:9887100). 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:11959990, PubMed:12778114,
CC PubMed:16543236, PubMed:16973622, PubMed:8917528, PubMed:9887100).
CC Interacts with CREBBP (via TAZ-type 1 domains) (PubMed:11959977,
CC PubMed:8917528). Interacts with NCOA1, NCOA2, APEX1 and HSP90
CC (PubMed:10202154, PubMed:10594042). 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:10944113,
CC PubMed:11006129, PubMed:12004076, PubMed:12050673, PubMed:16862177).
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=13; 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; O60224: SSX4B; NbExp=5; IntAct=EBI-447269, EBI-745513;
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=20; 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 ---------------------------------------------------------------------------
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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; 439.
DR ComplexPortal; CPX-7381; Hypoxia-inducible transcription factor complex, HIF1.
DR CORUM; Q16665; -.
DR DIP; DIP-29722N; -.
DR ELM; Q16665; -.
DR IntAct; Q16665; 110.
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 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; 2506 antibodies from 52 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.
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; Proteomics identification; Reference proteome; Repeat;
KW S-nitrosylation; Transcription; 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 R-
FT 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 K-
FT 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 K-
FT 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 HIF1A-
FT 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
//