Summary
Hypoxia-inducible factor 1 (HIF-1) is a basic helix-loop-helix protein that activates transcription of hypoxia-inducible genes, including those encoding erythropoietin, vascular endothelial growth factor, heme oxygenase-1, inducible nitric oxide synthase, and the glycolytic enzymes aldolase A, enolase 1, lactate dehydrogenase A, phosphofructokinase L, and phosphoglycerate kinase 1. Hypoxia response elements from these genes consist of a HIF-1-binding site as well as additional DNA sequences that are required for function, which in some elements include a second HIF-1-binding site. HIF-1 is a heterodimer: the HIF-lα subunit is unique to HIF-1, while HIF-1β (ARNT) can dimerize with other proteins. Cotransfection of HIF-1α and HIF-1β (ARNT) expression vectors and a reporter gene containing a wild-type hypoxia response element resulted in increased transcription in nonhypoxic cells and a superinduction of transcription in hypoxic cells, whereas HIF-1 expression vectors had no effect on transcription of reporter genes containing a HIF-1 binding-site mutation. In HeLa cells, HIF-lα and HIF-1β protein levels and HIF-1 DNA-binding activity increased exponentially as oxygen tension decreased, with maximum values at 0.5% oxygen and half-maximal values at 1.5%–2% oxygen. HIF-lα and HIF-1β (ARNT) mRNAs were detected in all human and rodent organs assayed. HIF-lα protein levels were induced in vivo when animals were subjected to anemia or hypoxia.
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References
Semenza GL (1996) Transcriptional regulation by hypoxia-inducible factor 1: molecular mechanisms of oxygen homeostasis. Trends Cardiovasc Med 6: 151–157
Semenza GL, Wang GL (1992) 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 12: 5447–5454
Semenza GL (1994) Regulation of erythropoietin production: new insights into molecular mechanisms of oxygen homeostasis. Hematol Oncol Clinics N Am 8: 863–884
Wang GL, Semenza GL (1996) Molecular basis of hypoxia-induced erythropoietin expression. Curr Opin Hematol 3: 156–162
Wang GL, Semenza GL (1996) Oxygen sensing and response to hypoxia by mammalian cells. Redox Rep 2: 89–96
Jiang B-H, Rue E, Wang GL, et al. (1996) Dimerization, DNA binding, and transactivation properties of hypoxia-inducible factor 1. J Biol Chem 271: 17771–17778
Levy AP, Levy NS, Wegner S, et al. (1995) Transcriptional regulation of the rat vascular endothelial growth factor gene by hypoxia. J Biol Chem 270: 13333–13340
Liu Y, Cox SR, Morita T, et al. (1995) Hypoxia regulates vascular endothelial growth factor gene expression in endothelial cells. Circ Res 77: 638–643
Forsythe JA, Jiang B-H, Iyer NV, et al. (1996) Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol 16: 4604–4613
Ikeda E, Achen MG, Breier G, et al. (1995) Hypoxia-induced transcriptional activation and increased mRNA stability of vascular endothelial growth factor in C6 glioma cells. J Biol Chem 270: 19761–19766
Firth JD, Ebert BL, Pugh CW, et al. (1994) Oxygen-regulated control elements in the phosphoglycerate kinase 1 and lactate dehydrogenase A genes: similarities with the erythropoietin 3’ enhancer. Proc Natl Acad Sci USA 91: 6496–6500
Firth JD, Ebert BL, Ratcliffe Pl (1995) Hypoxic regulation of lactate dehydrogenase A: interaction between hypoxia-inducible factor 1 and cAMP response elements. J Biol Chem 270: 21021–21027
Semenza GL, Roth PH, Fang H-M, et al. (1994) Transcriptional regulation of genes encoding glycolytic enzymes by hypoxia-inducible factor 1. J Biol Chem 269: 23757–23763
Semenza GL, Jiang B-H, Leung SW, et al. (1996) Hypoxia response elements in the aldolase A, enolase 1, and lactate dehydrogenase A gene promoters contain essential binding sites for hypoxia-inducible factor 1. J Biol Chem 271: 32529–32537
Li H, Ko HP, Whitlock JP Jr (1996) Induction of phosphoglycerate kinase gene expression by hypoxia: roles of ARNT and HIFIa. J Biol Chem 271: 21262–21267
Lee PJ, Jiang B-H, Chin BY, et al. (1997) Hypoxia-inducible factor 1 mediates transcriptional activation of the heme oxygenase-1 gene in response to hypoxia. J Biol Chem 272: 5375–5381
Melillo G, Musso T, Sica A, et al. (1995) A hypoxia-responsive element mediates a novel pathway of activation of the inducible nitric oxide synthase promoter. J Exp Med 182: 1683–1693
Wang GL, Semenza GL (1995) Purification and characterization of hypoxia-inducible factor 1. J Biol Chem 270: 1230–1237
Wang GL, Jiang B-H, Rue EA, et al. (1995) Hypoxia-inducible factor 1 is a basichelix-loop-helix-PAS heterodimer regulated by cellular 02 tension. Proc Natl Acad Sci USA 90: 5510–5514
Hoffman EC, Reyes H, Chu F-F, et al. (1991) Cloning of a factor required for activity of the Ah (dioxin) receptor. Science 252: 954–958
Nambu JR, Lewis JO, Wharton KA, et al. (1991) The Drosophila single-minded gene encodes a helix-loop-helix protein that acts as a master regulator of CNS midline development. Cell 67: 1157–1167
Nambu JR, Chen W, Hu S, et al. (1996) The Drosophila melanogaster-similar bHLHPAS gene encodes a protein related to human hypoxia-inducible factor la and Drosophila single-minded. Gene 172: 249–254
Isaac DD, Andrew DJ (1996) Tubulogenesis in Drosophila: a requirement for the trachealess gene product. Genes Dev 10: 103–117
Wilk R, Weizman I, Shilo B-Z (1996) trachealess encodes a bHLH-PAS protein that is an inducer of tracheal cell fates in Drosophila. Genes Dev 10: 93–102
Reisz-Porszasz S, Probst MR, Fukunaga BN, et al. (1994) Identification of functional domains of the aryl hydrocarbon receptor nuclear translocator protein ( ARNT ). Mol Cell Biol 14: 6075–6086
Lindebro MC, Poellinger L, Whitelaw ML (1995) Protein-protein interaction via PAS domains: role of the PAS domain in positive and negative regulation of the bHLH/PAS dioxin receptor-Arnt transcription factor complex. EMBO J 14: 3528–3539
Wood SM, Gleadle JM, Pugh CW, et al. (1996) The role of the aryl hydrocarbon receptor nuclear translocator (ARNT) in hypoxic induction of gene expression: studies in ARNT-deficient cells. J Biol Chem 271: 15117–15123
Whitelaw ML, Gustafsson J-A, Poellinger L (1994) Identification of transactivation and repression functions of the dioxin receptor and its basic helix-loop-helix/PAS partner factor Amt: inducible versus constitutive modes of regulation. Mol Cell Biol 14: 8343–8355
Li H, Dong L, Whitlock JP Jr (1994) Transcriptional activation function of the mouse Ah receptor nuclear translocator. J Biol Chem 269: 28098–28105
Rowlands JC, McEwan IJ, Gustafsson J-A (1996) trans-activation by the human aryl hydrocarbon receptor and aryl hydrocarbon receptor nuclear translocator proteins: direct interactions with basal transcription factors. Mol Pharmacol 50: 538–548
Jiang B-H, Semenza GL, Bauer C, et al. (1996) Hypoxia-inducible factor 1 levels vary exponentially over a physiologically relevant range of Oz tension. Am J Physiol 271: C1172 - C1180
Wiener CM, Booth G, Semenza GL (1996) In vivo expression of mRNAs encoding hypoxia-inducible factor 1. Biochem Biophys Res Commun 225: 485–488
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© 1998 Springer-Verlag Tokyo
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Semenza, G.L. et al. (1998). Transcriptional Responses Mediated by Hypoxia-Inducible Factor 1. In: Ishimura, Y., Shimada, H., Suematsu, M. (eds) Oxygen Homeostasis and Its Dynamics. Keio University Symposia for Life Science and Medicine, vol 1. Springer, Tokyo. https://doi.org/10.1007/978-4-431-68476-3_52
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DOI: https://doi.org/10.1007/978-4-431-68476-3_52
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