HIF1A

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Hypoxia inducible factor 1, alpha subunit (basic helix-loop-helix transcription factor)

PDB rendering based on 1h2k.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
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
Orthologs
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 protein that in humans is encoded by the HIF1A gene.[1][2] Two alternative transcripts encoding different isoforms have been identified.[3]

Structure[edit]

HIF1 is a heterodimeric basic helix-loop-helix structure[4] composed of Hif1a, the alpha subunit (this protein), and the aryl hydrocarbon receptor nuclear translocator (Arnt), the beta subunit.

Function[edit]

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.[5] This is one of the class of hypoxia inducible factors, a family that includes Hif1a, Hif2a, and Hif3a.

Regulation[edit]

HIF-1alpha abundance (and its subsequent activity) is regulated transcriptionally in an NF-κB-dependent manner.[6] In addition, the coordinated activity of the prolyl hydroxylases (PHDs) maintain the appropriate balance of HIF-1α protein in the post-translation phase.[7]

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

Factors increasing HIF-1α[8]

Factors decreasing HIF-1α[8]

Interactions[edit]

HIF1A has been shown to interact with pVHL,[9] PSMA7,[10] NR4A,[11] STAT3,[12] CREBB,[13][14][15] ARNTL,[16] ARNT,[2][17] P53,[18][19][20][21] EP300,[22][23] HIF1AN,[24] Mdm2,[18][19] VH[11][12][15][24][25][26][27][28][29][30] and UBC.[11][15][30]

Clinical significance[edit]

Overexpression of a natural antisense transcript (aHIF) of this gene is associated with nonpapillary renal carcinomas.[31]

See also[edit]

References[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, Perdew GH, Bradfield CA (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. ^ "Entrez Gene: HIF1A hypoxia-inducible factor 1, alpha subunit (basic helix-loop-helix transcription factor)". 
  4. ^ Wang FS, Wang CJ, Chen YJ, 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. 
  5. ^ Ratcliffe PJ (2003). "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. 
  6. ^ van Uden P, Kenneth NS, Rocha S (2008). "Regulation of hypoxia-inducible factor-1α by NF-κB". Biochem J. 412 (3): 477–484. doi:10.1042/BJ20080476. PMC 2474706. PMID 18393939. 
  7. ^ 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. 
  8. ^ 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. 
  9. ^ Haase VH (2009). "The VHL tumor suppressor: master regulator of HIF". Curr. Pharm. Des. 15 (33): 3895–903. doi:10.2174/138161209789649394. PMID 19671042. 
  10. ^ Cho, S; Choi Y J, Kim J M, Jeong S T, Kim J H, Kim S H, Ryu S E (Jun 2001). "Binding and regulation of HIF-1alpha by a subunit of the proteasome complex, PSMA7". FEBS Lett. (Netherlands) 498 (1): 62–6. doi:10.1016/S0014-5793(01)02499-1. ISSN 0014-5793. PMID 11389899. 
  11. ^ a b c Kim, Bu Yeon; Kim Hyungsoo, Cho Eun Jung, Youn Hong Duk (Feb 2008). "Nur77 upregulates HIF-α by inhibiting pVHL-mediated degradation". Exp. Mol. Med. (Korea (South)) 40 (1): 71–83. doi:10.3858/emm.2008.40.1.71. ISSN 1226-3613. PMC 2679322. PMID 18305400. 
  12. ^ a b Jung, Joo Eun; Kim Hong Sook, Lee Chang Seok, Shin Yong Jae, Kim Yong Nyun, Kang Gyeong Hoon, Kim Tae You, Juhnn Yong Sung, Kim Sung Joon, Park Jong Wan, Ye Sang Kyu, Chung Myung Hee (Oct 2008). "STAT3 inhibits the degradation of HIF-1α by pVHL-mediated ubiquitination". Exp. Mol. Med. (Korea (South)) 40 (5): 479–85. doi:10.3858/emm.2008.40.5.479. ISSN 1226-3613. PMC 2679355. PMID 18985005. 
  13. ^ Ema, M; Hirota K, Mimura J, Abe H, Yodoi J, Sogawa K, Poellinger L, Fujii-Kuriyama Y (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. (ENGLAND) 18 (7): 1905–14. doi:10.1093/emboj/18.7.1905. ISSN 0261-4189. PMC 1171276. PMID 10202154. 
  14. ^ Bhattacharya, S; Michels C L, Leung M K, Arany Z P, Kung A L, Livingston D M (Jan 1999). "Functional role of p35srj, a novel p300/CBP binding protein, during transactivation by HIF-1". Genes Dev. (UNITED STATES) 13 (1): 64–75. doi:10.1101/gad.13.1.64. ISSN 0890-9369. PMC 316375. PMID 9887100. 
  15. ^ a b c Park, Young-Kwon; Ahn Dae-Ro, Oh Myoungsuk, Lee Taekyoung, Yang Eun Gyeong, Son Miwon, Park Hyunsung (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. (United States) 74 (1): 236–45. doi:10.1124/mol.108.045278. PMID 18426857. 
  16. ^ Hogenesch, J B; Gu Y Z, Jain S, Bradfield C A (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. (UNITED STATES) 95 (10): 5474–9. doi:10.1073/pnas.95.10.5474. ISSN 0027-8424. PMC 20401. PMID 9576906. 
  17. ^ Woods, Susan L; Whitelaw Murray L (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. (United States) 277 (12): 10236–43. doi:10.1074/jbc.M110752200. ISSN 0021-9258. PMID 11782478. 
  18. ^ a b Chen, Delin; Li Muyang, Luo Jianyuan, Gu Wei (Apr 2003). "Direct interactions between HIF-1 alpha and Mdm2 modulate p53 function". J. Biol. Chem. (United States) 278 (16): 13595–8. doi:10.1074/jbc.C200694200. ISSN 0021-9258. PMID 12606552. 
  19. ^ a b Ravi, R; Mookerjee B, Bhujwalla Z M, Sutter C H, Artemov D, Zeng Q, Dillehay L E, Madan A, Semenza G L, Bedi A (Jan 2000). "Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1α". Genes Dev. (UNITED STATES) 14 (1): 34–44. ISSN 0890-9369. PMC 316350. PMID 10640274. 
  20. ^ Hansson, Lars O; Friedler Assaf, Freund Stefan, Rudiger Stefan, Fersht Alan R (Aug 2002). "Two sequence motifs from HIF-1α bind to the DNA-binding site of p53". Proc. Natl. Acad. Sci. U.S.A. (United States) 99 (16): 10305–9. doi:10.1073/pnas.122347199. ISSN 0027-8424. PMC 124909. PMID 12124396. 
  21. ^ An, W G; Kanekal M, Simon M C, Maltepe E, Blagosklonny M V, Neckers L M (Mar 1998). "Stabilization of wild-type p53 by hypoxia-inducible factor 1alpha". Nature (ENGLAND) 392 (6674): 405–8. doi:10.1038/32925. ISSN 0028-0836. PMID 9537326. 
  22. ^ Lando, David; Peet Daniel J, Whelan Dean A, Gorman Jeffrey J, Whitelaw Murray L (Feb 2002). "Asparagine hydroxylation of the HIF transactivation domain a hypoxic switch". Science (United States) 295 (5556): 858–61. doi:10.1126/science.1068592. PMID 11823643. 
  23. ^ Freedman, Steven J; Sun Zhen-Yu J, Poy Florence, Kung Andrew L, Livingston David M, Wagner Gerhard, Eck Michael J (Apr 2002). "Structural basis for recruitment of CBP/p300 by hypoxia-inducible factor-1α". Proc. Natl. Acad. Sci. U.S.A. (United States) 99 (8): 5367–72. doi:10.1073/pnas.082117899. ISSN 0027-8424. PMC 122775. PMID 11959990. 
  24. ^ a b Mahon, P C; Hirota K, Semenza G L (Oct 2001). "FIH-1: a novel protein that interacts with HIF-1α and VHL to mediate repression of HIF-1 transcriptional activity". Genes Dev. (United States) 15 (20): 2675–86. doi:10.1101/gad.924501. ISSN 0890-9369. PMC 312814. PMID 11641274. 
  25. ^ Corn, Paul G; McDonald E Robert, Herman James G, El-Deiry Wafik S (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. (United States) 35 (3): 229–37. doi:10.1038/ng1254. ISSN 1061-4036. PMID 14556007. 
  26. ^ Li, Zaibo; Wang Dakun, Na Xi, Schoen Susan R, Messing Edward M, Wu Guan (Apr 2003). "The VHL protein recruits a novel KRAB-A domain protein to repress HIF-1α transcriptional activity". EMBO J. (England) 22 (8): 1857–67. doi:10.1093/emboj/cdg173. ISSN 0261-4189. PMC 154465. PMID 12682018. 
  27. ^ Tanimoto, K; Makino Y, Pereira T, Poellinger L (Aug 2000). "Mechanism of regulation of the hypoxia-inducible factor-1α by the von Hippel-Lindau tumor suppressor protein". EMBO J. (ENGLAND) 19 (16): 4298–309. doi:10.1093/emboj/19.16.4298. ISSN 0261-4189. PMC 302039. PMID 10944113. 
  28. ^ Min, Jung-Hyun; Yang Haifeng, Ivan Mircea, Gertler Frank, Kaelin William G, Pavletich Nikola P (Jun 2002). "Structure of an HIF-1alpha -pVHL complex: hydroxyproline recognition in signaling". Science (United States) 296 (5574): 1886–9. doi:10.1126/science.1073440. PMID 12004076. 
  29. ^ Yu, F; White S B, Zhao Q, Lee F S (Aug 2001). "HIF-1α binding to VHL is regulated by stimulus-sensitive proline hydroxylation". Proc. Natl. Acad. Sci. U.S.A. (United States) 98 (17): 9630–5. doi:10.1073/pnas.181341498. ISSN 0027-8424. PMC 55503. PMID 11504942. 
  30. ^ a b André, Helder; Pereira Teresa S (Oct 2008). "Identification of an Alternative Mechanism of Degradation of the Hypoxia-inducible Factor-1α". J. Biol. Chem. (United States) 283 (43): 29375–84. doi:10.1074/jbc.M805919200. ISSN 0021-9258. PMC 2662024. PMID 18694926. 
  31. ^ 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 (2003). "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, et al. (2006). "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 (2007). "Effects of histone deacetylase inhibitors on HIF-1". Cell Cycle 5 (21): 2430–5. PMID 17102633.