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Hypoxia inducible factor 1, alpha subunit (basic helix-loop-helix transcription factor)
Protein HIF1A PDB 1h2k.png
PDB rendering based on 1h2k.
Available structures
PDB Ortholog search: PDBe, RCSB
Symbols HIF1A ; HIF-1A; HIF-1alpha; HIF1; HIF1-ALPHA; MOP1; PASD8; bHLHe78
External IDs OMIM603348 MGI106918 HomoloGene1171 ChEMBL: 4261 GeneCards: HIF1A Gene
RNA expression pattern
PBB GE HIF1A 200989 at.png
More reference expression data
Species Human Mouse
Entrez 3091 15251
Ensembl ENSG00000100644 ENSMUSG00000021109
UniProt Q16665 Q61221
RefSeq (mRNA) NM_001243084 NM_010431
RefSeq (protein) NP_001230013 NP_034561
Location (UCSC) Chr 14:
62.16 – 62.21 Mb
Chr 12:
73.9 – 73.95 Mb
PubMed search [1] [2]

Hypoxia-inducible factor 1-alpha, also known as HIF-1-alpha, is a subunit of a heterodimeric transcription factor hypoxia-inducible factor 1 (HIF-1) that is encoded by the HIF1A gene. .[1][2][3]It is a basic helix-loop-helix PAS-domain-containing protein, and is considered as the master transcriptional regulator of cellular and developmental response to hypoxia. [4][5]The dysregulation and overexpression of HIF1a by either hypoxia or genetic alternations have been heavily implicated in cancer biology, as well as a number of other pathophysiologies, specifically in areas of vascularization and angiogenesis, energy metabolism, cell survival, and tumor invasion. [6][7] Two other alternative transcripts encoding different isoforms have been identified.[8]


HIF1 is a heterodimeric basic helix-loop-helix structure[9] composed of Hif1a, the alpha subunit (this protein), and the aryl hydrocarbon receptor nuclear translocator (Arnt), the beta subunit.


The protein encoded by HIF1 is a bHLH - PAS transcription factor found in mammalian cells growing at low oxygen concentrations. It plays an essential role in cellular and systemic responses to hypoxia.[10] This is one of the class of hypoxia inducible factors, a family that includes Hif1a, Hif2a, and Hif3a.


HIF-1alpha abundance (and its subsequent activity) is regulated transcriptionally in an NF-κB-dependent manner.[11] In addition, the coordinated activity of the prolyl hydroxylases (PHDs) maintain the appropriate balance of HIF-1α protein in the post-translation phase.[12]

PHDs rely on iron among other molecules to hydroxylate HIF-1alpha; as such, iron chelators such as desferrioxamine (DFO) have proven successful in HIF-1alpha stabilization.[13] HBO (Hyperbaric oxygen therapy) and HIF-1alpha imitators such as cobalt chloride have also been successfully utilized.[13]

Factors increasing HIF-1α[14]

Factors decreasing HIF-1α[14]


HIF1A has been shown to interact with:

Clinical significance[edit]

Overexpression of a natural antisense transcript (aHIF) of this gene is associated with nonpapillary renal carcinomas.[37]

See also[edit]


  1. ^ Semenza GL, Rue EA, Iyer NV, Pang MG, Kearns WG (June 1996). "Assignment of the hypoxia-inducible factor 1alpha gene to a region of conserved synteny on mouse chromosome 12 and human chromosome 14q". Genomics 34 (3): 437–9. doi:10.1006/geno.1996.0311. PMID 8786149. 
  2. ^ a b Hogenesch JB, Chan WK, Jackiw VH, Brown RC, Gu YZ, Pray-Grant M et al. (March 1997). "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 (13): 8581–93. doi:10.1074/jbc.272.13.8581. PMID 9079689. 
  3. ^ http://www.ncbi.nlm.nih.gov/gene/3091.  Missing or empty |title= (help)
  4. ^ Wang, GL (1995). "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 (12): 5510–5514. 
  5. ^ Iyer, NV (1998). "Cellular and developmental control of O-2 homeostasis by hypoxia-inducible factor 1 alpha". Genes Dev 12 (2): 149–62. doi:10.1101/gad.12.2.149. PMID 9436976. 
  6. ^ http://www.ncbi.nlm.nih.gov/gene/3091.  Missing or empty |title= (help)
  7. ^ Semenza, GL (2003). "Targeting HIF-1 for cancer therapy". Nat Rev Cancer 3 (10): 721–32. doi:10.1038/nrc1187. 
  8. ^ "Entrez Gene: HIF1A hypoxia-inducible factor 1, alpha subunit (basic helix-loop-helix transcription factor)". 
  9. ^ Wang FS, Wang CJ, Chen YJ, Chang PR, Huang YT, Sun YC et al. (March 2004). "Ras induction of superoxide activates ERK-dependent angiogenic transcription factor HIF-1alpha and VEGF-A expression in shock wave-stimulated osteoblasts". J. Biol. Chem. 279 (11): 10331–7. doi:10.1074/jbc.M308013200. PMID 14681237. 
  10. ^ Ratcliffe PJ (2002). "From erythropoietin to oxygen: hypoxia-inducible factor hydroxylases and the hypoxia signal pathway". Blood Purif. 20 (5): 445–50. doi:10.1159/000065201. PMID 12207089. 
  11. ^ van Uden P, Kenneth NS, Rocha S (2008). "Regulation of hypoxia-inducible factor-1alpha by NF-kappaB". Biochem. J. 412 (3): 477–84. doi:10.1042/BJ20080476. PMC 2474706. PMID 18393939. 
  12. ^ Semenza GL (August 2004). "Hydroxylation of HIF-1: oxygen sensing at the molecular level". Physiology (Bethesda) 19 (4): 176–82. doi:10.1152/physiol.00001.2004. PMID 15304631. 
  13. ^ a b Xiao H, Gu Z, Wang G, Zhao T (2013). "The possible mechanisms underlying the impairment of HIF-1α pathway signaling in hyperglycemia and the beneficial effects of certain therapies". Int J Med Sci 10 (10): 1412–21. doi:10.7150/ijms.5630. PMC 3752727. PMID 23983604. 
  14. ^ a b Yee Koh M, Spivak-Kroizman TR, Powis G (November 2008). "HIF-1 regulation: not so easy come, easy go". Trends Biochem. Sci. 33 (11): 526–34. doi:10.1016/j.tibs.2008.08.002. PMID 18809331. 
  15. ^ Hogenesch JB, Gu YZ, Jain S, Bradfield CA (May 1998). "The basic-helix-loop-helix-PAS orphan MOP3 forms transcriptionally active complexes with circadian and hypoxia factors". Proc. Natl. Acad. Sci. U.S.A. 95 (10): 5474–9. doi:10.1073/pnas.95.10.5474. PMC 20401. PMID 9576906. 
  16. ^ Woods SL, Whitelaw ML (Mar 2002). "Differential activities of murine single minded 1 (SIM1) and SIM2 on a hypoxic response element. Cross-talk between basic helix-loop-helix/per-Arnt-Sim homology transcription factors". J. Biol. Chem. 277 (12): 10236–43. doi:10.1074/jbc.M110752200. PMID 11782478. 
  17. ^ Ema M, Hirota K, Mimura J, Abe H, Yodoi J, Sogawa K et al. (Apr 1999). "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 (7): 1905–14. doi:10.1093/emboj/18.7.1905. PMC 1171276. PMID 10202154. 
  18. ^ Bhattacharya S, Michels CL, Leung MK, Arany ZP, Kung AL, Livingston DM (Jan 1999). "Functional role of p35srj, a novel p300/CBP binding protein, during transactivation by HIF-1". Genes Dev. 13 (1): 64–75. doi:10.1101/gad.13.1.64. PMC 316375. PMID 9887100. 
  19. ^ a b c Park YK, Ahn DR, Oh M, Lee T, Yang EG, Son M et al. (Jul 2008). "Nitric oxide donor, (+/-)-S-nitroso-N-acetylpenicillamine, stabilizes transactive hypoxia-inducible factor-1alpha by inhibiting von Hippel-Lindau recruitment and asparagine hydroxylation". Mol. Pharmacol. 74 (1): 236–45. doi:10.1124/mol.108.045278. PMID 18426857. 
  20. ^ Lando D, Peet DJ, Whelan DA, Gorman JJ, Whitelaw ML (Feb 2002). "Asparagine hydroxylation of the HIF transactivation domain a hypoxic switch". Science 295 (5556): 858–61. doi:10.1126/science.1068592. PMID 11823643. 
  21. ^ Freedman SJ, Sun ZY, Poy F, Kung AL, Livingston DM, Wagner G et al. (Apr 2002). "Structural basis for recruitment of CBP/p300 by hypoxia-inducible factor-1 alpha". Proc. Natl. Acad. Sci. U.S.A. 99 (8): 5367–72. doi:10.1073/pnas.082117899. PMC 122775. PMID 11959990. 
  22. ^ a b Mahon PC, Hirota K, Semenza GL (Oct 2001). "FIH-1: a novel protein that interacts with HIF-1alpha and VHL to mediate repression of HIF-1 transcriptional activity". Genes Dev. 15 (20): 2675–86. doi:10.1101/gad.924501. PMC 312814. PMID 11641274. 
  23. ^ a b Chen D, Li M, Luo J, Gu W (Apr 2003). "Direct interactions between HIF-1 alpha and Mdm2 modulate p53 function". J. Biol. Chem. 278 (16): 13595–8. doi:10.1074/jbc.C200694200. PMID 12606552. 
  24. ^ a b Ravi R, Mookerjee B, Bhujwalla ZM, Sutter CH, Artemov D, Zeng Q et al. (Jan 2000). "Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1alpha". Genes Dev. 14 (1): 34–44. PMC 316350. PMID 10640274. 
  25. ^ a b c Kim BY, Kim H, Cho EJ, Youn HD (Feb 2008). "Nur77 upregulates HIF-alpha by inhibiting pVHL-mediated degradation". Exp. Mol. Med. 40 (1): 71–83. doi:10.3858/emm.2008.40.1.71. PMC 2679322. PMID 18305400. 
  26. ^ Hansson LO, Friedler A, Freund S, Rudiger S, Fersht AR (Aug 2002). "Two sequence motifs from HIF-1alpha bind to the DNA-binding site of p53". Proc. Natl. Acad. Sci. U.S.A. 99 (16): 10305–9. doi:10.1073/pnas.122347199. PMC 124909. PMID 12124396. 
  27. ^ An WG, Kanekal M, Simon MC, Maltepe E, Blagosklonny MV, Neckers LM (Mar 1998). "Stabilization of wild-type p53 by hypoxia-inducible factor 1alpha". Nature 392 (6674): 405–8. doi:10.1038/32925. PMID 9537326. 
  28. ^ Cho S, Choi YJ, Kim JM, Jeong ST, Kim JH, Kim SH et al. (Jun 2001). "Binding and regulation of HIF-1alpha by a subunit of the proteasome complex, PSMA7". FEBS Lett. 498 (1): 62–6. doi:10.1016/S0014-5793(01)02499-1. PMID 11389899. 
  29. ^ a b Jung JE, Kim HS, Lee CS, Shin YJ, Kim YN, Kang GH et al. (Oct 2008). "STAT3 inhibits the degradation of HIF-1alpha by pVHL-mediated ubiquitination". Exp. Mol. Med. 40 (5): 479–85. doi:10.3858/emm.2008.40.5.479. PMC 2679355. PMID 18985005. 
  30. ^ a b André H, Pereira TS (Oct 2008). "Identification of an alternative mechanism of degradation of the hypoxia-inducible factor-1alpha". J. Biol. Chem. 283 (43): 29375–84. doi:10.1074/jbc.M805919200. PMC 2662024. PMID 18694926.  Vancouver style error (help)
  31. ^ Corn PG, McDonald ER, Herman JG, El-Deiry WS (Nov 2003). "Tat-binding protein-1, a component of the 26S proteasome, contributes to the E3 ubiquitin ligase function of the von Hippel-Lindau protein". Nat. Genet. 35 (3): 229–37. doi:10.1038/ng1254. PMID 14556007. 
  32. ^ Li Z, Wang D, Na X, Schoen SR, Messing EM, Wu G (Apr 2003). "The VHL protein recruits a novel KRAB-A domain protein to repress HIF-1alpha transcriptional activity". EMBO J. 22 (8): 1857–67. doi:10.1093/emboj/cdg173. PMC 154465. PMID 12682018. 
  33. ^ Tanimoto K, Makino Y, Pereira T, Poellinger L (Aug 2000). "Mechanism of regulation of the hypoxia-inducible factor-1 alpha by the von Hippel-Lindau tumor suppressor protein". EMBO J. 19 (16): 4298–309. doi:10.1093/emboj/19.16.4298. PMC 302039. PMID 10944113. 
  34. ^ Min JH, Yang H, Ivan M, Gertler F, Kaelin WG, Pavletich NP (Jun 2002). "Structure of an HIF-1alpha -pVHL complex: hydroxyproline recognition in signaling". Science 296 (5574): 1886–9. doi:10.1126/science.1073440. PMID 12004076. 
  35. ^ Yu F, White SB, Zhao Q, Lee FS (Aug 2001). "HIF-1alpha binding to VHL is regulated by stimulus-sensitive proline hydroxylation". Proc. Natl. Acad. Sci. U.S.A. 98 (17): 9630–5. doi:10.1073/pnas.181341498. PMC 55503. PMID 11504942. 
  36. ^ Haase VH (2009). "The VHL tumor suppressor: master regulator of HIF". Curr. Pharm. Des. 15 (33): 3895–903. doi:10.2174/138161209789649394. PMC 3622710. PMID 19671042. 
  37. ^ Quintero M, Mackenzie N, Brennan PA (June 2004). "Hypoxia-inducible factor 1 (HIF-1) in cancer". Eur J Surg Oncol 30 (5): 465–8. doi:10.1016/j.ejso.2004.03.008. PMID 15135470. 

Further reading[edit]

  • Semenza GL (2000). "HIF-1 and human disease: one highly involved factor". Genes Dev. 14 (16): 1983–91. PMID 10950862. 
  • Semenza G (2002). "Signal transduction to hypoxia-inducible factor 1". Biochem. Pharmacol. 64 (5-6): 993–8. doi:10.1016/S0006-2952(02)01168-1. PMID 12213597. 
  • Arbeit JM (2002). "Quiescent hypervascularity mediated by gain of HIF-1 alpha function". Cold Spring Harb. Symp. Quant. Biol. 67: 133–42. doi:10.1101/sqb.2002.67.133. PMID 12858534. 
  • Sitkovsky M, Lukashev D (2005). "Regulation of immune cells by local-tissue oxygen tension: HIF1 alpha and adenosine receptors". Nat. Rev. Immunol. 5 (9): 712–21. doi:10.1038/nri1685. PMID 16110315. 
  • Mobasheri A, Richardson S, Mobasheri R, Shakibaei M, Hoyland JA (2005). "Hypoxia inducible factor-1 and facilitative glucose transporters GLUT1 and GLUT3: putative molecular components of the oxygen and glucose sensing apparatus in articular chondrocytes". Histol. Histopathol. 20 (4): 1327–38. PMID 16136514. 
  • Schipani E (2006). "Hypoxia and HIF-1 alpha in chondrogenesis". Semin. Cell Dev. Biol. 16 (4-5): 539–46. doi:10.1016/j.semcdb.2005.03.003. PMID 16144691. 
  • Haase VH (2006). "Hypoxia-inducible factors in the kidney". Am. J. Physiol. Renal Physiol. 291 (2): F271–81. doi:10.1152/ajprenal.00071.2006. PMID 16554418. 
  • Liang D, Kong X, Sang N (2006). "Effects of histone deacetylase inhibitors on HIF-1". Cell Cycle 5 (21): 2430–5. doi:10.4161/cc.5.21.3409. PMID 17102633.