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Gene Review

HIF1A  -  hypoxia inducible factor 1, alpha subunit...

Homo sapiens

Synonyms: ARNT-interacting protein, BHLHE78, Basic-helix-loop-helix-PAS protein MOP1, Class E basic helix-loop-helix protein 78, HIF-1-alpha, ...
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Disease relevance of HIF1A

  • HIF is stable and initiates gene transcription under hypoxia, whereas in normoxia, interaction with the von Hippel-Lindau tumor suppressor protein (VHL) leads to rapid degradation of the HIF1A subunit [1].
  • Hypoxia-inducible factor (HIF1A and HIF2A), angiogenesis, and chemoradiotherapy outcome of squamous cell head-and-neck cancer [2].
  • We also show that in hypoxia another sequence located upstream from the +1 initiation site plays an inhibitory role on HIF1A transcription in HMEC-1 but not in hepatoma cells and brings back this expression level to that observed in normoxia [3].
  • Polymorphisms in the hypoxia inducible factor-1alpha gene (HIF1A) are associated with the renal cell carcinoma phenotype [4].
  • In DCIS lesions, increased levels of HIF-1 alpha were statistically significantly associated with increased microvessel density [5].
  • During the late phase of intracellular chlamydial replication, host cell adaptation to hypoxia was actively silenced by pathogen-induced HIF-1alpha degradation [6].

Psychiatry related information on HIF1A

  • In conclusion, these data clearly demonstrate that physical activity induces the HIF-1-mediated signaling pathway in human skeletal muscle, providing the first evidence that human HIF-1alpha can be activated during physiologically relevant conditions [7].
  • Therefore, the use of immunohistochemical assessment of HIF-1alpha as a new predictor of poor outcome may improve clinical decision-making regarding adjuvant treatment of patients with lymph node negative breast carcinoma [8].
  • Therefore, HIF-1alpha expression in early stage oral carcinomas was evaluated in relation to established clinico-pathological features in order to determine its value as a prognostic marker [9].
  • RESULTS: When the period of alcohol consumption increased, the positive rate of expression of hypoxia-inducible factor-1 alpha (HIF-1alpha) mRNA was more significantly elevated in the liver of the alcohol group than in the control group (P</=0.05) [10].

High impact information on HIF1A

  • The protein pVHL functions in a multi-subunit E3 ubiquitin ligase that targets the hypoxia-inducible transcription factor Hif1 alpha for proteasomal degradation during normoxia [11].
  • Blockade of TBP-1 expression by small interfering RNA (siRNA) causes prolonged degradation kinetics of Hif1 alpha [11].
  • Recently, prolyl hydroxylation was identified as a key regulatory event that targets the HIF-1alpha subunit for proteasomal degradation via the pVHL ubiquitination complex [12].
  • Regulation and destabilization of HIF-1alpha by ARD1-mediated acetylation [12].
  • A molecular basis for O(2)-regulated expression of the HIF-1 alpha subunit has now been determined, providing a mechanism for changes in gene expression in response to changes in cellular oxygenation [13].

Chemical compound and disease context of HIF1A


Biological context of HIF1A


Anatomical context of HIF1A


Associations of HIF1A with chemical compounds

  • Growth factor-mediated induction of HIF-1alpha was ablated by transient expression of a dominant negative form of Akt/PKB or by treatment with LY294002 [24].
  • By using actinomycin D and cycloheximide we showed that A23187 induced HIF-1alpha mRNA expression, whereas BAPTA-am acted after transcription [25].
  • Coimmunoprecipitation and glutathione S-transferase pull downs indicated that PI does not disrupt interactions between HIF-1 alpha and p300 [26].
  • PI specifically inhibited the HIF-1 alpha CAD despite activating the HIF-1 alpha coactivator p300 and another p300 cysteine/histidine-rich domain 1-dependent transcription factor, STAT-2 [26].
  • Although A23187 induced a striking and stable induction of HIF-1alpha, BAPTA-am only mediated a fast and transient increase [25].
  • In clear cell RCC, HIF-1 alpha was significantly correlated with markers of apoptosis (p21, p53), the mammalian target of rapamycin pathway (pAkt, p27), CXCR3, and proteins of the vascular endothelial growth factor family [27].
  • These stimulatory effects were abrogated by cotransfection with either HIF-1 alpha siRNA or treatment with resveratrol [28].
  • All of these results indicate that Akt/mTOR-dependent translation of HIF-1alpha plays a critical role in the postirradiation up-regulation of intratumoral HIF-1 activity in response to radiation-induced alterations of glucose and oxygen availability in a solid tumor [29].

Physical interactions of HIF1A


Enzymatic interactions of HIF1A


Co-localisations of HIF1A

  • The HIF-target gene VEGF colocalized with HIF-1alpha protein in glomeruli and medullary collecting ducts [37].

Regulatory relationships of HIF1A


Other interactions of HIF1A


Analytical, diagnostic and therapeutic context of HIF1A

  • Expression of caspase 9 and HIF1A protein was confirmed by Western blotting [14].
  • Relative quantification of EPO, VEGF and HIF1A mRNAs, based on the TaqMan reverse transcription-polymerase chain reaction (RT-PCR), was performed on autopsy tissue specimens from the heart (n = 10), brain (n = 10), kidney (n = 16) and lung (n = 8) after preservation at room temperature for various storage times [47].
  • Forced expression of HIF-1alpha in p53-expressing tumor cells increases hypoxia-induced VEGF expression and augments neovascularization and growth of tumor xenografts [48].
  • Immunofluorescence studies revealed that the HBx-induced HIF-1alpha was partially translocated into the nucleus in majority of cells while additional CoCl2-induced hypoxic condition caused complete nuclear translocation [49].
  • NPR(-) cells lacked EPO induction under hypoxia, and HIF-1alpha in NPR(-) cells did not respond to either transcriptional activation or translocation to the nucleus based on electrophoretic mobility shift assays and reporter gene assay including hypoxia response element [50].


  1. Dynamic HIF1A regulation during human placental development. Ietta, F., Wu, Y., Winter, J., Xu, J., Wang, J., Post, M., Caniggia, I. Biol. Reprod. (2006) [Pubmed]
  2. Hypoxia-inducible factor (HIF1A and HIF2A), angiogenesis, and chemoradiotherapy outcome of squamous cell head-and-neck cancer. Koukourakis, M.I., Giatromanolaki, A., Sivridis, E., Simopoulos, C., Turley, H., Talks, K., Gatter, K.C., Harris, A.L. Int. J. Radiat. Oncol. Biol. Phys. (2002) [Pubmed]
  3. HIF1A gene transcription is dependent on a core promoter sequence encompassing activating and inhibiting sequences located upstream from the transcription initiation site and cis elements located within the 5'UTR. Minet, E., Ernest, I., Michel, G., Roland, I., Remacle, J., Raes, M., Michiels, C. Biochem. Biophys. Res. Commun. (1999) [Pubmed]
  4. Polymorphisms in the hypoxia inducible factor-1alpha gene (HIF1A) are associated with the renal cell carcinoma phenotype. Ollerenshaw, M., Page, T., Hammonds, J., Demaine, A. Cancer Genet. Cytogenet. (2004) [Pubmed]
  5. Levels of hypoxia-inducible factor-1 alpha during breast carcinogenesis. Bos, R., Zhong, H., Hanrahan, C.F., Mommers, E.C., Semenza, G.L., Pinedo, H.M., Abeloff, M.D., Simons, J.W., van Diest, P.J., van der Wall, E. J. Natl. Cancer Inst. (2001) [Pubmed]
  6. Chlamydia pneumoniae directly interferes with HIF-1alpha stabilization in human host cells. Rupp, J., Gieffers, J., Klinger, M., van Zandbergen, G., Wrase, R., Maass, M., Solbach, W., Deiwick, J., Hellwig-Burgel, T. Cell. Microbiol. (2007) [Pubmed]
  7. Physiological activation of hypoxia inducible factor-1 in human skeletal muscle. Ameln, H., Gustafsson, T., Sundberg, C.J., Okamoto, K., Jansson, E., Poellinger, L., Makino, Y. FASEB J. (2005) [Pubmed]
  8. Levels of hypoxia-inducible factor-1alpha independently predict prognosis in patients with lymph node negative breast carcinoma. Bos, R., van der Groep, P., Greijer, A.E., Shvarts, A., Meijer, S., Pinedo, H.M., Semenza, G.L., van Diest, P.J., van der Wall, E. Cancer (2003) [Pubmed]
  9. HIF1-alpha overexpression indicates a good prognosis in early stage squamous cell carcinomas of the oral floor. Fillies, T., Werkmeister, R., van Diest, P.J., Brandt, B., Joos, U., Buerger, H. BMC Cancer (2005) [Pubmed]
  10. Is the hypoxia-inducible factor-1 alpha mRNA expression activated by ethanol-induced injury, the mechanism underlying alcoholic liver disease? Li, L., Chen, S.H., Zhang, Y., Yu, C.H., Li, S.D., Li, Y.M. HBPD INT (2006) [Pubmed]
  11. Tat-binding protein-1, a component of the 26S proteasome, contributes to the E3 ubiquitin ligase function of the von Hippel-Lindau protein. Corn, P.G., McDonald, E.R., Herman, J.G., El-Deiry, W.S. Nat. Genet. (2003) [Pubmed]
  12. 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 (2002) [Pubmed]
  13. HIF-1, O(2), and the 3 PHDs: how animal cells signal hypoxia to the nucleus. Semenza, G.L. Cell (2001) [Pubmed]
  14. Bimodal effect of hypoxia in cancer: role of hypoxia inducible factor in apoptosis. Wang, Y., Pakunlu, R.I., Tsao, W., Pozharov, V., Minko, T. Mol. Pharm. (2004) [Pubmed]
  15. Carboxyl-terminal transactivation activity of hypoxia-inducible factor 1 alpha is governed by a von Hippel-Lindau protein-independent, hydroxylation-regulated association with p300/CBP. Sang, N., Fang, J., Srinivas, V., Leshchinsky, I., Caro, J. Mol. Cell. Biol. (2002) [Pubmed]
  16. Evidence for a role of p38 kinase in hypoxia-inducible factor 1-independent induction of vascular endothelial growth factor expression by sodium arsenite. Duyndam, M.C., Hulscher, S.T., van der Wall, E., Pinedo, H.M., Boven, E. J. Biol. Chem. (2003) [Pubmed]
  17. HIF-1alpha, STAT3, CBP/p300 and Ref-1/APE are components of a transcriptional complex that regulates Src-dependent hypoxia-induced expression of VEGF in pancreatic and prostate carcinomas. Gray, M.J., Zhang, J., Ellis, L.M., Semenza, G.L., Evans, D.B., Watowich, S.S., Gallick, G.E. Oncogene (2005) [Pubmed]
  18. Reactive oxygen species regulate epidermal growth factor-induced vascular endothelial growth factor and hypoxia-inducible factor-1alpha expression through activation of AKT and P70S6K1 in human ovarian cancer cells. Liu, L.Z., Hu, X.W., Xia, C., He, J., Zhou, Q., Shi, X., Fang, J., Jiang, B.H. Free Radic. Biol. Med. (2006) [Pubmed]
  19. Structural and functional analysis of hypoxia-inducible factor 1. Semenza, G.L., Agani, F., Booth, G., Forsythe, J., Iyer, N., Jiang, B.H., Leung, S., Roe, R., Wiener, C., Yu, A. Kidney Int. (1997) [Pubmed]
  20. The human hypoxia-inducible factor 1alpha gene: HIF1A structure and evolutionary conservation. Iyer, N.V., Leung, S.W., Semenza, G.L. Genomics (1998) [Pubmed]
  21. Assignment of the hypoxia-inducible factor 1alpha gene to a region of conserved synteny on mouse chromosome 12 and human chromosome 14q. Semenza, G.L., Rue, E.A., Iyer, N.V., Pang, M.G., Kearns, W.G. Genomics (1996) [Pubmed]
  22. Epstein-Barr virus latent membrane protein 1 induces synthesis of hypoxia-inducible factor 1 alpha. Wakisaka, N., Kondo, S., Yoshizaki, T., Murono, S., Furukawa, M., Pagano, J.S. Mol. Cell. Biol. (2004) [Pubmed]
  23. Cell-type-specific regulation of degradation of hypoxia-inducible factor 1 alpha: role of subcellular compartmentalization. Zheng, X., Ruas, J.L., Cao, R., Salomons, F.A., Cao, Y., Poellinger, L., Pereira, T. Mol. Cell. Biol. (2006) [Pubmed]
  24. Growth factor-mediated induction of HDM2 positively regulates hypoxia-inducible factor 1alpha expression. Bárdos, J.I., Chau, N.M., Ashcroft, M. Mol. Cell. Biol. (2004) [Pubmed]
  25. Induction of plasminogen activator inhibitor I gene expression by intracellular calcium via hypoxia-inducible factor-1. Liu, Q., Möller, U., Flügel, D., Kietzmann, T. Blood (2004) [Pubmed]
  26. Proteasomal inhibition attenuates transcriptional activity of hypoxia-inducible factor 1 (HIF-1) via specific effect on the HIF-1alpha C-terminal activation domain. Kaluz, S., Kaluzová, M., Stanbridge, E.J. Mol. Cell. Biol. (2006) [Pubmed]
  27. Hypoxia-inducible factor 1 alpha in clear cell renal cell carcinoma. Klatte, T., Seligson, D.B., Riggs, S.B., Leppert, J.T., Berkman, M.K., Kleid, M.D., Yu, H., Kabbinavar, F.F., Pantuck, A.J., Belldegrun, A.S. Clin. Cancer Res. (2007) [Pubmed]
  28. Overexpression of human papillomavirus type 16 oncoproteins enhances hypoxia-inducible factor 1 alpha protein accumulation and vascular endothelial growth factor expression in human cervical carcinoma cells. Tang, X., Zhang, Q., Nishitani, J., Brown, J., Shi, S., Le, A.D. Clin. Cancer Res. (2007) [Pubmed]
  29. The Akt/mTOR pathway assures the synthesis of HIF-1alpha protein in a glucose- and reoxygenation-dependent manner in irradiated tumors. Harada, H., Itasaka, S., Kizaka-Kondoh, S., Shibuya, K., Morinibu, A., Shinomiya, K., Hiraoka, M. J. Biol. Chem. (2009) [Pubmed]
  30. 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. (2000) [Pubmed]
  31. Insulin induces transcription of target genes through the hypoxia-inducible factor HIF-1alpha/ARNT. Zelzer, E., Levy, Y., Kahana, C., Shilo, B.Z., Rubinstein, M., Cohen, B. EMBO J. (1998) [Pubmed]
  32. Histone deacetylase 7 associates with hypoxia-inducible factor 1alpha and increases transcriptional activity. Kato, H., Tamamizu-Kato, S., Shibasaki, F. J. Biol. Chem. (2004) [Pubmed]
  33. Dephosphorylated hypoxia-inducible factor 1alpha as a mediator of p53-dependent apoptosis during hypoxia. Suzuki, H., Tomida, A., Tsuruo, T. Oncogene (2001) [Pubmed]
  34. Suppression of the dual-specificity phosphatase MKP-1 enhances HIF-1 trans-activation and increases expression of EPO. Liu, C., Shi, Y., Han, Z., Pan, Y., Liu, N., Han, S., Chen, Y., Lan, M., Qiao, T., Fan, D. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
  35. VHL protein-interacting deubiquitinating enzyme 2 deubiquitinates and stabilizes HIF-1alpha. Li, Z., Wang, D., Messing, E.M., Wu, G. EMBO Rep. (2005) [Pubmed]
  36. The zinc chelator, N,N,N',N'-tetrakis (2-pyridylmethyl) ethylenediamine, increases the level of nonfunctional HIF-1alpha protein in normoxic cells. Choi, S.M., Choi, K.O., Lee, N., Oh, M., Park, H. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  37. Expression of hypoxia-inducible transcription factors in developing human and rat kidneys. Bernhardt, W.M., Schmitt, R., Rosenberger, C., Münchenhagen, P.M., Gröne, H.J., Frei, U., Warnecke, C., Bachmann, S., Wiesener, M.S., Willam, C., Eckardt, K.U. Kidney Int. (2006) [Pubmed]
  38. Role of hypoxia-inducible factor (HIF)-1alpha versus HIF-2alpha in the regulation of HIF target genes in response to hypoxia, insulin-like growth factor-I, or loss of von Hippel-Lindau function: implications for targeting the HIF pathway. Carroll, V.A., Ashcroft, M. Cancer Res. (2006) [Pubmed]
  39. Mechanisms underlying PTEN regulation of vascular endothelial growth factor and angiogenesis. Gomez-Manzano, C., Fueyo, J., Jiang, H., Glass, T.L., Lee, H.Y., Hu, M., Liu, J.L., Jasti, S.L., Liu, T.J., Conrad, C.A., Yung, W.K. Ann. Neurol. (2003) [Pubmed]
  40. Suppression of hypoxia-inducible factor 1alpha (HIF-1alpha) transcriptional activity by the HIF prolyl hydroxylase EGLN1. To, K.K., Huang, L.E. J. Biol. Chem. (2005) [Pubmed]
  41. The forkhead transcription factor FOXO4 induces the down-regulation of hypoxia-inducible factor 1 alpha by a von Hippel-Lindau protein-independent mechanism. Tang, T.T., Lasky, L.A. J. Biol. Chem. (2003) [Pubmed]
  42. Spermidine/spermine N(1)-acetyltransferase-1 binds to hypoxia-inducible factor-1alpha (HIF-1alpha) and RACK1 and promotes ubiquitination and degradation of HIF-1alpha. Baek, J.H., Liu, Y.V., McDonald, K.R., Wesley, J.B., Zhang, H., Semenza, G.L. J. Biol. Chem. (2007) [Pubmed]
  43. 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. (1999) [Pubmed]
  44. HIF prolyl-hydroxylase 2 is the key oxygen sensor setting low steady-state levels of HIF-1alpha in normoxia. Berra, E., Benizri, E., Ginouvès, A., Volmat, V., Roux, D., Pouysségur, J. EMBO J. (2003) [Pubmed]
  45. DNA damage is a prerequisite for p53-mediated proteasomal degradation of HIF-1alpha in hypoxic cells and downregulation of the hypoxia marker carbonic anhydrase IX. Kaluzová, M., Kaluz, S., Lerman, M.I., Stanbridge, E.J. Mol. Cell. Biol. (2004) [Pubmed]
  46. Inflammatory levels of nitric oxide inhibit airway epithelial cell migration by inhibition of the kinase ERK1/2 and activation of hypoxia-inducible factor-1 alpha. Bove, P.F., Hristova, M., Wesley, U.V., Olson, N., Lounsbury, K.M., van der Vliet, A. J. Biol. Chem. (2008) [Pubmed]
  47. Real-time RT-PCR quantitative assays and postmortem degradation profiles of erythropoietin, vascular endothelial growth factor and hypoxia-inducible factor 1 alpha mRNA transcripts in forensic autopsy materials. Zhao, D., Zhu, B.L., Ishikawa, T., Quan, L., Li, D.R., Maeda, H. Legal medicine (Tokyo, Japan) (2006) [Pubmed]
  48. Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1alpha. Ravi, R., Mookerjee, B., Bhujwalla, Z.M., Sutter, C.H., Artemov, D., Zeng, Q., Dillehay, L.E., Madan, A., Semenza, G.L., Bedi, A. Genes Dev. (2000) [Pubmed]
  49. Hepatitis B virus X protein enhances transcriptional activity of hypoxia-inducible factor-1alpha through activation of mitogen-activated protein kinase pathway. Yoo, Y.G., Oh, S.H., Park, E.S., Cho, H., Lee, N., Park, H., Kim, D.K., Yu, D.Y., Seong, J.K., Lee, M.O. J. Biol. Chem. (2003) [Pubmed]
  50. NADPH-cytochrome P-450 reductase in the plasma membrane modulates the activation of hypoxia-inducible factor 1. Osada, M., Imaoka, S., Sugimoto, T., Hiroi, T., Funae, Y. J. Biol. Chem. (2002) [Pubmed]
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