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Q16665

- HIF1A_HUMAN

UniProt

Q16665 - HIF1A_HUMAN

Protein

Hypoxia-inducible factor 1-alpha

Gene

HIF1A

Organism
Homo sapiens (Human)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 175 (01 Oct 2014)
      Sequence version 1 (01 Nov 1996)
      Previous versions | rss
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    Functioni

    Functions as a master transcriptional regulator of the adaptive response to hypoxia. Under hypoxic conditions, activates the transcription of over 40 genes, including erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor, HILPDA, and other genes whose protein products increase oxygen delivery or facilitate metabolic adaptation to hypoxia. Plays an essential role in embryonic vascularization, tumor angiogenesis and pathophysiology of ischemic disease. Binds to core DNA sequence 5'-[AG]CGTG-3' within the hypoxia response element (HRE) of target gene promoters. Activation requires recruitment of transcriptional coactivators such as CREBPB and EP300. Activity is enhanced by interaction with both, NCOA1 or NCOA2. Interaction with redox regulatory protein APEX seems to activate CTAD and potentiates activation by NCOA1 and CREBBP. Involved in the axonal distribution and transport of mitochondria in neurons during hypoxia.10 Publications

    GO - Molecular functioni

    1. enzyme binding Source: UniProtKB
    2. histone acetyltransferase binding Source: UniProtKB
    3. Hsp90 protein binding Source: BHF-UCL
    4. nuclear hormone receptor binding Source: UniProtKB
    5. protein binding Source: UniProtKB
    6. protein heterodimerization activity Source: UniProtKB
    7. protein kinase binding Source: UniProtKB
    8. RNA polymerase II core promoter proximal region sequence-specific DNA binding transcription factor activity involved in positive regulation of transcription Source: Ensembl
    9. RNA polymerase II distal enhancer sequence-specific DNA binding transcription factor activity Source: BHF-UCL
    10. RNA polymerase II transcription factor binding transcription factor activity Source: Ensembl
    11. sequence-specific DNA binding Source: Ensembl
    12. sequence-specific DNA binding transcription factor activity Source: UniProtKB
    13. signal transducer activity Source: InterPro
    14. transcription factor binding Source: BHF-UCL
    15. transcription factor binding transcription factor activity Source: BHF-UCL
    16. transcription regulatory region DNA binding Source: UniProtKB
    17. ubiquitin protein ligase binding Source: UniProtKB

    GO - Biological processi

    1. angiogenesis Source: Ensembl
    2. axon transport of mitochondrion Source: UniProtKB
    3. B-1 B cell homeostasis Source: Ensembl
    4. cardiac ventricle morphogenesis Source: Ensembl
    5. cartilage development Source: Ensembl
    6. cellular iron ion homeostasis Source: Ensembl
    7. cellular response to hypoxia Source: UniProtKB
    8. cellular response to interleukin-1 Source: BHF-UCL
    9. cerebral cortex development Source: Ensembl
    10. collagen metabolic process Source: BHF-UCL
    11. connective tissue replacement involved in inflammatory response wound healing Source: BHF-UCL
    12. digestive tract morphogenesis Source: Ensembl
    13. dopaminergic neuron differentiation Source: Ensembl
    14. elastin metabolic process Source: BHF-UCL
    15. embryonic hemopoiesis Source: Ensembl
    16. embryonic placenta development Source: Ensembl
    17. epithelial cell differentiation involved in mammary gland alveolus development Source: Ensembl
    18. epithelial to mesenchymal transition Source: BHF-UCL
    19. glucose homeostasis Source: Ensembl
    20. heart looping Source: Ensembl
    21. hemoglobin biosynthetic process Source: Ensembl
    22. intestinal epithelial cell maturation Source: Ensembl
    23. lactate metabolic process Source: Ensembl
    24. lactation Source: Ensembl
    25. mRNA transcription from RNA polymerase II promoter Source: BHF-UCL
    26. muscle cell cellular homeostasis Source: Ensembl
    27. negative regulation of bone mineralization Source: Ensembl
    28. negative regulation of growth Source: Ensembl
    29. negative regulation of mesenchymal cell apoptotic process Source: Ensembl
    30. negative regulation of neuron apoptotic process Source: Ensembl
    31. negative regulation of thymocyte apoptotic process Source: Ensembl
    32. negative regulation of TOR signaling Source: Ensembl
    33. neural crest cell migration Source: Ensembl
    34. neural fold elevation formation Source: Ensembl
    35. Notch signaling pathway Source: Reactome
    36. outflow tract morphogenesis Source: Ensembl
    37. oxygen homeostasis Source: HGNC
    38. positive regulation of angiogenesis Source: BHF-UCL
    39. positive regulation of chemokine-mediated signaling pathway Source: BHF-UCL
    40. positive regulation of chemokine production Source: BHF-UCL
    41. positive regulation of endothelial cell proliferation Source: BHF-UCL
    42. positive regulation of epithelial cell migration Source: BHF-UCL
    43. positive regulation of erythrocyte differentiation Source: BHF-UCL
    44. positive regulation of glycolytic process Source: BHF-UCL
    45. positive regulation of hormone biosynthetic process Source: BHF-UCL
    46. positive regulation of insulin secretion involved in cellular response to glucose stimulus Source: Ensembl
    47. positive regulation of neuroblast proliferation Source: Ensembl
    48. positive regulation of nitric-oxide synthase activity Source: BHF-UCL
    49. positive regulation of receptor biosynthetic process Source: BHF-UCL
    50. positive regulation of transcription, DNA-templated Source: UniProtKB
    51. positive regulation of transcription from RNA polymerase II promoter Source: UniProtKB
    52. positive regulation of transcription from RNA polymerase II promoter in response to hypoxia Source: UniProtKB
    53. positive regulation of vascular endothelial growth factor receptor signaling pathway Source: BHF-UCL
    54. positive regulation vascular endothelial growth factor production Source: UniProtKB
    55. regulation of gene expression Source: UniProtKB
    56. regulation of transcription, DNA-templated Source: UniProtKB
    57. regulation of transcription from RNA polymerase II promoter in response to hypoxia Source: Reactome
    58. regulation of transcription from RNA polymerase II promoter in response to oxidative stress Source: BHF-UCL
    59. regulation of transforming growth factor beta2 production Source: BHF-UCL
    60. response to hypoxia Source: UniProtKB
    61. response to muscle activity Source: Ensembl
    62. retina vasculature development in camera-type eye Source: Ensembl
    63. signal transduction Source: BHF-UCL
    64. vascular endothelial growth factor production Source: BHF-UCL
    65. visual learning Source: Ensembl

    Keywords - Molecular functioni

    Activator

    Keywords - Biological processi

    Transcription, Transcription regulation

    Keywords - Ligandi

    DNA-binding

    Enzyme and pathway databases

    ReactomeiREACT_118780. NOTCH1 Intracellular Domain Regulates Transcription.
    REACT_120916. Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha.
    REACT_121092. Regulation of gene expression by Hypoxia-inducible Factor.
    REACT_121226. Oxygen-dependent asparagine hydroxylation of Hypoxia-inducible Factor Alpha.
    REACT_24941. Circadian Clock.
    SignaLinkiQ16665.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Hypoxia-inducible factor 1-alpha
    Short name:
    HIF-1-alpha
    Short name:
    HIF1-alpha
    Alternative name(s):
    ARNT-interacting protein
    Basic-helix-loop-helix-PAS protein MOP1
    Class E basic helix-loop-helix protein 78
    Short name:
    bHLHe78
    Member of PAS protein 1
    PAS domain-containing protein 8
    Gene namesi
    Name:HIF1A
    Synonyms:BHLHE78, MOP1, PASD8
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    ProteomesiUP000005640: Chromosome 14

    Organism-specific databases

    HGNCiHGNC:4910. HIF1A.

    Subcellular locationi

    Cytoplasm. Nucleus
    Note: Cytoplasmic in normoxia, nuclear translocation in response to hypoxia. Colocalizes with SUMO1 in the nucleus, under hypoxia.

    GO - Cellular componenti

    1. cytoplasm Source: BHF-UCL
    2. cytosol Source: UniProtKB
    3. motile cilium Source: Ensembl
    4. nucleolus Source: HPA
    5. nucleoplasm Source: Reactome
    6. nucleus Source: UniProtKB
    7. transcription factor complex Source: MGI

    Keywords - Cellular componenti

    Cytoplasm, Nucleus

    Pathology & Biotechi

    Mutagenesis

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Mutagenesisi247 – 2471S → A: Constitutive kinase activity. 1 Publication
    Mutagenesisi247 – 2471S → D: Impaired kinase activity. 1 Publication
    Mutagenesisi377 – 3771K → R: No change in HIF1A protein turnover rate but increased transcriptional activity; when associated with R-391; R-477 and R-532. 1 Publication
    Mutagenesisi389 – 3891K → R: No change in sumoylation. 1 Publication
    Mutagenesisi391 – 3911K → 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. 2 Publications
    Mutagenesisi392 – 3921K → R: No change in sumoylation. 1 Publication
    Mutagenesisi394 – 3941P → A: No change in VHLE3-dependent ubiquitination. 1 Publication
    Mutagenesisi397 – 3971L → A: Abolishes VHLE3-dependent ubiquitination; when associated with A-400. 1 Publication
    Mutagenesisi400 – 4001L → A: Abolishes VHLE3-dependent ubiquitination; when associated with A-397. 1 Publication
    Mutagenesisi402 – 4021P → 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. Increases HIF1A instability and reduces HIF1A-induced target gene transcriptional activation; when associated with A-564. 3 Publications
    Mutagenesisi442 – 4421K → R: No change in sumoylation. 1 Publication
    Mutagenesisi460 – 4601K → R: No change in sumoylation nor in ARD1-mediated acetylation. 1 Publication
    Mutagenesisi477 – 4771K → R: Abolishes 1 sumoylation. Abolishes 2 sumoylations; when associated with R-391. No change in HIF1A protein turnover rate but increased transcriptional activity; when associated with R-377; R-391 and R-532. 2 Publications
    Mutagenesisi532 – 5321K → 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. 5 Publications
    Mutagenesisi538 – 5381K → 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. 3 Publications
    Mutagenesisi547 – 5471K → 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. 3 Publications
    Mutagenesisi551 – 5511S → G: Constitutive expression under nonhypoxic conditions by decreasing ubiquitination. 1 Publication
    Mutagenesisi552 – 5521T → A: Constitutive expression under nonhypoxic conditions by decreasing ubiquitination. 1 Publication
    Mutagenesisi564 – 5641P → A: Increases HIF1A instability and reduces HIF1A-induced target gene transcriptional activation; when associated with A-402. 3 Publications
    Mutagenesisi564 – 5641P → G: No change in VHL-dependent ubiquitination. Partially reduced VHLE target site ubiquitination. No VHLE target site ubiquitination; when associated with A-402. 3 Publications
    Mutagenesisi576 – 5761S → A: Induces stabilization of the protein. 1 Publication
    Mutagenesisi657 – 6571S → A: Induces stabilization of the protein. 1 Publication
    Mutagenesisi709 – 7091K → R: Abolishes SIRT2-mediated deacetylation, increases HIF1A instability and reduces HIF1A-induced target gene transcriptional activation. Increases interaction with EGLN1. 1 Publication
    Mutagenesisi719 – 7191K → T: Dramatic reduction of accumulation in the nucleus in response to hypoxia. 2 Publications
    Mutagenesisi795 – 7951L → A: Inhibits interaction with EP300 and transactivation activity. 1 Publication
    Mutagenesisi800 – 8001C → A: Blocks increase in transcriptional activation caused by nitrosylation. 2 Publications
    Mutagenesisi800 – 8001C → S: Abolishes hypoxia-inducible transcriptional activation of ctaD. 2 Publications
    Mutagenesisi803 – 8031N → 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. 2 Publications

    Organism-specific databases

    PharmGKBiPA29283.

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Chaini1 – 826826Hypoxia-inducible factor 1-alphaPRO_0000127220Add
    BLAST

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Modified residuei247 – 2471Phosphoserine; by CK11 Publication
    Cross-linki391 – 391Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO)
    Modified residuei402 – 40214-hydroxyproline1 Publication
    Cross-linki477 – 477Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO)
    Modified residuei532 – 5321N6-acetyllysine1 Publication
    Cross-linki532 – 532Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)1 Publication
    Cross-linki538 – 538Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)1 Publication
    Cross-linki547 – 547Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)1 Publication
    Modified residuei551 – 5511Phosphoserine; by GSK3-beta1 Publication
    Modified residuei555 – 5551Phosphothreonine; by GSK3-beta1 Publication
    Modified residuei564 – 56414-hydroxyproline3 Publications
    Modified residuei576 – 5761Phosphoserine; by PLK31 Publication
    Modified residuei589 – 5891Phosphoserine; by GSK3-beta1 Publication
    Modified residuei657 – 6571Phosphoserine; by PLK31 Publication
    Modified residuei709 – 7091N6-acetyllysine1 Publication
    Modified residuei800 – 8001S-nitrosocysteine2 Publications
    Modified residuei803 – 8031(3S)-3-hydroxyasparagine1 Publication

    Post-translational modificationi

    In normoxia, is hydroxylated on Pro-402 and Pro-564 in the oxygen-dependent degradation domain (ODD) by EGLN1/PHD1 and EGLN2/PHD2. EGLN3/PHD3 has also been shown to hydroxylate Pro-564. The hydroxylated prolines promote interaction with VHL, initiating rapid ubiquitination and subsequent proteasomal degradation. Deubiquitinated by USP20. Under hypoxia, proline hydroxylation is impaired and ubiquitination is attenuated, resulting in stabilization.4 Publications
    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.1 Publication
    S-nitrosylation of Cys-800 may be responsible for increased recruitment of p300 coactivator necessary for transcriptional activity of HIF-1 complex.2 Publications
    Requires phosphorylation for DNA-binding. Phosphorylation at Ser-247 by CSNK1D/CK1 represses kinase activity and impairs ARNT binding. Phosphorylation by GSK3-beta and PLK3 promote degradation by the proteasome.2 Publications
    Sumoylated; with SUMO1 under hypoxia. Sumoylation is enhanced through interaction with RWDD3. Both sumoylation and desumoylation seem to be involved in the regulation of its stability during hypoxia. Sumoylation can promote either its stabilization or its VHL-dependent degradation by promoting hydroxyproline-independent HIF1A-VHL complex binding, thus leading to HIF1A ubiquitination and proteasomal degradation. Desumoylation by SENP1 increases its stability amd transcriptional activity. There is a disaccord between various publications on the effect of sumoylation and desumoylation on its stability and transcriptional activity.4 Publications
    Acetylation of Lys-532 by ARD1 increases interaction with VHL and stimulates subsequent proteasomal degradation. Deacetylation of Lys-709 by SIRT2 increases its interaction with and hydroxylation by EGLN1 thereby inactivating HIF1A activity by inducing its proteasomal degradation.1 Publication
    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-803.3 Publications
    The iron and 2-oxoglutarate dependent 3-hydroxylation of asparagine is (S) stereospecific within HIF CTAD domains.

    Keywords - PTMi

    Acetylation, Hydroxylation, Isopeptide bond, Phosphoprotein, S-nitrosylation, Ubl conjugation

    Proteomic databases

    PaxDbiQ16665.
    PRIDEiQ16665.

    PTM databases

    PhosphoSiteiQ16665.

    Expressioni

    Tissue specificityi

    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. A higher level expression seen in pituitary tumors as compared to the pituitary gland.1 Publication

    Inductioni

    Under reduced oxygen tension. Induced also by various receptor-mediated factors such as growth factors, cytokines, and circulatory factors such as PDGF, EGF, FGF2, IGF2, TGFB1, HGF, TNF, IL1B/interleukin-1 beta, angiotensin-2 and thrombin. However, this induction is less intense than that stimulated by hypoxia. Repressed by HIPK2 and LIMD1.3 Publications

    Gene expression databases

    ArrayExpressiQ16665.
    BgeeiQ16665.
    CleanExiHS_HIF1A.
    GenevestigatoriQ16665.

    Organism-specific databases

    HPAiCAB017442.
    HPA001275.

    Interactioni

    Subunit structurei

    Interacts with the HIF1A beta/ARNT subunit; heterodimerization is required for DNA binding. Interacts with COPS5; the interaction increases the transcriptional activity of HIF1A through increased stability By similarity. Interacts with EP300 (via TAZ-type 1 domains); the interaction is stimulated in response to hypoxia and inhibited by CITED2. Interacts with CREBBP (via TAZ-type 1 domains). Interacts with NCOA1, NCOA2, APEX and HSP90. Interacts (hydroxylated within the ODD domain) with VHLL (via beta domain); the interaction, leads to polyubiquitination and subsequent HIF1A proteasomal degradation. During hypoxia, sumoylated HIF1A also binds VHL; the interaction promotes the ubiquitination of HIF1A. Interacts with SENP1; the interaction desumoylates HIF1A resulting in stabilization and activation of transcription. Interacts (Via the ODD domain) with ARD1A; the interaction appears not to acetylate HIF1A nor have any affect on protein stability, during hypoxia. Interacts with RWDD3; the interaction enhances HIF1A sumoylation. Interacts with TSGA10 By similarity. Interacts with RORA (via the DNA binding domain); the interaction enhances HIF1A transcription under hypoxia through increasing protein stability. Interaction with PSMA7 inhibits the transactivation activity of HIF1A under both normoxic and hypoxia-mimicking conditions. Interacts with USP20. Interacts with GNB2L1/RACK1; promotes HIF1A ubiquitination and proteasome-mediated degradation. Interacts (via N-terminus) with USP19. Interacts with SIRT2. Interacts (deacetylated form) with EGLN1.By similarity28 Publications

    Binary interactionsi

    WithEntry#Exp.IntActNotes
    ARP102752EBI-447269,EBI-608057
    ARNTP275409EBI-447269,EBI-80809
    ARRB1P494073EBI-447269,EBI-743313
    CBX4O0025715EBI-447269,EBI-722425
    CREBBPQ927932EBI-447269,EBI-81215
    E2f7Q6S7F23EBI-447269,EBI-8030813From a different organism.
    e2f7Q5RIX92EBI-447269,EBI-8030618From a different organism.
    EGLN1Q9GZT94EBI-447269,EBI-1174818
    EGLN2Q96KS02EBI-447269,EBI-726614
    EGLN3Q9H6Z93EBI-447269,EBI-1175354
    EP300Q0947215EBI-447269,EBI-447295
    HIF1ANQ9NWT64EBI-447269,EBI-745632
    KAT2BQ928312EBI-447269,EBI-477430
    MTA1Q133306EBI-447269,EBI-714236
    OS9Q134389EBI-447269,EBI-725454
    PIAS4Q8N2W93EBI-447269,EBI-473160
    PKMP14618-17EBI-447269,EBI-4304679
    Rbfox3Q8BIF22EBI-447269,EBI-4567146From a different organism.
    RorcP51450-22EBI-447269,EBI-4422078From a different organism.
    SEPT9Q9UHD8-14EBI-447269,EBI-851558
    SP1P080473EBI-447269,EBI-298336
    SUMO1P631654EBI-447269,EBI-80140
    UBXN7O948883EBI-447269,EBI-1993627
    USP8P408182EBI-447269,EBI-1050865
    VHLP4033717EBI-447269,EBI-301246

    Protein-protein interaction databases

    BioGridi109338. 110 interactions.
    DIPiDIP-29722N.
    IntActiQ16665. 60 interactions.
    MINTiMINT-133270.
    STRINGi9606.ENSP00000338018.

    Structurei

    Secondary structure

    1
    826
    Legend: HelixTurnBeta strand
    Show more details
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Beta strandi241 – 2466
    Beta strandi251 – 2555
    Helixi258 – 2636
    Helixi267 – 2704
    Helixi275 – 2773
    Turni281 – 2833
    Helixi284 – 29714
    Beta strandi298 – 3014
    Beta strandi305 – 3084
    Beta strandi310 – 32516
    Turni327 – 3293
    Beta strandi332 – 34110
    Helixi559 – 5613
    Turni779 – 7835
    Helixi784 – 7874
    Beta strandi789 – 7924
    Helixi797 – 8037
    Beta strandi807 – 8093
    Helixi815 – 8228

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    EntryMethodResolution (Å)ChainPositionsPDBsum
    1D7Gmodel-D15-73[»]
    1H2KX-ray2.15S786-826[»]
    1H2LX-ray2.25S786-826[»]
    1H2MX-ray2.50S775-826[»]
    1L3ENMR-A786-826[»]
    1L8CNMR-B776-826[»]
    1LM8X-ray1.85H556-575[»]
    1LQBX-ray2.00D549-582[»]
    2ILMX-ray2.30S786-826[»]
    3HQRX-ray2.00S558-574[»]
    3HQUX-ray2.30S558-574[»]
    4AJYX-ray1.73H559-577[»]
    4H6JX-ray1.52A238-348[»]
    DisProtiDP00262.
    ProteinModelPortaliQ16665.
    SMRiQ16665. Positions 19-374, 776-826.
    ModBaseiSearch...
    MobiDBiSearch...

    Miscellaneous databases

    EvolutionaryTraceiQ16665.

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Domaini17 – 7054bHLHPROSITE-ProRule annotationAdd
    BLAST
    Domaini85 – 15874PAS 1PROSITE-ProRule annotationAdd
    BLAST
    Domaini228 – 29871PAS 2PROSITE-ProRule annotationAdd
    BLAST
    Domaini302 – 34544PACAdd
    BLAST

    Region

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Regioni1 – 401401Interaction with TSGA10By similarityAdd
    BLAST
    Regioni380 – 41738N-terminal VHL recognition siteAdd
    BLAST
    Regioni401 – 603203ODDAdd
    BLAST
    Regioni531 – 57545NTADAdd
    BLAST
    Regioni556 – 57217C-terminal VHL recognition siteAdd
    BLAST
    Regioni576 – 785210IDAdd
    BLAST
    Regioni786 – 82641CTADAdd
    BLAST

    Motif

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Motifi718 – 7214Nuclear localization signalSequence Analysis

    Compositional bias

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Compositional biasi615 – 6217Poly-Thr

    Domaini

    Contains two independent C-terminal transactivation domains, NTAD and CTAD, which function synergistically. Their transcriptional activity is repressed by an intervening inhibitory domain (ID).

    Sequence similaritiesi

    Contains 1 bHLH (basic helix-loop-helix) domain.PROSITE-ProRule annotation
    Contains 2 PAS (PER-ARNT-SIM) domains.PROSITE-ProRule annotation

    Keywords - Domaini

    Repeat

    Phylogenomic databases

    eggNOGiNOG289264.
    HOGENOMiHOG000234306.
    HOVERGENiHBG060456.
    KOiK08268.
    OMAiQNAQRKR.
    OrthoDBiEOG7JDQX8.
    PhylomeDBiQ16665.
    TreeFamiTF317772.

    Family and domain databases

    InterProiIPR011598. bHLH_dom.
    IPR001321. HIF-1_alpha.
    IPR014887. HIF-1_TAD_C.
    IPR021537. HIF_alpha_subunit.
    IPR001610. PAC.
    IPR000014. PAS.
    IPR013767. PAS_fold.
    [Graphical view]
    PfamiPF11413. HIF-1. 1 hit.
    PF08778. HIF-1a_CTAD. 1 hit.
    PF00989. PAS. 1 hit.
    [Graphical view]
    PRINTSiPR01080. HYPOXIAIF1A.
    SMARTiSM00353. HLH. 1 hit.
    SM00086. PAC. 1 hit.
    SM00091. PAS. 2 hits.
    [Graphical view]
    SUPFAMiSSF47459. SSF47459. 1 hit.
    SSF55785. SSF55785. 2 hits.
    TIGRFAMsiTIGR00229. sensory_box. 2 hits.
    PROSITEiPS50888. BHLH. 1 hit.
    PS50112. PAS. 2 hits.
    [Graphical view]

    Sequences (3)i

    Sequence statusi: Complete.

    This entry describes 3 isoformsi produced by alternative splicing. Align

    Isoform 1 (identifier: Q16665-1) [UniParc]FASTAAdd to Basket

    This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

    « Hide

    MEGAGGANDK KKISSERRKE KSRDAARSRR SKESEVFYEL AHQLPLPHNV    50
    SSHLDKASVM RLTISYLRVR KLLDAGDLDI EDDMKAQMNC FYLKALDGFV 100
    MVLTDDGDMI YISDNVNKYM GLTQFELTGH SVFDFTHPCD HEEMREMLTH 150
    RNGLVKKGKE QNTQRSFFLR MKCTLTSRGR TMNIKSATWK VLHCTGHIHV 200
    YDTNSNQPQC GYKKPPMTCL VLICEPIPHP SNIEIPLDSK TFLSRHSLDM 250
    KFSYCDERIT ELMGYEPEEL LGRSIYEYYH ALDSDHLTKT HHDMFTKGQV 300
    TTGQYRMLAK RGGYVWVETQ ATVIYNTKNS QPQCIVCVNY VVSGIIQHDL 350
    IFSLQQTECV LKPVESSDMK MTQLFTKVES EDTSSLFDKL KKEPDALTLL 400
    APAAGDTIIS LDFGSNDTET DDQQLEEVPL YNDVMLPSPN EKLQNINLAM 450
    SPLPTAETPK PLRSSADPAL NQEVALKLEP NPESLELSFT MPQIQDQTPS 500
    PSDGSTRQSS PEPNSPSEYC FYVDSDMVNE FKLELVEKLF AEDTEAKNPF 550
    STQDTDLDLE MLAPYIPMDD DFQLRSFDQL SPLESSSASP ESASPQSTVT 600
    VFQQTQIQEP TANATTTTAT TDELKTVTKD RMEDIKILIA SPSPTHIHKE 650
    TTSATSSPYR DTQSRTASPN RAGKGVIEQT EKSHPRSPNV LSVALSQRTT 700
    VPEEELNPKI LALQNAQRKR KMEHDGSLFQ AVGIGTLLQQ PDDHAATTSL 750
    SWKRVKGCKS SEQNGMEQKT IILIPSDLAC RLLGQSMDES GLPQLTSYDC 800
    EVNAPIQGSR NLLQGEELLR ALDQVN 826
    Length:826
    Mass (Da):92,670
    Last modified:November 1, 1996 - v1
    Checksum:iABD4F7DAA135BE2D
    GO
    Isoform 2 (identifier: Q16665-2) [UniParc]FASTAAdd to Basket

    The sequence of this isoform differs from the canonical sequence as follows:
         735-735: G → I
         736-826: Missing.

    Note: No experimental confirmation available.

    Show »
    Length:735
    Mass (Da):82,746
    Checksum:i34DD604FB4E4418E
    GO
    Isoform 3 (identifier: Q16665-3) [UniParc]FASTAAdd to Basket

    Also known as: I.3

    The sequence of this isoform differs from the canonical sequence as follows:
         1-12: MEGAGGANDKKK → MSSQCRSLENKFVFLKEGLGNSKPEELEEIRIENGR

    Note: Up-regulated in peripheral T-lymphocytes after T-cell receptor stimulation. Highest expression in peripheral blood leukocytes and thymus.

    Show »
    Length:850
    Mass (Da):95,634
    Checksum:i272C9EFAFD7A1E48
    GO

    Experimental Info

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Sequence conflicti572 – 5721F → L in AAC68568. (PubMed:9782081)Curated

    Natural variant

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Natural varianti582 – 5821P → S.
    Corresponds to variant rs11549465 [ dbSNP | Ensembl ].
    VAR_049541
    Natural varianti588 – 5881A → T.
    Corresponds to variant rs11549467 [ dbSNP | Ensembl ].
    VAR_049542
    Natural varianti796 – 7961T → A.
    Corresponds to variant rs1802821 [ dbSNP | Ensembl ].
    VAR_015854

    Alternative sequence

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Alternative sequencei1 – 1212MEGAG…NDKKK → MSSQCRSLENKFVFLKEGLG NSKPEELEEIRIENGR in isoform 3. 1 PublicationVSP_044942Add
    BLAST
    Alternative sequencei735 – 7351G → I in isoform 2. 1 PublicationVSP_047335
    Alternative sequencei736 – 82691Missing in isoform 2. 1 PublicationVSP_007738Add
    BLAST

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    U22431 mRNA. Translation: AAC50152.1.
    U29165 mRNA. Translation: AAC51210.1.
    AF050127
    , AF050115, AF050116, AF050117, AF050118, AF050119, AF050120, AF050121, AF050122, AF050123, AF050124, AF050125, AF050126 Genomic DNA. Translation: AAC68568.1.
    FJ790247 mRNA. Translation: ACN88547.1.
    AF207601 mRNA. Translation: AAF20139.1.
    AF207602 mRNA. Translation: AAF20140.1.
    AF208487 Genomic DNA. Translation: AAF20149.1.
    AF304431 mRNA. Translation: AAG43026.1.
    AB073325 mRNA. Translation: BAB70608.1.
    BT009776 mRNA. Translation: AAP88778.1.
    AL137129 Genomic DNA. No translation available.
    BC012527 mRNA. Translation: AAH12527.1.
    CCDSiCCDS58324.1. [Q16665-3]
    CCDS9753.1. [Q16665-1]
    CCDS9754.1. [Q16665-2]
    PIRiI38972.
    RefSeqiNP_001230013.1. NM_001243084.1. [Q16665-3]
    NP_001521.1. NM_001530.3. [Q16665-1]
    NP_851397.1. NM_181054.2. [Q16665-2]
    UniGeneiHs.597216.
    Hs.719495.

    Genome annotation databases

    EnsembliENST00000323441; ENSP00000323326; ENSG00000100644. [Q16665-2]
    ENST00000337138; ENSP00000338018; ENSG00000100644. [Q16665-1]
    ENST00000539097; ENSP00000437955; ENSG00000100644. [Q16665-3]
    GeneIDi3091.
    KEGGihsa:3091.
    UCSCiuc001xfq.2. human. [Q16665-1]
    uc021rua.1. human.

    Polymorphism databases

    DMDMi2498017.

    Keywords - Coding sequence diversityi

    Alternative splicing, Polymorphism

    Cross-referencesi

    Web resourcesi

    Wikipedia

    Hypoxia inducible factor entry

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    U22431 mRNA. Translation: AAC50152.1 .
    U29165 mRNA. Translation: AAC51210.1 .
    AF050127
    , AF050115 , AF050116 , AF050117 , AF050118 , AF050119 , AF050120 , AF050121 , AF050122 , AF050123 , AF050124 , AF050125 , AF050126 Genomic DNA. Translation: AAC68568.1 .
    FJ790247 mRNA. Translation: ACN88547.1 .
    AF207601 mRNA. Translation: AAF20139.1 .
    AF207602 mRNA. Translation: AAF20140.1 .
    AF208487 Genomic DNA. Translation: AAF20149.1 .
    AF304431 mRNA. Translation: AAG43026.1 .
    AB073325 mRNA. Translation: BAB70608.1 .
    BT009776 mRNA. Translation: AAP88778.1 .
    AL137129 Genomic DNA. No translation available.
    BC012527 mRNA. Translation: AAH12527.1 .
    CCDSi CCDS58324.1. [Q16665-3 ]
    CCDS9753.1. [Q16665-1 ]
    CCDS9754.1. [Q16665-2 ]
    PIRi I38972.
    RefSeqi NP_001230013.1. NM_001243084.1. [Q16665-3 ]
    NP_001521.1. NM_001530.3. [Q16665-1 ]
    NP_851397.1. NM_181054.2. [Q16665-2 ]
    UniGenei Hs.597216.
    Hs.719495.

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    Entry Method Resolution (Å) Chain Positions PDBsum
    1D7G model - D 15-73 [» ]
    1H2K X-ray 2.15 S 786-826 [» ]
    1H2L X-ray 2.25 S 786-826 [» ]
    1H2M X-ray 2.50 S 775-826 [» ]
    1L3E NMR - A 786-826 [» ]
    1L8C NMR - B 776-826 [» ]
    1LM8 X-ray 1.85 H 556-575 [» ]
    1LQB X-ray 2.00 D 549-582 [» ]
    2ILM X-ray 2.30 S 786-826 [» ]
    3HQR X-ray 2.00 S 558-574 [» ]
    3HQU X-ray 2.30 S 558-574 [» ]
    4AJY X-ray 1.73 H 559-577 [» ]
    4H6J X-ray 1.52 A 238-348 [» ]
    DisProti DP00262.
    ProteinModelPortali Q16665.
    SMRi Q16665. Positions 19-374, 776-826.
    ModBasei Search...
    MobiDBi Search...

    Protein-protein interaction databases

    BioGridi 109338. 110 interactions.
    DIPi DIP-29722N.
    IntActi Q16665. 60 interactions.
    MINTi MINT-133270.
    STRINGi 9606.ENSP00000338018.

    Chemistry

    BindingDBi Q16665.
    ChEMBLi CHEMBL4261.

    PTM databases

    PhosphoSitei Q16665.

    Polymorphism databases

    DMDMi 2498017.

    Proteomic databases

    PaxDbi Q16665.
    PRIDEi Q16665.

    Protocols and materials databases

    DNASUi 3091.
    Structural Biology Knowledgebase Search...

    Genome annotation databases

    Ensembli ENST00000323441 ; ENSP00000323326 ; ENSG00000100644 . [Q16665-2 ]
    ENST00000337138 ; ENSP00000338018 ; ENSG00000100644 . [Q16665-1 ]
    ENST00000539097 ; ENSP00000437955 ; ENSG00000100644 . [Q16665-3 ]
    GeneIDi 3091.
    KEGGi hsa:3091.
    UCSCi uc001xfq.2. human. [Q16665-1 ]
    uc021rua.1. human.

    Organism-specific databases

    CTDi 3091.
    GeneCardsi GC14P062162.
    HGNCi HGNC:4910. HIF1A.
    HPAi CAB017442.
    HPA001275.
    MIMi 603348. gene.
    neXtProti NX_Q16665.
    PharmGKBi PA29283.
    GenAtlasi Search...

    Phylogenomic databases

    eggNOGi NOG289264.
    HOGENOMi HOG000234306.
    HOVERGENi HBG060456.
    KOi K08268.
    OMAi QNAQRKR.
    OrthoDBi EOG7JDQX8.
    PhylomeDBi Q16665.
    TreeFami TF317772.

    Enzyme and pathway databases

    Reactomei REACT_118780. NOTCH1 Intracellular Domain Regulates Transcription.
    REACT_120916. Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha.
    REACT_121092. Regulation of gene expression by Hypoxia-inducible Factor.
    REACT_121226. Oxygen-dependent asparagine hydroxylation of Hypoxia-inducible Factor Alpha.
    REACT_24941. Circadian Clock.
    SignaLinki Q16665.

    Miscellaneous databases

    ChiTaRSi HIF1A. human.
    EvolutionaryTracei Q16665.
    GeneWikii HIF1A.
    GenomeRNAii 3091.
    NextBioi 12265.
    PROi Q16665.
    SOURCEi Search...

    Gene expression databases

    ArrayExpressi Q16665.
    Bgeei Q16665.
    CleanExi HS_HIF1A.
    Genevestigatori Q16665.

    Family and domain databases

    InterProi IPR011598. bHLH_dom.
    IPR001321. HIF-1_alpha.
    IPR014887. HIF-1_TAD_C.
    IPR021537. HIF_alpha_subunit.
    IPR001610. PAC.
    IPR000014. PAS.
    IPR013767. PAS_fold.
    [Graphical view ]
    Pfami PF11413. HIF-1. 1 hit.
    PF08778. HIF-1a_CTAD. 1 hit.
    PF00989. PAS. 1 hit.
    [Graphical view ]
    PRINTSi PR01080. HYPOXIAIF1A.
    SMARTi SM00353. HLH. 1 hit.
    SM00086. PAC. 1 hit.
    SM00091. PAS. 2 hits.
    [Graphical view ]
    SUPFAMi SSF47459. SSF47459. 1 hit.
    SSF55785. SSF55785. 2 hits.
    TIGRFAMsi TIGR00229. sensory_box. 2 hits.
    PROSITEi PS50888. BHLH. 1 hit.
    PS50112. PAS. 2 hits.
    [Graphical view ]
    ProtoNeti Search...

    Publicationsi

    1. "Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension."
      Wang G.L., Jiang B.-H., Rue E.A., Semenza G.L.
      Proc. Natl. Acad. Sci. U.S.A. 92:5510-5514(1995) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA], PROTEIN SEQUENCE OF 166-170; 259-289 AND 771-781.
    2. "Characterization of a subset of the basic-helix-loop-helix-PAS superfamily that interacts with components of the dioxin signaling pathway."
      Hogenesch J.B., Chan W.K., Jackiw V.H., Brown R.C., Gu Y.-Z., Pray-Grant M., Perdew G.H., Bradfield C.A.
      J. Biol. Chem. 272:8581-8593(1997) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA].
      Tissue: Hepatoma.
    3. "The human hypoxia-inducible factor 1alpha gene: HIF1A structure and evolutionary conservation."
      Iyer N.V., Leung S.W., Semenza G.L.
      Genomics 52:159-165(1998) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM 1).
    4. "Preferential expression of the novel alternative isoform I.3 of hypoxia-inducible factor 1alpha in activated human T lymphocytes."
      Lukashev D., Sitkovsky M.
      Hum. Immunol. 69:421-425(2008) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3), ALTERNATIVE SPLICING.
    5. "HIF1a sequence in the Quechua, a high altitude population."
      Rupert J.L., Hochachka P.W.
      Submitted (NOV-1999) to the EMBL/GenBank/DDBJ databases
      Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA].
    6. Sun B., Zhao H.R., Yu R.T., Ni M.S.H.
      Submitted (SEP-2000) to the EMBL/GenBank/DDBJ databases
      Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
      Tissue: Glial tumor.
    7. "Hypoxia-inducible factor-1 alpha variant isolated from human liver tissue."
      Tanaka S., Sugimachi K.
      Submitted (OCT-2001) to the EMBL/GenBank/DDBJ databases
      Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
      Tissue: Liver.
    8. "Cloning of human full-length CDSs in BD Creator(TM) system donor vector."
      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.
      Submitted (AUG-2003) to the EMBL/GenBank/DDBJ databases
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
    9. "The DNA sequence and analysis of human chromosome 14."
      Heilig R., Eckenberg R., Petit J.-L., Fonknechten N., Da Silva C., Cattolico L., Levy M., Barbe V., De Berardinis V., Ureta-Vidal A., Pelletier E., Vico V., Anthouard V., Rowen L., Madan A., Qin S., Sun H., Du H.
      , Pepin K., Artiguenave F., Robert C., Cruaud C., Bruels T., Jaillon O., Friedlander L., Samson G., Brottier P., Cure S., Segurens B., Aniere F., Samain S., Crespeau H., Abbasi N., Aiach N., Boscus D., Dickhoff R., Dors M., Dubois I., Friedman C., Gouyvenoux M., James R., Madan A., Mairey-Estrada B., Mangenot S., Martins N., Menard M., Oztas S., Ratcliffe A., Shaffer T., Trask B., Vacherie B., Bellemere C., Belser C., Besnard-Gonnet M., Bartol-Mavel D., Boutard M., Briez-Silla S., Combette S., Dufosse-Laurent V., Ferron C., Lechaplais C., Louesse C., Muselet D., Magdelenat G., Pateau E., Petit E., Sirvain-Trukniewicz P., Trybou A., Vega-Czarny N., Bataille E., Bluet E., Bordelais I., Dubois M., Dumont C., Guerin T., Haffray S., Hammadi R., Muanga J., Pellouin V., Robert D., Wunderle E., Gauguet G., Roy A., Sainte-Marthe L., Verdier J., Verdier-Discala C., Hillier L.W., Fulton L., McPherson J., Matsuda F., Wilson R., Scarpelli C., Gyapay G., Wincker P., Saurin W., Quetier F., Waterston R., Hood L., Weissenbach J.
      Nature 421:601-607(2003) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
    10. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
      The MGC Project Team
      Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
      Tissue: Choriocarcinoma and Placenta.
    11. Cited for: IDENTIFICATION IN COMPLEX WITH EP300 AND CREBBP, INTERACTION WITH EP300.
    12. "Transactivation and inhibitory domains of hypoxia-inducible factor 1alpha. Modulation of transcriptional activity by oxygen tension."
      Jiang B.H., Zheng J.Z., Leung S.W., Roe R., Semenza G.L.
      J. Biol. Chem. 272:19253-19260(1997) [PubMed] [Europe PMC] [Abstract]
      Cited for: TRANSACTIVATION DOMAINS NTAD AND CTAD.
    13. "Signal transduction in hypoxic cells: inducible nuclear translocation and recruitment of the CBP/p300 coactivator by the hypoxia-inducible factor-1alpha."
      Kallio P.J., Okamoto K., O'Brien S., Carrero P., Makino Y., Tanaka H., Poellinger L.
      EMBO J. 17:6573-6586(1998) [PubMed] [Europe PMC] [Abstract]
      Cited for: SUBCELLULAR LOCATION, MUTAGENESIS OF LYS-719.
    14. "Regulation of hypoxia-inducible factor 1alpha is mediated by an O2-dependent degradation domain via the ubiquitin-proteasome pathway."
      Huang L.E., Gu J., Schau M., Bunn H.F.
      Proc. Natl. Acad. Sci. U.S.A. 95:7987-7992(1998) [PubMed] [Europe PMC] [Abstract]
      Cited for: OXYGEN-DEPENDENT DEGRADATION DOMAIN.
    15. "Molecular mechanisms of transcription activation by HLF and HIF1alpha in response to hypoxia: their stabilization and redox signal-induced interaction with CBP/p300."
      Ema M., Hirota K., Mimura J., Abe H., Yodoi J., Sogawa K., Poellinger L., Fujii-Kuriyama Y.
      EMBO J. 18:1905-1914(1999) [PubMed] [Europe PMC] [Abstract]
      Cited for: TRANSACTIVATION DOMAINS NTAD AND CTAD, INTERACTION WITH APEX, MUTAGENESIS OF CYS-800.
    16. "Functional role of p35srj, a novel p300/CBP binding protein, during transactivation by HIF-1."
      Bhattacharya S., Michels C.M., Leung M.K., Arany Z.P., Kung A.L., Livingston D.M.
      Genes Dev. 13:64-75(1999) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION, DNA-BINDING, INTERACTION WITH EP300.
    17. "Drosophila von Hippel-Lindau tumor suppressor complex possesses E3 ubiquitin ligase activity."
      Aso T., Yamazaki K., Aigaki T., Kitajima S.
      Biochem. Biophys. Res. Commun. 276:355-361(2000) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH VHL.
    18. "Mechanism of regulation of the hypoxia-inducible factor-1 alpha by the von Hippel-Lindau tumor suppressor protein."
      Tanimoto K., Makino Y., Pereira T., Poellinger L.
      EMBO J. 19:4298-4309(2000) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH VHL AND ARNT, MUTAGENESIS OF LYS-532; LYS-538; LYS-547 AND LYS-719.
    19. "Redox-regulated recruitment of the transcriptional coactivators CREB-binding protein and SRC-1 to hypoxia-inducible factor 1alpha."
      Carrero P., Okamoto K., Coumailleau P., O'Brien S., Tanaka H., Poellinger L.
      Mol. Cell. Biol. 20:402-415(2000) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH NCOA1; NCOA2 AND APEX.
    20. "Hypoxia-inducible factor 1alpha protein expression is controlled by oxygen-regulated ubiquitination that is disrupted by deletions and missense mutations."
      Sutter C.H., Laughner E., Semenza G.L.
      Proc. Natl. Acad. Sci. U.S.A. 97:4748-4753(2000) [PubMed] [Europe PMC] [Abstract]
      Cited for: MUTAGENESIS OF SER-551 AND THR-552, UBIQUITINATION.
    21. "Independent function of two destruction domains in hypoxia-inducible factor-alpha chains activated by prolyl hydroxylation."
      Masson N., Willam C., Maxwell P.H., Pugh C.W., Ratcliffe P.J.
      EMBO J. 20:5197-5206(2001) [PubMed] [Europe PMC] [Abstract]
      Cited for: HYDROXYLATION AT PRO-402 AND PRO-564, UBIQUITINATION, INTERACTION WITH THE VHLE COMPLEX, FUNCTION, MUTAGENESIS OF PRO-394; LEU-397; LEU-400; PRO-402 AND PRO-564.
    22. "Binding and regulation of HIF-1alpha by a subunit of the proteasome complex, PSMA7."
      Cho S., Choi Y.J., Kim J.M., Jeong S.T., Kim J.H., Kim S.H., Ryu S.E.
      FEBS Lett. 498:62-66(2001) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH PSMA7.
    23. "Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation."
      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.
      Science 292:468-472(2001) [PubMed] [Europe PMC] [Abstract]
      Cited for: UBIQUITINATION, FUNCTION, HYDROXYLATION AT PRO-564.
    24. "Regulation and destabilization of HIF-1alpha by ARD1-mediated acetylation."
      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.
      Cell 111:709-720(2002) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH ARD1A.
    25. "FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor."
      Lando D., Peet D.J., Gorman J.J., Whelan D.A., Whitelaw M.L., Bruick R.K.
      Genes Dev. 16:1466-1471(2002) [PubMed] [Europe PMC] [Abstract]
      Cited for: HYDROXYLATION AT ASN-803, IDENTIFICATION BY MASS SPECTROMETRY.
    26. "Biochemical purification and pharmacological inhibition of a mammalian prolyl hydroxylase acting on hypoxia-inducible factor."
      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.
      Proc. Natl. Acad. Sci. U.S.A. 99:13459-13464(2002) [PubMed] [Europe PMC] [Abstract]
      Cited for: HYDROXYLATION AT PRO-564, IDENTIFICATION BY MASS SPECTROMETRY.
    27. "S-nitrosation of Cys-800 of HIF-1alpha protein activates its interaction with p300 and stimulates its transcriptional activity."
      Yasinska I.M., Sumbayev V.V.
      FEBS Lett. 549:105-109(2003) [PubMed] [Europe PMC] [Abstract]
      Cited for: S-NITROSYLATION AT CYS-800, MUTAGENESIS OF CYS-800.
    28. "HIF-1 alpha protein as a target for S-nitrosation."
      Sumbayev V.V., Budde A., Zhou J., Bruene B.
      FEBS Lett. 535:106-112(2003) [PubMed] [Europe PMC] [Abstract]
      Cited for: S-NITROSYLATION.
    29. "Structural basis for negative regulation of hypoxia-inducible factor-1alpha by CITED2."
      Freedman S.J., Sun Z.Y., Kung A.L., France D.S., Wagner G., Eck M.J.
      Nat. Struct. Biol. 10:504-512(2003) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH EP300, MUTAGENESIS OF LEU-795.
    30. "Sumoylation increases HIF-1alpha stability and its transcriptional activity."
      Bae S.-H., Jeong J.-W., Park J.A., Kim S.-H., Bae M.-K., Choi S.-J., Kim K.-W.
      Biochem. Biophys. Res. Commun. 324:394-400(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: SUMOYLATION AT LYS-391 AND LYS-477, FUNCTION, MUTAGENESIS OF LYS-389; LYS-391; LYS-392; LYS-442; LYS-460; LYS-477; LYS-532; LYS-538 AND LYS-547.
    31. "Molecular cloning and characterization of the von Hippel-Lindau-like protein."
      Qi H., Gervais M.L., Li W., DeCaprio J.A., Challis J.R.G., Ohh M.
      Mol. Cancer Res. 2:43-52(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH VHLL.
    32. "VHL protein-interacting deubiquitinating enzyme 2 deubiquitinates and stabilizes HIF-1alpha."
      Li Z., Wang D., Messing E.M., Wu G.
      EMBO Rep. 6:373-378(2005) [PubMed] [Europe PMC] [Abstract]
      Cited for: UBIQUITINATION, DEUBIQUITINATION BY USP20, INTERACTION WITH USP20.
    33. "Interaction between HIF-1 alpha (ODD) and hARD1 does not induce acetylation and destabilization of HIF-1 alpha."
      Arnesen T., Kong X., Evjenth R., Gromyko D., Varhaug J.E., Lin Z., Sang N., Caro J., Lillehaug J.R.
      FEBS Lett. 579:6428-6432(2005) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH ARD1A, MUTAGENESIS OF LYS-532.
    34. "Histone deacetylase inhibitors repress the transactivation potential of hypoxia-inducible factors independently of direct acetylation of HIF-alpha."
      Fath D.M., Kong X., Liang D., Lin Z., Chou A., Jiang Y., Fang J., Caro J., Sang N.
      J. Biol. Chem. 281:13612-13619(2006) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION, INTERACTION WITH EP300 IN THE HIF1A/EP300/CREBBP COMPLEX, MUTAGENESIS OF ASN-803.
    35. "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."
      Choi S.M., Choi K.-O., Park Y.K., Cho H., Yang E.G., Park H.
      J. Biol. Chem. 281:34056-34063(2006) [PubMed] [Europe PMC] [Abstract]
      Cited for: UBIQUITINATION, HYDROXYLATION, FUNCTION, INTERACTION WITH CBPP, IDENTIFICATION BY MASS SPECTROMETRY, MUTAGENESIS OF ASN-803.
    36. "SUMOylation of hypoxia-inducible factor-1alpha reduces its transcriptional activity."
      Berta M.A., Mazure N., Hattab M., Pouyssegur J., Brahimi-Horn M.C.
      Biochem. Biophys. Res. Commun. 360:646-652(2007) [PubMed] [Europe PMC] [Abstract]
      Cited for: SUMOYLATION AT LYS-391 AND LYS-477, FUNCTION, MUTAGENESIS OF LYS-377; LYS-391; LYS-477 AND LYS-532.
    37. "RSUME, a small RWD-containing protein, enhances SUMO conjugation and stabilizes HIF-1alpha during hypoxia."
      Carbia-Nagashima A., Gerez J., Perez-Castro C., Paez-Pereda M., Silberstein S., Stalla G.K., Holsboer F., Arzt E.
      Cell 131:309-323(2007) [PubMed] [Europe PMC] [Abstract]
      Cited for: SUMOYLATION, INTERACTION WITH RWDD3.
    38. "RACK1 competes with HSP90 for binding to HIF-1alpha and is required for O(2)-independent and HSP90 inhibitor-induced degradation of HIF-1alpha."
      Liu Y.V., Baek J.H., Zhang H., Diez R., Cole R.N., Semenza G.L.
      Mol. Cell 25:207-217(2007) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH GNB2L1.
    39. "HIF-1alpha and EPAS ubiquitination mediated by the VHL tumour suppressor involves flexibility in the ubiquitination mechanism, similar to other RING E3 ligases."
      Paltoglou S., Roberts B.J.
      Oncogene 26:604-609(2007) [PubMed] [Europe PMC] [Abstract]
      Cited for: UBIQUITINATION AT LYS-532; LYS-538 AND LYS-547, INTERACTION WITH VHL, MUTAGENESIS OF PRO-402; LYS-532; LYS-538; LYS-547 AND PRO-564.
    40. "Transcriptional activation of HIF-1 by RORalpha and its role in hypoxia signaling."
      Kim E.J., Yoo Y.G., Yang W.K., Lim Y.S., Na T.Y., Lee I.K., Lee M.O.
      Arterioscler. Thromb. Vasc. Biol. 28:1796-1802(2008) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH RORA.
    41. Cited for: REVIEW ON REGULATION.
    42. "Transcriptional regulation of hypoxia-inducible factor 1alpha by HIPK2 suggests a novel mechanism to restrain tumor growth."
      Nardinocchi L., Puca R., Guidolin D., Belloni A.S., Bossi G., Michiels C., Sacchi A., Onisto M., D'Orazi G.
      Biochim. Biophys. Acta 1793:368-377(2009) [PubMed] [Europe PMC] [Abstract]
      Cited for: INDUCTION BY HIPK2.
    43. "HUMMR, a hypoxia- and HIF-1alpha-inducible protein, alters mitochondrial distribution and transport."
      Li Y., Lim S., Hoffman D., Aspenstrom P., Federoff H.J., Rempe D.A.
      J. Cell Biol. 185:1065-1081(2009) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION IN MITOCHONDRIAL TRANSPORT.
    44. "Hypoxia-inducible protein 2 is a novel lipid droplet protein and a specific target gene of hypoxia-inducible factor-1."
      Gimm T., Wiese M., Teschemacher B., Deggerich A., Schodel J., Knaup K.X., Hackenbeck T., Hellerbrand C., Amann K., Wiesener M.S., Honing S., Eckardt K.U., Warnecke C.
      FASEB J. 24:4443-4458(2010) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION.
    45. "Plk3 functions as an essential component of the hypoxia regulatory pathway by direct phosphorylation of HIF-1alpha."
      Xu D., Yao Y., Lu L., Costa M., Dai W.
      J. Biol. Chem. 285:38944-38950(2010) [PubMed] [Europe PMC] [Abstract]
      Cited for: PHOSPHORYLATION AT SER-551; THR-555; SER-576; SER-589 AND SER-657, MUTAGENESIS OF SER-576 AND SER-657.
    46. "Casein kinase 1 regulates human hypoxia-inducible factor HIF-1."
      Kalousi A., Mylonis I., Politou A.S., Chachami G., Paraskeva E., Simos G.
      J. Cell Sci. 123:2976-2986(2010) [PubMed] [Europe PMC] [Abstract]
      Cited for: PHOSPHORYLATION AT SER-247 BY CSNK1D/CK1, MUTAGENESIS OF SER-247, INTERACTION WITH ARNT.
    47. "RSUME is implicated in HIF-1-induced VEGF-A production in pituitary tumour cells."
      Shan B., Gerez J., Haedo M., Fuertes M., Theodoropoulou M., Buchfelder M., Losa M., Stalla G.K., Arzt E., Renner U.
      Endocr. Relat. Cancer 19:13-27(2012) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, INDUCTION.
    48. "Ubiquitin-specific protease 19 (USP19) regulates hypoxia-inducible factor 1alpha (HIF-1alpha) during hypoxia."
      Altun M., Zhao B., Velasco K., Liu H., Hassink G., Paschke J., Pereira T., Lindsten K.
      J. Biol. Chem. 287:1962-1969(2012) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH USP19.
    49. Cited for: INDUCTION.
    50. "In silico structural and functional characterization of the RSUME splice variants."
      Gerez J., Fuertes M., Tedesco L., Silberstein S., Sevlever G., Paez-Pereda M., Holsboer F., Turjanski A.G., Arzt E.
      PLoS ONE 8:E57795-E57795(2013) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH RWDD3.
    51. "SIRT2 regulates tumour hypoxia response by promoting HIF-1alpha hydroxylation."
      Seo K.S., Park J.H., Heo J.Y., Jing K., Han J., Min K.N., Kim C., Koh G.Y., Lim K., Kang G.Y., Uee Lee J., Yim Y.H., Shong M., Kwak T.H., Kweon G.R.
      Oncogene 0:0-0(2014) [PubMed] [Europe PMC] [Abstract]
      Cited for: ACETYLATION, DEACETYLATION AT LYS-709 BY SIRT2, HYDROXYLATION, INTERACTION WITH SIRT2 AND EGLN1, MUTAGENESIS OF PRO-402; PRO-564 AND LYS-709.
    52. "A model for the complex between the hypoxia-inducible factor-1 (HIF-1) and its consensus DNA sequence."
      Michel G., Minet E., Ernest I., Roland I., Durant F., Remacle J., Michiels C.
      J. Biomol. Struct. Dyn. 18:169-179(2000) [PubMed] [Europe PMC] [Abstract]
      Cited for: 3D-STRUCTURE MODELING.
    53. "Structure of factor-inhibiting hypoxia-inducible factor (HIF) reveals mechanism of oxidative modification of HIF-1 alpha."
      Elkins J.M., Hewitson K.S., McNeill L.A., Seibel J.F., Schlemminger I., Pugh C.W., Ratcliffe P.J., Schofield C.J.
      J. Biol. Chem. 278:1802-1806(2003) [PubMed] [Europe PMC] [Abstract]
      Cited for: X-RAY CRYSTALLOGRAPHY (2.15 ANGSTROMS) OF 775-826 IN COMPLEX WITH HIF1AN.
    54. "Structural basis for recruitment of CBP/p300 by hypoxia-inducible factor-1 alpha."
      Freedman S.J., Sun Z.-Y.J., Poy F., Kung A.L., Livingston D.M., Wagner G., Eck M.J.
      Proc. Natl. Acad. Sci. U.S.A. 99:5367-5372(2002) [PubMed] [Europe PMC] [Abstract]
      Cited for: STRUCTURE BY NMR OF 786-826 IN COMPLEX WITH 302-418 OF EP300.
    55. "Structural basis for Hif-1 alpha /CBP recognition in the cellular hypoxic response."
      Dames S.A., Martinez-Yamout M., De Guzman R.N., Dyson H.J., Wright P.E.
      Proc. Natl. Acad. Sci. U.S.A. 99:5271-5276(2002) [PubMed] [Europe PMC] [Abstract]
      Cited for: STRUCTURE BY NMR OF 776-826 IN COMPLEX WITH 345-439 OF CREBBP.
    56. "Structure of an HIF-1alpha-pVHL complex: hydroxyproline recognition in signaling."
      Min J.-H., Yang H., Ivan M., Gertler F., Kaelin W.G. Jr., Pavletich N.P.
      Science 296:1886-1889(2002) [PubMed] [Europe PMC] [Abstract]
      Cited for: X-RAY CRYSTALLOGRAPHY (1.85 ANGSTROMS) OF 556-575 IN COMPLEX WITH TCEB1; TCEB2 AND 54-213 OF VHL.
    57. Cited for: X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 549-582 IN COMPLEX WITH 17-112 OF TCEB1; TCEB2 AND 52-213 OF VHL.

    Entry informationi

    Entry nameiHIF1A_HUMAN
    AccessioniPrimary (citable) accession number: Q16665
    Secondary accession number(s): C0LZJ3
    , Q53XP6, Q96PT9, Q9UPB1
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: November 1, 1997
    Last sequence update: November 1, 1996
    Last modified: October 1, 2014
    This is version 175 of the entry and version 1 of the sequence. [Complete history]
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programChordata Protein Annotation Program
    DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

    Miscellaneousi

    Keywords - Technical termi

    3D-structure, Complete proteome, Direct protein sequencing, Reference proteome

    Documents

    1. Human chromosome 14
      Human chromosome 14: entries, gene names and cross-references to MIM
    2. Human entries with polymorphisms or disease mutations
      List of human entries with polymorphisms or disease mutations
    3. Human polymorphisms and disease mutations
      Index of human polymorphisms and disease mutations
    4. MIM cross-references
      Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
    5. PDB cross-references
      Index of Protein Data Bank (PDB) cross-references
    6. SIMILARITY comments
      Index of protein domains and families

    External Data

    Dasty 3