Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Hypoxia-Inducible Factor-1

  • Tong Zhang
  • Zhaoji Liu
  • Zhaoyong Li
  • Huafeng ZhangEmail author
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101697


Historical Background

HIF-1, which is expressed in all metazoan organisms and serves as a transcriptional factor that responds to changes of available oxygen in the cellular environment, is a heterodimeric DNA-binding complex that is composed of two basic helix-loop-helix proteins of the PAS family: a constitutively expressed HIF-1β subunit (also known as the aryl hydrocarbon receptor nuclear translocator 1[ARNT1]) and a tightly regulated HIF-1α subunit (Wang et al. 1995). Hypoxia-inducible factor 1 (HIF-1) was first identified, biochemical purified, and molecular characterized by Gregg Semenza’s research group in the early 1990s (Semenza and Wang 1992). Both HIF-1α and HIF-1β are members of the bHLH-PAS superfamily proteins containing basic-helix-loop-helix (bHLH) and PER-ARNT-SIM (PAS) domains (Wang et al. 1995) (Fig. 1). HIF-1β subunit is a nonoxygen responsive protein, while the HIF-1α subunit is remarkably...
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  1. Barsoum IB, Smallwood CA, Siemens DR, Graham CH. A mechanism of hypoxia-mediated escape from adaptive immunity in cancer cells. Cancer Res. 2014;74:665–74.PubMedCrossRefGoogle Scholar
  2. Casazza A, Laoui D, Wenes M, Rizzolio S, Bassani N, Mambretti M, Deschoemaeker S, Van Ginderachter JA, Tamagnone L, Mazzone M. Impeding macrophage entry into hypoxic tumor areas by Sema3A/Nrp1 signaling blockade inhibits angiogenesis and restores antitumor immunity. Cancer Cell. 2013;24:695–709.PubMedCrossRefGoogle Scholar
  3. Chaffer CL, Weinberg RA. A perspective on cancer cell metastasis. Science. 2011;331(6024):1559–64.PubMedCrossRefGoogle Scholar
  4. Dang EV, Barbi J, Yang HY, Jinasena D, Yu H, Zheng Y, Bordman Z, Fu J, Kim Y, Yen HR. Control of T(H)17/T(reg) balance by hypoxia-inducible factor 1. Cell. 2011;146:772–84.PubMedPubMedCentralCrossRefGoogle Scholar
  5. Doedens AL, Phan AT, Stradner MH, Fujimoto JK, Nguyen JV, Yang E, Johnson RS, Goldrath AW. Hypoxia-inducible factors enhance the effector responses of CD8+ T cells to persistent antigen. Nat Immunol. 2013;14:1173–82.PubMedPubMedCentralCrossRefGoogle Scholar
  6. Haschemi A, Kosma P, Gille L, Evans CR, Burant CF, Starkl P, Knapp B, Haas R, Schmid JA, Jandl C, Amir S, Lubec G, Park J, Esterbauer H, Bilban M, Brizuela L, Pospisilik JA, Otterbein LE, Wagner O. The sedoheptulose kinase CARKL directs macrophage polarization through control of glucose metabolism. Cell Metab. 2012;15:813–26.PubMedPubMedCentralCrossRefGoogle Scholar
  7. Huang D, Li T, Li X, Zhang L, Sun L, He X, Zhong X, Jia D, Song L, Semenza GL, Gao P, Zhang H. HIF-1-mediated suppression of acyl-CoA dehydrogenases and fatty acid oxidation is critical for cancer progression. Cell Rep. 2014;8(6):1930–42.PubMedCrossRefGoogle Scholar
  8. Jiang J, Tang YL, Liang XH. EMT: a new vision of hypoxia promoting cancer progression. Cancer Biol Ther. 2011;11(8):714–23.PubMedCrossRefGoogle Scholar
  9. Kim JW, Tchernyshyov I, Semenza GL, Dang CV. HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab. 2006;3:177–85.PubMedCrossRefPubMedCentralGoogle Scholar
  10. Liu YV, Baek JH, Zhang H, Diez R, Cole RN, Semenza GL. RACK1 competes with HSP90 for binding to HIF-1 and is required for O2-independent and HSP90 inhibitor-induced degradation of HIF-1. Mol Cell. 2007;25:207–17.PubMedPubMedCentralCrossRefGoogle Scholar
  11. Majmundar AJ, Wong WJ, Simon MC. Hypoxia-inducible factors and the response to hypoxic stress. Mol Cell. 2010;40(2):294–309.PubMedPubMedCentralCrossRefGoogle Scholar
  12. Noman MZ, Buart S, Van Pelt J, Richon C, Hasmim M, Leleu N, Suchorska WM, Jalil A, Lecluse Y, El Hage F. The cooperative induction of hypoxia-inducible factor-1 alpha and STAT3 during hypoxia induced an impairment of tumor susceptibility to CTL-mediated cell lysis. J Immunol. 2009;182:3510–21.PubMedCrossRefGoogle Scholar
  13. Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer. 2003;3:721–32.PubMedCrossRefGoogle Scholar
  14. Semenza GL. Hypoxia-inducible factors mediators of cancer progression and targets for cancer therapy. Trends Pharmacol Sci. 2012;33(4):207–14.PubMedPubMedCentralCrossRefGoogle Scholar
  15. Semenza GL, Wang GL. A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol Cell Biol. 1992;12(12):5447–54.PubMedPubMedCentralCrossRefGoogle Scholar
  16. Simon MC. Coming up for air: HIF-1 and mitochondrial oxygen consumption. Cell Metabol. 2006;3:150–1.CrossRefGoogle Scholar
  17. Wang GL, Jiang BH, Rue EA, Semenza GL. Hypoxia-inducible factor-1 is a basic-helix-loop-helix-Pas heterodimer regulated by cellular O2tension. Proc Natl Acad Sci USA. 1995;92:5510–4.PubMedPubMedCentralCrossRefGoogle Scholar
  18. Wong CC, Gilkes DM, Zhang HF, Chen J, Wei H, Chaturvedi P, Fraley SI, Wong CM, Khoo US, Ng IO, Wirtz D, Semenza GL. Hypoxia-inducible factor 1 is a master regulator of breast cancer metastatic niche formation. Proc Natl Acad Sci USA. 2011;108(39):16369–74.PubMedPubMedCentralCrossRefGoogle Scholar
  19. Zhang H, Gao P, Fukuda R, Kumar G, Krishnamachary B, Zeller KI, Dang CV, Semenza GL. HIF-1 inhibits mitochondrial biogenesis and cellular respiration in VHL-deficient renal cell carcinoma by repression of C-MYC activity. Cancer Cell. 2007;11(5):407–20.PubMedCrossRefGoogle Scholar
  20. Zhang H, Wong CC, Wei H, Gilkes DM, Korangath P, Chaturvedi P, Schito L, Chen J, Krishnamachary B, Winnard Jr PT, Raman V, Zhen L, Mitzner WA, Sukumar S, Semenza GL. HIF-1-dependent expression of angiopoietin-like 4 and L1CAM mediates vascular metastasis of hypoxic breast cancer cells to the lungs. Oncogene. 2012;31(14):1757–70.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Tong Zhang
    • 1
  • Zhaoji Liu
    • 1
  • Zhaoyong Li
    • 1
  • Huafeng Zhang
    • 1
    Email author
  1. 1.Hefei National Laboratory for Physical Sciences at Microscale, CAS Key Laboratory of Innate Immunity and Chronic DiseaseInnovation Center for Cell Signaling Network, and School of Life Sciences, University of Science and Technology of ChinaHefeiChina