[1]	NUCLEOTIDE SEQUENCE [MRNA], AND PROTEIN SEQUENCE OF 166-170; 259-289 AND 771-781. DOI=10.1073/pnas.92.12.5510; PubMed=7539918 [NCBI, ExPASy, EBI, Israel, Japan] Wang G.L., Jiang B.-H., Rue E.A., Semenza G.L.; "Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension."; Proc. Natl. Acad. Sci. U.S.A. 92:5510-5514(1995).
[2]	NUCLEOTIDE SEQUENCE [MRNA]. TISSUE=Hepatoma; DOI=10.1074/jbc.272.13.8581; PubMed=9079689 [NCBI, ExPASy, EBI, Israel, Japan] Hogenesch J.B., Chan W.K., Jackiw V.H., Brown R.C., Gu Y.-Z., Pray-Grant M., Perdew G.H., Bradfield C.A.; "Characterization of a subset of the basic-helix-loop-helix-PAS superfamily that interacts with components of the dioxin signaling pathway."; J. Biol. Chem. 272:8581-8593(1997).
[3]	NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM 1). DOI=10.1006/geno.1998.5416; PubMed=9782081 [NCBI, ExPASy, EBI, Israel, Japan] Iyer N.V., Leung S.W., Semenza G.L.; "The human hypoxia-inducible factor 1alpha gene: HIF1A structure and evolutionary conservation."; Genomics 52:159-165(1998).
[4]	NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA]. Rupert J.L., Hochachka P.W.; "HIF1a sequence in the Quechua, a high altitude population."; Submitted (NOV-1999) to the EMBL/GenBank/DDBJ databases.
[5]	NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). TISSUE=Glial tumor; Sun B., Zhao H.R., Yu R.T., Ni M.S.H.; Submitted (SEP-2000) to the EMBL/GenBank/DDBJ databases.
[6]	NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2). TISSUE=Liver; Tanaka S., Sugimachi K.; "Hypoxia-inducible factor-1 alpha variant isolated from human liver tissue."; Submitted (OCT-2001) to the EMBL/GenBank/DDBJ databases.
[7]	NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., Phelan M., Farmer A.; "Cloning of human full-length CDSs in BD Creator(TM) system donor vector."; Submitted (AUG-2003) to the EMBL/GenBank/DDBJ databases.
[8]	NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). TISSUE=Choriocarcinoma, and Placenta; DOI=10.1101/gr.2596504; PubMed=15489334 [NCBI, ExPASy, EBI, Israel, Japan] The MGC Project Team; "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."; Genome Res. 14:2121-2127(2004).
[9]	IDENTIFICATION IN COMPLEX WITH EP300 AND CREBBP, AND INTERACTION WITH EP300. DOI=10.1073/pnas.93.23.12969; PubMed=8917528 [NCBI, ExPASy, EBI, Israel, Japan] Arany Z., Huang L.E., Eckner R., Bhattacharya S., Jiang C., Goldberg M.A., Bunn H.F., Livingston D.M.; "An essential role for p300/CBP in the cellular response to hypoxia."; Proc. Natl. Acad. Sci. U.S.A. 93:12969-12973(1996).
[10]	TRANSACTIVATION DOMAINS NTAD AND CTAD. DOI=10.1074/jbc.272.31.19253; PubMed=9235919 [NCBI, ExPASy, EBI, Israel, Japan] Jiang B.H., Zheng J.Z., Leung S.W., Roe R., Semenza G.L.; "Transactivation and inhibitory domains of hypoxia-inducible factor 1alpha. Modulation of transcriptional activity by oxygen tension."; J. Biol. Chem. 272:19253-19260(1997).
[11]	SUBCELLULAR LOCATION, AND MUTAGENESIS OF LYS-719. DOI=10.1093/emboj/17.22.6573; PubMed=9822602 [NCBI, ExPASy, EBI, Israel, Japan] Kallio P.J., Okamoto K., O'Brien S., Carrero P., Makino Y., Tanaka H., Poellinger L.; "Signal transduction in hypoxic cells: inducible nuclear translocation and recruitment of the CBP/p300 coactivator by the hypoxia-inducible factor-1alpha."; EMBO J. 17:6573-6586(1998).
[12]	OXYGEN-DEPENDENT DEGRADATION DOMAIN. DOI=10.1073/pnas.95.14.7987; PubMed=9653127 [NCBI, ExPASy, EBI, Israel, Japan] Huang L.E., Gu J., Schau M., Bunn H.F.; "Regulation of hypoxia-inducible factor 1alpha is mediated by an O2-dependent degradation domain via the ubiquitin-proteasome pathway."; Proc. Natl. Acad. Sci. U.S.A. 95:7987-7992(1998).
[13]	TRANSACTIVATION DOMAINS NTAD AND CTAD, INTERACTION WITH APEX, AND MUTAGENESIS OF CYS-800. DOI=10.1093/emboj/18.7.1905; PubMed=10202154 [NCBI, ExPASy, EBI, Israel, Japan] Ema M., Hirota K., Mimura J., Abe H., Yodoi J., Sogawa K., Poellinger L., Fujii-Kuriyama Y.; "Molecular mechanisms of transcription activation by HLF and HIF1alpha in response to hypoxia: their stabilization and redox signal-induced interaction with CBP/p300."; EMBO J. 18:1905-1914(1999).
[14]	INTERACTION WITH VHL. DOI=10.1006/bbrc.2000.3451; PubMed=11006129 [NCBI, ExPASy, EBI, Israel, Japan] Aso T., Yamazaki K., Aigaki T., Kitajima S.; "Drosophila von Hippel-Lindau tumor suppressor complex possesses E3 ubiquitin ligase activity."; Biochem. Biophys. Res. Commun. 276:355-361(2000).
[15]	INTERACTION WITH VHL AND ARNT, AND MUTAGENESIS OF LYS-532; LYS-538; LYS-547 AND LYS-719. DOI=10.1093/emboj/19.16.4298; PubMed=10944113 [NCBI, ExPASy, EBI, Israel, Japan] Tanimoto K., Makino Y., Pereira T., Poellinger L.; "Mechanism of regulation of the hypoxia-inducible factor-1 alpha by the von Hippel-Lindau tumor suppressor protein."; EMBO J. 19:4298-4309(2000).
[16]	INTERACTION WITH NCOA1; NCOA2 AND APEX. PubMed=10594042 [NCBI, ExPASy, EBI, Israel, Japan] Carrero P., Okamoto K., Coumailleau P., O'Brien S., Tanaka H., Poellinger L.; "Redox-regulated recruitment of the transcriptional coactivators CREB-binding protein and SRC-1 to hypoxia-inducible factor 1alpha."; Mol. Cell. Biol. 20:402-415(2000).
[17]	MUTAGENESIS OF SER-551 AND THR-552, AND UBIQUITATION. DOI=10.1073/pnas.080072497; PubMed=10758161 [NCBI, ExPASy, EBI, Israel, Japan] Sutter C.H., Laughner E., Semenza G.L.; "Hypoxia-inducible factor 1alpha protein expression is controlled by oxygen-regulated ubiquitination that is disrupted by deletions and missense mutations."; Proc. Natl. Acad. Sci. U.S.A. 97:4748-4753(2000).
[18]	HYDROXYLATION AT PRO-402 AND PRO-564, UBIQUITINATION, INTERACTION WITH THE VHLE COMPLEX, FUNCTION, AND MUTAGENESIS OF PRO-394; LEU-397; LEU-400; PRO-402 AND PRO-564. DOI=10.1093/emboj/20.18.5197; PubMed=11566883 [NCBI, ExPASy, EBI, Israel, Japan] Masson N., Willam C., Maxwell P.H., Pugh C.W., Ratcliffe P.J.; "Independent function of two destruction domains in hypoxia-inducible factor-alpha chains activated by prolyl hydroxylation."; EMBO J. 20:5197-5206(2001).
[19]	UBIQUITINATION, FUNCTION, AND HYDROXYLATION AT PRO-564. DOI=10.1126/science.1059796; PubMed=11292861 [NCBI, ExPASy, EBI, Israel, Japan] Jaakkola P., Mole D.R., Tian Y.-M., Wilson M.I., Gielbert J., Gaskell S.J., von Kriegsheim A., Hebestreit H.F., Mukherji M., Schofield C.J., Maxwell P.H., Pugh C.W., Ratcliffe P.J.; "Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation."; Science 292:468-472(2001).
[20]	INTERACTION WITH ARD1A. DOI=10.1016/S0092-8674(02)01085-1; PubMed=12464182 [NCBI, ExPASy, EBI, Israel, Japan] Jeong J.-W., Bae M.-K., Ahn M.-Y., Kim S.-H., Sohn T.-K., Bae M.-H., Yoo M.-A., Song E.-J., Lee K.-J., Kim K.-W.; "Regulation and destabilization of HIF-1alpha by ARD1-mediated acetylation."; Cell 111:709-720(2002).
[21]	HYDROXYLATION AT ASN-803, AND MASS SPECTROMETRY. DOI=10.1101/gad.991402; PubMed=12080085 [NCBI, ExPASy, EBI, Israel, Japan] Lando D., Peet D.J., Gorman J.J., Whelan D.A., Whitelaw M.L., Bruick R.K.; "FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor."; Genes Dev. 16:1466-1471(2002).
[22]	HYDROXYLATION AT PRO-564, AND MASS SPECTROMETRY. DOI=10.1073/pnas.192342099; PubMed=12351678 [NCBI, ExPASy, EBI, Israel, Japan] Ivan M., Haberberger T., Gervasi D.C., Michelson K.S., Guenzler V., Kondo K., Yang H., Sorokina I., Conaway R.C., Conaway J.W., Kaelin W.G. Jr.; "Biochemical purification and pharmacological inhibition of a mammalian prolyl hydroxylase acting on hypoxia-inducible factor."; Proc. Natl. Acad. Sci. U.S.A. 99:13459-13464(2002).
[23]	NITROSYLATION AT CYS-800, AND MUTAGENESIS OF CYS-800. DOI=10.1016/S0014-5793(03)00807-X; PubMed=12914934 [NCBI, ExPASy, EBI, Israel, Japan] Yasinska I.M., Sumbayev V.V.; "S-nitrosation of Cys-800 of HIF-1alpha protein activates its interaction with p300 and stimulates its transcriptional activity."; FEBS Lett. 549:105-109(2003).
[24]	S-NITROSYLATION. DOI=10.1016/S0014-5793(02)03887-5; PubMed=12560087 [NCBI, ExPASy, EBI, Israel, Japan] Sumbayev V.V., Budde A., Zhou J., Bruene B.; "HIF-1 alpha protein as a target for S-nitrosation."; FEBS Lett. 535:106-112(2003).
[25]	SUMOYLATION AT LYS-391 AND LYS-477, FUNCTION, AND MUTAGENESIS OF LYS-389; LYS-391; LYS-392; LYS-442; LYS-460; LYS-477; LYS-532; LYS-538 AND LYS-547. DOI=10.1016/j.bbrc.2004.09.068; PubMed=15465032 [NCBI, ExPASy, EBI, Israel, Japan] Bae S.-H., Jeong J.-W., Park J.A., Kim S.-H., Bae M.-K., Choi S.-J., Kim K.-W.; "Sumoylation increases HIF-1alpha stability and its transcriptional activity."; Biochem. Biophys. Res. Commun. 324:394-400(2004).
[26]	INTERACTION WITH VHLL. PubMed=14757845 [NCBI, ExPASy, EBI, Israel, Japan] Qi H., Gervais M.L., Li W., DeCaprio J.A., Challis J.R.G., Ohh M.; "Molecular cloning and characterization of the von Hippel-Lindau-like protein."; Mol. Cancer Res. 2:43-52(2004).
[27]	INTERACTION WITH ARD1A, AND MUTAGENESIS OF LYS-532. DOI=10.1016/j.febslet.2005.10.036; PubMed=16288748 [NCBI, ExPASy, EBI, Israel, Japan] Arnesen T., Kong X., Evjenth R., Gromyko D., Varhaug J.E., Lin Z., Sang N., Caro J., Lillehaug J.R.; "Interaction between HIF-1 alpha (ODD) and hARD1 does not induce acetylation and destabilization of HIF-1 alpha."; FEBS Lett. 579:6428-6432(2005).
[28]	FUNCTION, INTERACTION WITH EP300 IN THE HIF1A/EP300/CREBBP COMPLEX, AND MUTAGENESIS OF ASN-803. DOI=10.1074/jbc.M600456200; PubMed=16543236 [NCBI, ExPASy, EBI, Israel, Japan] Fath D.M., Kong X., Liang D., Lin Z., Chou A., Jiang Y., Fang J., Caro J., Sang N.; "Histone deacetylase inhibitors repress the transactivation potential of hypoxia-inducible factors independently of direct acetylation of HIF-alpha."; J. Biol. Chem. 281:13612-13619(2006).
[29]	UBIQUITINATION, HYDROXYLATION, FUNCTION, INTERACTION WITH CBPP, MASS SPECTROMETRY, AND MUTAGENESIS OF ASN-803. DOI=10.1074/jbc.M603913200; PubMed=16973622 [NCBI, ExPASy, EBI, Israel, Japan] Choi S.M., Choi K.-O., Park Y.K., Cho H., Yang E.G., Park H.; "Clioquinol, a Cu(II)/Zn(II) chelator, inhibits both ubiquitination and asparagine hydroxylation of hypoxia-inducible factor-1alpha, leading to expression of vascular endothelial growth factor and erythropoietin in normoxic cells."; J. Biol. Chem. 281:34056-34063(2006).
[30]	SUMOYLATION AT LYS-391 AND LYS-477, FUNCTION, AND MUTAGENESIS OF LYS-377; LYS-391; LYS-477 AND LYS-532. DOI=10.1016/j.bbrc.2007.06.103; PubMed=17610843 [NCBI, ExPASy, EBI, Israel, Japan] Berta M.A., Mazure N., Hattab M., Pouyssegur J., Brahimi-Horn M.C.; "SUMOylation of hypoxia-inducible factor-1alpha reduces its transcriptional activity."; Biochem. Biophys. Res. Commun. 360:646-652(2007).
[31]	SUMOYLATION, AND INTERACTION WITH RWDD3. DOI=10.1016/j.cell.2007.07.044; PubMed=17956732 [NCBI, ExPASy, EBI, Israel, Japan] Carbia-Nagashima A., Gerez J., Perez-Castro C., Paez-Pereda M., Silberstein S., Stalla G.K., Holsboer F., Arzt E.; "RSUME, a small RWD-containing protein, enhances SUMO conjugation and stabilizes HIF-1alpha during hypoxia."; Cell 131:309-323(2007).
[32]	UBIQUITINATION AT LYS-532; LYS-538 AND LYS-547, INTERACTION WITH VHL, AND MUTAGENESIS OF PRO-402; LYS-532; LYS-538; LYS-547 AND PRO-564. DOI=10.1038/sj.onc.1209818; PubMed=16862177 [NCBI, ExPASy, EBI, Israel, Japan] Paltoglou S., Roberts B.J.; "HIF-1alpha and EPAS ubiquitination mediated by the VHL tumour suppressor involves flexibility in the ubiquitination mechanism, similar to other RING E3 ligases."; Oncogene 26:604-609(2007).
[33]	UBIQUITINATION [LARGE SCALE ANALYSIS] AT LYS-538, AND MASS SPECTROMETRY. DOI=10.1021/pr800468j; PubMed=18781797 [NCBI, ExPASy, EBI, Israel, Japan] Meierhofer D., Wang X., Huang L., Kaiser P.; "Quantitative analysis of global ubiquitination in HeLa cells by mass spectrometry."; J. Proteome Res. 7:4566-4576(2008).
[34]	3D-STRUCTURE MODELING. PubMed=11089639 [NCBI, ExPASy, EBI, Israel, Japan] Michel G., Minet E., Ernest I., Roland I., Durant F., Remacle J., Michiels C.; "A model for the complex between the hypoxia-inducible factor-1 (HIF-1) and its consensus DNA sequence."; J. Biomol. Struct. Dyn. 18:169-179(2000).
[35]	X-RAY CRYSTALLOGRAPHY (2.15 ANGSTROMS) OF 775-826 IN COMPLEX WITH HIF1AN. DOI=10.1074/jbc.C200644200; PubMed=12446723 [NCBI, ExPASy, EBI, Israel, Japan] Elkins J.M., Hewitson K.S., McNeill L.A., Seibel J.F., Schlemminger I., Pugh C.W., Ratcliffe P.J., Schofield C.J.; "Structure of factor-inhibiting hypoxia-inducible factor (HIF) reveals mechanism of oxidative modification of HIF-1 alpha."; J. Biol. Chem. 278:1802-1806(2003).
[36]	STRUCTURE BY NMR OF 786-826 IN COMPLEX WITH 302-418 OF EP300. DOI=10.1073/pnas.082117899; PubMed=11959990 [NCBI, ExPASy, EBI, Israel, Japan] Freedman S.J., Sun Z.-Y.J., Poy F., Kung A.L., Livingston D.M., Wagner G., Eck M.J.; "Structural basis for recruitment of CBP/p300 by hypoxia-inducible factor-1 alpha."; Proc. Natl. Acad. Sci. U.S.A. 99:5367-5372(2002).
[37]	STRUCTURE BY NMR OF 776-826 IN COMPLEX WITH 345-439 OF CREBBP. DOI=10.1073/pnas.082121399; PubMed=11959977 [NCBI, ExPASy, EBI, Israel, Japan] Dames S.A., Martinez-Yamout M., De Guzman R.N., Dyson H.J., Wright P.E.; "Structural basis for Hif-1 alpha /CBP recognition in the cellular hypoxic response."; Proc. Natl. Acad. Sci. U.S.A. 99:5271-5276(2002).
[38]	X-RAY CRYSTALLOGRAPHY (1.85 ANGSTROMS) OF 556-575 IN COMPLEX WITH TCEB1; TCEB2 AND 54-213 OF VHL. DOI=10.1126/science.1073440; PubMed=12004076 [NCBI, ExPASy, EBI, Israel, Japan] Min J.-H., Yang H., Ivan M., Gertler F., Kaelin W.G. Jr., Pavletich N.P.; "Structure of an HIF-1alpha-pVHL complex: hydroxyproline recognition in signaling."; Science 296:1886-1889(2002).
[39]	X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 549-582 IN COMPLEX WITH 17-112 OF TCEB1; TCEB2 AND 52-213 OF VHL. DOI=10.1038/nature00767; PubMed=12050673 [NCBI, ExPASy, EBI, Israel, Japan] Hon W.-C., Wilson M.I., Harlos K., Claridge T.D.W., Schofield C.J., Pugh C.W., Maxwell P.H., Ratcliffe P.J., Stuart D.I., Jones E.Y.; "Structural basis for the recognition of hydroxyproline in HIF-1 alpha by pVHL."; Nature 417:975-978(2002).

Comments

FUNCTION: Functions as a master transcriptional regulator of the adaptive response to hypoxia. Under hypoxic conditions activates the transcription of over 40 genes, including, erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor, and other genes whose protein products increase oxygen delivery or facilitate metabolic adaptation to hypoxia. Plays an essential role in embryonic vascularization, tumor angiogenesis and pathophysiology of ischemic disease. Binds to core DNA sequence 5'-[AG]CGTG-3' within the hypoxia response element (HRE) of target gene promoters. Activation requires recruitment of transcriptional coactivators such as CREBPB and EP300. Activity is enhanced by interaction with both, NCOA1 or NCOA2. Interaction with redox regulatory protein APEX seems to activate CTAD and potentiates activation by NCOA1 and CREBBP.
SUBUNIT: Interacts with the HIF1A beta/ARNT subunit; heterodimerization is required for DNA binding. Interacts with COPS5; the interaction increases the transcriptional activity of HIF1A through increased stability (By similarity). Interacts with CREBBP and EP300 (via TAZ-type 1 domains). Interacts with NCOA1, NCOA2, APEX and HSP90. Interacts (hydroxylated within the ODD domain) with VHLL (via beta domain); the interaction, leads to polyubiquitination and subsequent HIF1A proteasomal degradation. During hypoxia, sumoylated HIF1A also binds VHL; the interaction promotes the ubiquitination of HIF1A. Interacts with SENP1; the interaction desumoylates HIF1A resulting in stabilization and activation of transcription. Interacts (Via the ODD domain) with ARD1A; the interaction appears not to acetylate HIF1A nor have any affect on protein stability, during hypoxia. Interacts with RWDD3; the interaction enhances HIF1A sumoylation. Interacts with TSGA10 (By similarity).
INTERACTION:
P10275:AR; NbExp=1; IntAct=EBI-447269, EBI-608057;
Q09472:EP300; NbExp=2; IntAct=EBI-447269, EBI-447295;
Q96CS3:FAF2; NbExp=1; IntAct=EBI-447269, EBI-1055805;
Q9NWT6:HIF1AN; NbExp=1; IntAct=EBI-447269, EBI-745632;
P61244:MAX; NbExp=1; IntAct=EBI-447269, EBI-878388;
Q13438:OS9; NbExp=2; IntAct=EBI-447269, EBI-1174342;
Q13438-1:OS9; NbExp=1; IntAct=EBI-447269, EBI-1174351;
Q13438-2:OS9; NbExp=1; IntAct=EBI-447269, EBI-1174355;
Q92831:PCAF; NbExp=2; IntAct=EBI-447269, EBI-477430;
Q9Y3V2:RWDD3; NbExp=1; IntAct=EBI-447269, EBI-1549885;
Q9UHD8-1:SEPT9; NbExp=3; IntAct=EBI-447269, EBI-851558;
O94888:UBXN7; NbExp=2; IntAct=EBI-447269, EBI-1993627;
P40337:VHL; NbExp=1; IntAct=EBI-447269, EBI-301246;
SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Note=Cytoplasmic in normoxia, nuclear translocation in response to hypoxia. Colocalizes with SUMO1 in the nucleus, under hypoxia.

ALTERNATIVE PRODUCTS: 2 named isoforms [FASTA] produced by alternative splicing.

Name	1
Isoform ID	Q16665-1
This is the isoform sequence displayed in this entry.

Name	2
Isoform ID	Q16665-2
Note: No experimental confirmation available.
Features which should be applied to build the isoform sequence: VSP_007738.

TISSUE SPECIFICITY: Expressed in most tissues with highest levels in kidney and heart. Overexpressed in the majority of common human cancers and their metastases, due to the presence of intratumoral hypoxia and as a result of mutations in genes encoding oncoproteins and tumor suppressors.
INDUCTION: Under reduced oxygen tension. Induced also by various receptor-mediated factors such as growth factors, cytokines, and circulatory factors such as PDGF, EGF FGF-2 FGF-2 IGF-2, TGF-1 beta, HGF, TNF alpha, IL-1 beta, angiotensin-2 and thrombin. However, this induction is less intense than that stimulated by hypoxia.
DOMAIN: Contains two independent C-terminal transactivation domains, NTAD and CTAD, which function synergistically. Their transcriptional activity is repressed by an intervening inhibitory domain (ID).
PTM: In normoxia, is hydroxylated on Pro-402 and Pro-564 in the oxygen-dependent degradation domain (ODD) by EGLN1/PHD1 and EGLN2/PHD2. EGLN3/PHD3 has also been shown to hydroxylate Pro-564. The hydroxylated prolines promote interaction with VHL, initiating rapid ubiquitination and subsequent proteasomal degradation. Under hypoxia, proline hydroxylation is impaired and ubiquitination is attenuated, resulting in stabilization.
PTM: In normoxia, is hydroxylated on Asn-803 by HIF1AN, thus abrogating interaction with CREBBP and EP300 and preventing transcriptional activation. This hydroxylation is inhibited by the Cu/Zn-chelator, Clioquinol.
PTM: S-nitrosylation of Cys-800 may be responsible for increased recruitment of p300 coactivator necessary for transcriptional activity of HIF-1 complex.
PTM: Requires phosphorylation for DNA-binding.
PTM: Sumoylated; by SUMO1 under hypoxia. Sumoylation is enhanced through interaction with RWDD3. Desumoylation by SENP1 leads to increased HIF1A stability and transriptional activity (By similarity).
PTM: Ubiquitinated; in normoxia, following hydroxylation and interaction with VHL. Lys-532 appears to be the principal site of ubiquitination. Clioquinol, the Cu/Zn-chelator, inhibits ubiquitination through preventing hydroxylation at Asn-803.
PTM: The iron and 2-oxoglutarate dependent 3-hydroxylation of asparagine is (S) stereospecific within HIF CTAD domains.
SIMILARITY: Contains 1 basic helix-loop-helix (bHLH) domain.
SIMILARITY: Contains 1 PAC (PAS-associated C-terminal) domain.
SIMILARITY: Contains 2 PAS (PER-ARNT-SIM) domains.
WEB RESOURCE: Name=Wikipedia; Note=Hypoxia inducible factor entry; URL="http://en.wikipedia.org/wiki/Hypoxia_inducible_factor";.

Copyright

Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms. Distributed under the Creative Commons Attribution-NoDerivs License.

Cross-references

Sequence databases

EMBL

U22431; AAC50152.1; -; mRNA.	[EMBL / GenBank / DDBJ] [CoDingSequence]
U29165; AAC51210.1; -; mRNA.	[EMBL / GenBank / DDBJ] [CoDingSequence]
AF050127; AAC68568.1; -; Genomic_DNA.	[EMBL / GenBank / DDBJ] [CoDingSequence]
AF050115; AAC68568.1; JOINED; Genomic_DNA.	[EMBL / GenBank / DDBJ] [CoDingSequence]
AF050116; AAC68568.1; JOINED; Genomic_DNA.	[EMBL / GenBank / DDBJ] [CoDingSequence]
AF050117; AAC68568.1; JOINED; Genomic_DNA.	[EMBL / GenBank / DDBJ] [CoDingSequence]
AF050118; AAC68568.1; JOINED; Genomic_DNA.	[EMBL / GenBank / DDBJ] [CoDingSequence]
AF050119; AAC68568.1; JOINED; Genomic_DNA.	[EMBL / GenBank / DDBJ] [CoDingSequence]
AF050120; AAC68568.1; JOINED; Genomic_DNA.	[EMBL / GenBank / DDBJ] [CoDingSequence]
AF050121; AAC68568.1; JOINED; Genomic_DNA.	[EMBL / GenBank / DDBJ] [CoDingSequence]
AF050122; AAC68568.1; JOINED; Genomic_DNA.	[EMBL / GenBank / DDBJ] [CoDingSequence]
AF050123; AAC68568.1; JOINED; Genomic_DNA.	[EMBL / GenBank / DDBJ] [CoDingSequence]
AF050124; AAC68568.1; JOINED; Genomic_DNA.	[EMBL / GenBank / DDBJ] [CoDingSequence]
AF050125; AAC68568.1; JOINED; Genomic_DNA.	[EMBL / GenBank / DDBJ] [CoDingSequence]
AF050126; AAC68568.1; JOINED; Genomic_DNA.	[EMBL / GenBank / DDBJ] [CoDingSequence]
AF207601; AAF20139.1; -; mRNA.	[EMBL / GenBank / DDBJ] [CoDingSequence]
AF207602; AAF20140.1; -; mRNA.	[EMBL / GenBank / DDBJ] [CoDingSequence]
AF208487; AAF20149.1; -; Genomic_DNA.	[EMBL / GenBank / DDBJ] [CoDingSequence]
AF304431; AAG43026.1; -; mRNA.	[EMBL / GenBank / DDBJ] [CoDingSequence]
AB073325; BAB70608.1; -; mRNA.	[EMBL / GenBank / DDBJ] [CoDingSequence]
BT009776; AAP88778.1; -; mRNA.	[EMBL / GenBank / DDBJ] [CoDingSequence]
BC012527; AAH12527.1; -; mRNA.	[EMBL / GenBank / DDBJ] [CoDingSequence]

IPI

IPI00003442; -.
IPI00332963; -.

PIR

I38972; I38972.

RefSeq

NP_001521.1; -.
NP_851397.1; -.

UniGene

Hs.597216

3D structure databases

PDB

1D7G; Model; -; D=15-73.	[ExPASy / RCSB / EBI]
1H2K; X-ray; 2.15 A; S=786-826.	[ExPASy / RCSB / EBI]
1H2L; X-ray; 2.25 A; S=786-826.	[ExPASy / RCSB / EBI]
1H2M; X-ray; 2.50 A; S=775-826.	[ExPASy / RCSB / EBI]
1L3E; NMR; -; A=786-826.	[ExPASy / RCSB / EBI]
1L8C; NMR; -; B=776-826.	[ExPASy / RCSB / EBI]
1LM8; X-ray; 1.85 A; H=556-575.	[ExPASy / RCSB / EBI]
1LQB; X-ray; 2.00 A; D=549-582.	[ExPASy / RCSB / EBI]
2ILM; X-ray; 2.30 A; S=786-826.	[ExPASy / RCSB / EBI]

Detailed list of linked structures.

PDBsum

1D7G; -.
1H2K; -.
1H2L; -.
1H2M; -.
1L3E; -.
1L8C; -.
1LM8; -.
1LQB; -.
2ILM; -.

Q16665; 237-345.

DP00262; -.

Protein-protein interaction databases

IntAct

Q16665; 19.

PTM databases

PhosphoSite

Q16665; -.

Enzyme and pathway databases

Pathway_Interaction_DB

hif1_tfpathway; HIF-1-alpha transcription factor network.
hif1apathway; Hypoxic and oxygen homeostasis regulation of HIF-1-alpha.
pdgfrbpathway; PDGFR-beta signaling pathway.
vegfr1_2_pathway; Signaling events mediated by VEGFR1 and VEGFR2.
vegfr1_pathway; VEGFR1 specific signals.

Organism-specific databases

GC14P061231; -.

HIX0011721; -.

HGNC:4910; HIF1A.

CAB017442; -.
HPA001275; -.

MIM

603348; gene. [NCBI / EBI]

Orphanet

90042; Polycythemia, familial, primary.

PharmGKB

PA29283; -.

Gene expression databases

Q16665; -.

Q16665; -.

HS_HIF1A; -.

ENSG00000100644; Homo sapiens.

Ontologies

GO:0005737;	Cellular component: cytoplasm (inferred from direct assay from HPA).
GO:0005730;	Cellular component: nucleolus (inferred from direct assay from HPA).
GO:0005667;	Cellular component: transcription factor complex (inferred from physical interaction from MGI).
GO:0035035;	Molecular function: histone acetyltransferase binding (inferred from physical interaction from UniProtKB).
GO:0051879;	Molecular function: Hsp90 protein binding (inferred from direct assay from UniProtKB).
GO:0046982;	Molecular function: protein heterodimerization activity (inferred from physical interaction from UniProtKB).
GO:0003705;	Molecular function: RNA polymerase II transcription factor activity, enhancer binding (inferred from direct assay from UniProtKB).
GO:0004871;	Molecular function: signal transducer activity (inferred from electronic annotation from InterPro).
GO:0008134;	Molecular function: transcription factor binding (inferred from physical interaction from UniProtKB).
GO:0032963;	Biological process: collagen metabolic process (inferred from sequence or structural similarity from UniProtKB).
GO:0002248;	Biological process: connective tissue replacement during inflammatory response (inferred from sequence or structural similarity from UniProtKB).
GO:0051541;	Biological process: elastin metabolic process (inferred from sequence or structural similarity from UniProtKB).
GO:0001837;	Biological process: epithelial to mesenchymal transition (inferred from sequence or structural similarity from UniProtKB).
GO:0042789;	Biological process: mRNA transcription from RNA polymerase II promoter (inferred by curator from UniProtKB).
GO:0032364;	Biological process: oxygen homeostasis (inferred from direct assay from HGNC).
GO:0045766;	Biological process: positive regulation of angiogenesis (inferred by curator from UniProtKB).
GO:0032722;	Biological process: positive regulation of chemokine production (traceable author statement from UniProtKB).
GO:0001938;	Biological process: positive regulation of endothelial cell proliferation (inferred by curator from UniProtKB).
GO:0010634;	Biological process: positive regulation of epithelial cell migration (inferred from sequence or structural similarity from UniProtKB).
GO:0045648;	Biological process: positive regulation of erythrocyte differentiation (inferred by curator from UniProtKB).
GO:0043193;	Biological process: positive regulation of gene-specific transcription (inferred from direct assay from UniProtKB).
GO:0045821;	Biological process: positive regulation of glycolysis (inferred by curator from UniProtKB).
GO:0046886;	Biological process: positive regulation of hormone biosynthetic process (inferred from direct assay from UniProtKB).
GO:0051000;	Biological process: positive regulation of nitric-oxide synthase activity (traceable author statement from UniProtKB).
GO:0045944;	Biological process: positive regulation of transcription from RNA polymerase II promoter (inferred from genetic interaction from MGI).
GO:0030949;	Biological process: positive regulation of vascular endothelial growth factor receptor signaling pathway (inferred by curator from UniProtKB).
GO:0010575;	Biological process: positive regulation vascular endothelial growth factor production (inferred from direct assay from UniProtKB).
GO:0043619;	Biological process: regulation of transcription from RNA polymerase II promoter in response to oxidative stress (inferred from direct assay from UniProtKB).
GO:0032909;	Biological process: regulation of transforming growth factor-beta2 production (inferred from mutant phenotype from UniProtKB).
GO:0001666;	Biological process: response to hypoxia (inferred from direct assay from UniProtKB).
GO:0007165;	Biological process: signal transduction (inferred from mutant phenotype from UniProtKB).
QuickGo view.

Family and domain databases

InterPro

IPR014887; HIF-1_TAD_C.
IPR001092; HLH_basic.
IPR001321; HypoxindF1A_PAS.
IPR001610; PAC.
IPR000014; PAS.
IPR013655; PAS_fold_3.
Graphical view of domain structure.

Pfam

PF08778; HIF-1a_CTAD; 1.
PF08447; PAS_3; 1.
Pfam graphical view of domain structure.

PRINTS

PR01080; HYPOXIAIF1A.

SMART

SM00353; HLH; 1.
SM00086; PAC; 1.
SM00091; PAS; 2.
SMART graphical view of domain structure.

PROSITE

PS50888; HLH; 1.
PS50113; PAC; FALSE_NEG.
PS50112; PAS; 2.
PROSITE graphical view of domain structure (profiles).

Proteomic databases

PRIDE

Q16665; -.

Genome annotation databases

Ensembl

ENSG00000100644; Homo sapiens. [Contig view]

GeneID

3091; -.

KEGG

hsa:3091; -.

Phylogenomic databases

HOGENOM

Q16665; -.

HOVERGEN

Q16665; -.

Other

12265; -.

HIF1A; Homo sapiens.

View cluster of proteins with at least 50% / 90% / 100% identity.

Keywords

3D-structure; Activator; Alternative splicing; Cytoplasm; Direct protein sequencing; DNA-binding; Hydroxylation; Isopeptide bond; Nucleus; Phosphoprotein; Polymorphism; Repeat; S-nitrosylation; Transcription; Transcription regulation; Ubl conjugation.

Features

Feature table viewer

Feature aligner

`Key`	`From To`	`Length`	`Description`	`FTId`
`CHAIN`	`1 826`	`826`	`Hypoxia-inducible factor 1 alpha.`	`PRO_0000127220`
`DOMAIN`	`31 71`	`41`	`Helix-loop-helix motif.`
`DOMAIN`	`85 158`	`74`	`PAS 1.`
`DOMAIN`	`228 298`	`71`	`PAS 2.`
`DOMAIN`	`302 345`	`44`	`PAC.`
`DNA_BIND`	`17 30`	`14`	`Basic motif.`
`REGION`	`1 401`	`401`	`Interaction with TSGA10 (By similarity).`
`REGION`	`380 417`	`38`	`N-terminal VHL recognition site.`
`REGION`	`401 603`	`203`	`ODD.`
`REGION`	`531 575`	`45`	`NTAD.`
`REGION`	`556 572`	`17`	`C-terminal VHL recognition site.`
`REGION`	`576 785`	`210`	`ID.`
`REGION`	`786 826`	`41`	`CTAD.`
`MOTIF`	`718 721`	`4`	`Nuclear localization signal (Potential).`
`COMPBIAS`	`615 621`	`7`	`Poly-Thr.`
`MOD_RES`	`402 402`		`4-hydroxyproline.`
`MOD_RES`	`564 564`		`4-hydroxyproline.`
`MOD_RES`	`800 800`		`S-nitrosocysteine (Probable).`
`MOD_RES`	`803 803`		`(3S)-3-hydroxyasparagine.`
`CROSSLNK`	`391 391`		`Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO).`
`CROSSLNK`	`477 477`		`Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO).`
`CROSSLNK`	`532 532`		`Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) (Probable).`
`CROSSLNK`	`538 538`		`Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) (Probable).`
`CROSSLNK`	`547 547`		`Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) (Probable).`
`VAR_SEQ`	`736 826`		`Missing (in isoform 2).`	`VSP_007738`
`VARIANT`	`582 582`	`1`	`P -> S (in dbSNP:rs11549465 [NCBI]).`	`VAR_049541`
`VARIANT`	`588 588`	`1`	`A -> T (in dbSNP:rs11549467 [NCBI]).`	`VAR_049542`
`VARIANT`	`796 796`	`1`	`T -> A (in dbSNP:rs1802821 [NCBI]).`	`VAR_015854 [3D]`
`MUTAGEN`	`377 377`		`K->R: No change in HIF1A protein turnover rate but increased transcriptional activity; when associated with R-391; R-477 and R-532.`
`MUTAGEN`	`389 389`		`K->R: No change in sumoylation.`
`MUTAGEN`	`391 391`		`K->R: Abolishes 1 sumoylation. Abolishes 1 sumoylation; when associated with R-532. Abolishes 2 sumoylations; when associated with R-477. No change in HIF1A protein turnover rate but increased transcriptional activity; when associated with R-377; R-477 and R-532.`
`MUTAGEN`	`392 392`		`K->R: No change in sumoylation.`
`MUTAGEN`	`394 394`		`P->A: No change in VHLE3-dependent ubiquitination.`
`MUTAGEN`	`397 397`		`L->A: Abolishes VHLE3-dependent ubiquitination; when associated with A-400.`
`MUTAGEN`	`400 400`		`L->A: Abolishes VHLE3-dependent ubiquitination; when associated with A-397.`
`MUTAGEN`	`402 402`		`P->A: Abolishes in VHLE3-dependent ubiquitination, abolishes oxygen-dependent regulation of VP16, partially reduced VHLE target site ubiquitination and no interaction with VHL. No VHLE target site ubiquitination; when associated with G-564.`
`MUTAGEN`	`442 442`		`K->R: No change in sumoylation.`
`MUTAGEN`	`460 460`		`K->R: No change in sumoylation nor in ARD1-mediated acetylation.`
`MUTAGEN`	`477 477`		`K->R: Abolishes 1 sumoylation. Abolishes 2 sumoylations; when asociated with R-391. No change in HIF1A protein turnover rate but increased transcriptional activity; when associated with R-377; R-391 and R-532.`
`MUTAGEN`	`532 532`		`K->R: Reduced ubiquitination. No change in sumoylation nor on interaction with ARD1A. No change in HIF1A protein turnover rate but increased transcriptional activity; when associated with R-377; R-391 and R-477. Complete loss of ubiquitination, but no change in VHL binding; when associated with K-538 and K-547.`
`MUTAGEN`	`538 538`		`K->R: No change in sumoylation, but reduced ubiquitination. Complete loss of ubiquitination, but no change in VHL binding; when associated with K-532 and K-547.`
`MUTAGEN`	`547 547`		`K->R: No change in sumoylation, but reduced ubiquitination. Complete loss of ubiquitination, but no change in VHL binding; when associated with K-532 and K-538.`
`MUTAGEN`	`551 551`		`S->G: Constitutive expression under nonhypoxic conditions by decreasing ubiquitination.`
`MUTAGEN`	`552 552`		`T->A: Constitutive expression under nonhypoxic conditions by decreasing ubiquitination.`
`MUTAGEN`	`564 564`		`P->G: No change in VHL-dependent ubiquitination. Partially reduced VHLE target site ubiquitination. No VHLE target site ubiquitination; when associated with A-402.`
`MUTAGEN`	`719 719`		`K->T: Dramatic reduction of accumulation in the nucleus in response to hypoxia.`
`MUTAGEN`	`800 800`		`C->A: Blocks increase in transcriptional activation caused by nitrosylation.`
`MUTAGEN`	`800 800`		`C->S: Abolishes hypoxia-inducible transcriptional activation of ctaD.`
`MUTAGEN`	`803 803`		`N->A: Recruits CREBBP. No enhancement of CREBBP by Clioquinol in the presence of FIH1. No change in nuclear location nor on repression of transcriptional activity in the presence of histone deacetylase inhibitor.`
`CONFLICT`	`572 572`		`F -> L (in Ref. 3; AAC68568).`
`CONFLICT`	`735 735`		`G -> I (in Ref. 6; BAB70608).`
`TURN`	`779 783`	`5`
`HELIX`	`815 822`	`8`

Sequence information

Length: 826 AA [This is the length of the unprocessed precursor]

Molecular weight: 92670 Da [This is the MW of the unprocessed precursor]

CRC64: ABD4F7DAA135BE2D [This is a checksum on the sequence]

        10         20         30         40         50         60 
MEGAGGANDK KKISSERRKE KSRDAARSRR SKESEVFYEL AHQLPLPHNV SSHLDKASVM 

        70         80         90        100        110        120 
RLTISYLRVR KLLDAGDLDI EDDMKAQMNC FYLKALDGFV MVLTDDGDMI YISDNVNKYM 

       130        140        150        160        170        180 
GLTQFELTGH SVFDFTHPCD HEEMREMLTH RNGLVKKGKE QNTQRSFFLR MKCTLTSRGR 

       190        200        210        220        230        240 
TMNIKSATWK VLHCTGHIHV YDTNSNQPQC GYKKPPMTCL VLICEPIPHP SNIEIPLDSK 

       250        260        270        280        290        300 
TFLSRHSLDM KFSYCDERIT ELMGYEPEEL LGRSIYEYYH ALDSDHLTKT HHDMFTKGQV 

       310        320        330        340        350        360 
TTGQYRMLAK RGGYVWVETQ ATVIYNTKNS QPQCIVCVNY VVSGIIQHDL IFSLQQTECV 

       370        380        390        400        410        420 
LKPVESSDMK MTQLFTKVES EDTSSLFDKL KKEPDALTLL APAAGDTIIS LDFGSNDTET 

       430        440        450        460        470        480 
DDQQLEEVPL YNDVMLPSPN EKLQNINLAM SPLPTAETPK PLRSSADPAL NQEVALKLEP 

       490        500        510        520        530        540 
NPESLELSFT MPQIQDQTPS PSDGSTRQSS PEPNSPSEYC FYVDSDMVNE FKLELVEKLF 

       550        560        570        580        590        600 
AEDTEAKNPF STQDTDLDLE MLAPYIPMDD DFQLRSFDQL SPLESSSASP ESASPQSTVT 

       610        620        630        640        650        660 
VFQQTQIQEP TANATTTTAT TDELKTVTKD RMEDIKILIA SPSPTHIHKE TTSATSSPYR 

       670        680        690        700        710        720 
DTQSRTASPN RAGKGVIEQT EKSHPRSPNV LSVALSQRTT VPEEELNPKI LALQNAQRKR 

       730        740        750        760        770        780 
KMEHDGSLFQ AVGIGTLLQQ PDDHAATTSL SWKRVKGCKS SEQNGMEQKT IILIPSDLAC 

       790        800        810        820 
RLLGQSMDES GLPQLTSYDC EVNAPIQGSR NLLQGEELLR ALDQVN

Q16665 in FASTA format

View entry in raw text format (no links)
Report form for errors/updates in this UniProtKB/Swiss-Prot entry

	BLAST submission on ExPASy/SIB or at NCBI (USA)		Sequence analysis tools: ProtParam, ProtScale, Compute pI/Mw, PeptideMass, PeptideCutter, Dotlet (Java)
	ScanProsite, MotifScan		Submit a homology modeling request to SWISS-MODEL
	NPSA Sequence analysis tools