Skip to main content
SpringerLink
Log in

Hypoxia-responsive transcription factors

  • Invited Review
  • Published:
Pflügers Archiv Aims and scope Submit manuscript

Abstract

Hypoxia is a common pathophysiological occurrence with a profound impact on the cellular transcriptome. The consequences of hypoxia-induced or hypoxia-repressed gene expression have important implications in disease processes as diverse as tumour development and chronic inflammation. While the hypoxia-inducible factor (HIF-1) plays a major role in controlling the ubiquitous transcriptional response to hypoxia, it is clear that a number of other transcription factors are also activated either directly or indirectly. In this review, we comprehensively discuss the transcription factors that have been reported to be hypoxia-responsive and the signalling mechanisms leading to their activation. Understanding such events will enhance our understanding of cellular oxygen sensing.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Achison M, Hupp TR (2003) Hypoxia attenuates the p53 response to cellular damage. Oncogene 22:3431–3440

    Article  PubMed  Google Scholar 

  2. Alarcon R, Koumenis C, Geyer RK, Maki CG, Giaccia AJ (1999) Hypoxia induces p53 accumulation through MDM2 down-regulation and inhibition of E6-mediated degradation. Cancer Res 59:6046–6051

    PubMed  Google Scholar 

  3. Ameyar M, Wisniewska M, Weitzman JB (2003) A role for AP-1 in apoptosis: the case for and against. Biochimie 85:747–752

    Article  PubMed  Google Scholar 

  4. Bae SK, Bae MH, Ahn MY, Son MJ, Lee YM, Bae MK, Lee OH, Park BC, Kim KW (1999) Egr-1 mediates transcriptional activation of IGF-II gene in response to hypoxia. Cancer Res 59:5989–5994

    PubMed  Google Scholar 

  5. Beitner-Johnson D, Millhorn DE (1998) Hypoxia induces phosphorylation of the cyclic AMP response element-binding protein by a novel signaling mechanism. J Biol Chem 273:19834–19839

    Article  PubMed  Google Scholar 

  6. Birbach A, Gold P, Binder BR, Hofer E, de Martin R, Schmid JA (2002) Signaling molecules of the NF-κB pathway shuttle constitutively between cytoplasm and nucleus. J Biol Chem 277:10842–10851

    Article  PubMed  Google Scholar 

  7. Bontemps Y, Vuillermoz B, Antonicelli F, Perreau C, Danan JL, Maquart FX, Wegrowski Y (2003) Specific protein-1 is a universal regulator of UDP-glucose dehydrogenase expression: its positive involvement in transforming growth factor-beta signaling and inhibition in hypoxia. J Biol Chem 278:21566–21575

    Article  PubMed  Google Scholar 

  8. Bouwman P, Philipsen S (2002) Regulation of the activity of Sp1-related transcription factors. Mol Cell Endocrinol 195:27–38

    Article  PubMed  Google Scholar 

  9. Boveris A, Chance B (1973) The mitochondrial generation of hydrogen peroxide. General properties and effect of hyperbaric oxygen. Biochem J 134:707–716

    PubMed  Google Scholar 

  10. Carmeliet P, Dor Y, Herbert JM, Fukumura D, Brusselmans K, Dewerchin M, Neeman M, Bono F, Abramovitch R, Maxwell P, Koch CJ, Ratcliffe P, Moons L, Jain RK, Collen D, Keshert E (1998) Role of HIF-1α in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. Nature 394:485–490

    Article  PubMed  Google Scholar 

  11. Carriere A, Carmona MC, Fernandez Y, Rigoulet M, Wenger RH, Penicaud L, Casteilla L (2004) Mitochondrial reactive oxygen species control the transcription factor CHOP-10/GADD153 and adipocyte differentiation: a mechanism for hypoxia-dependent effect. J Biol Chem 279:40462–40469

    Article  PubMed  Google Scholar 

  12. Chandel NS, Maltepe E, Goldwasser E, Mathieu CE, Simon MC, Schumacker PT (1998) Mitochondrial reactive oxygen species trigger hypoxia-induced transcription. Proc Natl Acad Sci USA 95:11715–11720

    Article  PubMed  Google Scholar 

  13. Chandel NS, McClintock DS, Feliciano CE, Wood TM, Melendez JA, Rodriguez AM, Schumacker PT (2000) Reactive oxygen species generated at mitochondrial complex III stabilize hypoxia-inducible factor-1alpha during hypoxia: a mechanism of O2 sensing. J Biol Chem 275:25130–25138

    Article  PubMed  Google Scholar 

  14. Chandel NS, Schumacker PT (2000) Cellular oxygen sensing by mitochondria: old questions, new insight. J Appl Physiol 88:1880–1889

    Article  PubMed  Google Scholar 

  15. Chandel NS, Trzyna WC, McClintock DS, Schumacker PT (2000) Role of oxidants in NF-κB activation and TNF-α gene transcription induced by hypoxia and endotoxin. J Immunol 165:1013–10121

    PubMed  Google Scholar 

  16. Chandel NS, Vander Heiden MG, Thompson CB, Schumacker PT (2000) Redox regulation of p53 during hypoxia. Oncogene 19:3840–3848

    Article  PubMed  Google Scholar 

  17. Chen D, Li M, Luo J, Gu W (2003) Direct interactions between HIF-1 alpha and Mdm2 modulate p53 function. J Biol Chem 278:13595–13598

    Article  PubMed  Google Scholar 

  18. Chen F, Castranova V, Shi X, Demers LM (1999) New insights into the role of nuclear factor-κB, a ubiquitous transcription factor in the initiation of diseases. Clin Chem 45:7–17

    CAS  PubMed  Google Scholar 

  19. Chen R, Harrod KS, Olson JW, Gillespie MN (2000) Regulation of gadd153 mRNA expression by hypoxia in pulmonary artery smooth muscle cells. Res Commun Mol Pathol Pharmacol 108:3–14

    PubMed  Google Scholar 

  20. Comerford KM, Leonard MO, Karhausen J, Carey R, Colgan SP, Taylor CT (2003) Small ubiquitin-related modifier-1 modification mediates resolution of CREB-dependent responses to hypoxia. Proc Natl Acad Sci USA 100:986–991

    Article  PubMed  Google Scholar 

  21. Comerford KM, Wallace TJ, Karhausen J, Louis NA, Montalto MC, Colgan SP (2002) Hypoxia-inducible factor-1-dependent regulation of the multidrug resistance (MDR1) gene. Cancer Res 62:3387–3394

    PubMed  Google Scholar 

  22. Discher DJ, Bishopric NH, Wu X, Peterson CA, Webster KA (1998) Hypoxia regulates β-enolase and pyruvate kinase-M promoters by modulating Sp1/Sp3 binding to a conserved GC element. J Biol Chem 273:26087–26093

    Article  PubMed  Google Scholar 

  23. Eferl R, Wagner EF (2003) AP-1: a double-edged sword in tumorigenesis. Nat Rev Cancer 3:859–868

    Article  PubMed  Google Scholar 

  24. Ema M, Taya S, Yokotani N, Sogawa K, Matsuda Y, Fujii-Kuriyama Y (1997) A novel bHLH-PAS factor with close sequence similarity to hypoxia-inducible factor 1α regulates the VEGF expression and is potentially involved in lung and vascular development. Proc Natl Acad Sci USA 94:4273–4278

    Article  PubMed  Google Scholar 

  25. Euskirchen G, Royce TE, Bertone P, Martone R, Rinn JL, Nelson FK, Sayward F, Luscombe NM, Miller P, Gerstein M, Weissman S, Snyder M (2004) CREB binds to multiple loci on human chromosome 22. Mol Cell Biol 24:3804–3814

    Article  PubMed  Google Scholar 

  26. Fandrey J, Frede S, Jelkmann W (1994) Role of hydrogen peroxide in hypoxia-induced erythropoietin production. Biochem J 303:507–510

    PubMed  Google Scholar 

  27. Fantozzi I, Zhang S, Platoshyn O, Remillard CV, Cowling RT, Yuan JX (2003) Hypoxia increases AP-1 binding activity by enhancing capacitative Ca2+ entry in human pulmonary artery endothelial cells. Am J Physiol 285:L1233–L1245

    Google Scholar 

  28. Fu XW, Wang D, Nurse CA, Dinauer MC, Cutz E (2000) NADPH oxidase is an O2 sensor in airway chemoreceptors: evidence from K+ current modulation in wild-type and oxidase-deficient mice. Proc Natl Acad Sci USA 97:4374–4379

    Article  PubMed  Google Scholar 

  29. Gnaiger E, Lassnig B, Kuznetsov AV, Margreiter R (1998) Mitochondrial respiration in the low oxygen environment of the cell. Effect of ADP on oxygen kinetics. Biochim Biophys Acta 1365:249–254

    PubMed  Google Scholar 

  30. Grimm SL, Rosen JM (2003) The role of C/EBPbeta in mammary gland development and breast cancer. J Mammary Gland Biol Neoplasia 8:191–204

    Article  PubMed  Google Scholar 

  31. Hagen T, Taylor CT, Lam F, Moncada S (2003) Redistribution of intracellular oxygen in hypoxia by nitric oxide: effect on HIF1α. Science 302:1975–1978

    Article  PubMed  Google Scholar 

  32. Hammond EM, Denko NC, Dorie MJ, Abraham RT, Giaccia AJ (2002) Hypoxia links ATR and p53 through replication arrest. Mol Cell Biol 22:1834–1843

    Article  PubMed  Google Scholar 

  33. Hansson LO, Friedler A, Freund S, Rudiger S, Fersht AR (2002) Two sequence motifs from HIF-1α bind to the DNA-binding site of p53. Proc Natl Acad Sci USA 99:10305–10309

    Article  PubMed  Google Scholar 

  34. Harris AL (2002) Hypoxia—a key regulatory factor in tumour growth. Nat Rev Cancer 2:38–47

    Article  PubMed  Google Scholar 

  35. Hirsila M, Koivunen P, Gunzler V, Kivirikko KI, Myllyharju J (2003) Characterization of the human prolyl 4-hydroxylases that modify the hypoxia-inducible factor. J Biol Chem 278:30772–30780

    Article  PubMed  Google Scholar 

  36. Hoffmann A, Gloe T, Pohl U (2001) Hypoxia-induced upregulation of eNOS gene expression is redox-sensitive: a comparison between hypoxia and inhibitors of cell metabolism. J Cell Physiol 188:33–44

    Article  PubMed  Google Scholar 

  37. Imagawa S, Izumi T, Miura Y (1994) Positive and negative regulation of the erythropoietin gene. J Biol Chem 269:9038–9044

    PubMed  Google Scholar 

  38. Imagawa S, Suzuki N, Ohmine K, Obara N, Mukai HY, Ozawa K, Yamamoto M, Nagasawa T (2002) GATA suppresses erythropoietin gene expression through GATA site in mouse erythropoietin gene promoter. Int J Hematol 75:376–381

    PubMed  Google Scholar 

  39. Jiang B, Kamat A, Mendelson CR (2000) Hypoxia prevents induction of aromatase expression in human trophoblast cells in culture: potential inhibitory role of the hypoxia-inducible transcription factor Mash-2 (mammalian achaete-scute homologous protein-2). Mol Endocrinol 14:1661–1673

    Article  PubMed  Google Scholar 

  40. Jiang B, Mendelson CR (2003) USF1 and USF2 mediate inhibition of human trophoblast differentiation and CYP19 gene expression by Mash-2 and hypoxia. Mol Cell Biol 23:6117–6128

    Article  PubMed  Google Scholar 

  41. Jin N, Hatton N, Swartz DR, Xia X, Harrington MA, Larsen SH, Rhoades RA (2000) Hypoxia activates jun-N-terminal kinase, extracellular signal-regulated protein kinase, and p38 kinase in pulmonary arteries. Am J Respir Cell Mol Biol 23:593–601

    PubMed  Google Scholar 

  42. Jochum W, Passegue E, Wagner EF (2001) AP-1 in mouse development and tumorigenesis. Oncogene 20:2401–2412

    Article  PubMed  Google Scholar 

  43. Joung YH, Park JH, Park T, Lee CS, Kim OH, Ye SK, Yang UM, Lee KJ, Yang YM (2003) Hypoxia activates signal transducers and activators of transcription 5 (STAT5) and increases its binding activity to the GAS element in mammary epithelial cells. Exp Mol Med 35:350–357

    PubMed  Google Scholar 

  44. Kaluz S, Kaluzova M, Stanbridge EJ (2003) Expression of the hypoxia marker carbonic anhydrase IX is critically dependent on SP1 activity Identification of a novel type of hypoxia-responsive enhancer. Cancer Res 63:917–922

    PubMed  Google Scholar 

  45. Kietzmann T, Fandrey J, Acker H (2000) Oxygen radicals as messengers in oxygen-dependent gene expression. News Physiol Sci 15:202–208

    PubMed  Google Scholar 

  46. Killilea DW, Hester R, Balczon R, Babal P, Gillespie MN (2000) Free radical production in hypoxic pulmonary artery smooth muscle cells. Am J Physiol 279:L408–L412

    Google Scholar 

  47. Koong AC, Chen EY, Giaccia AJ (1994) Hypoxia causes the activation of nuclear factor κB through the phosphorylation of I κBα on tyrosine residues. Cancer Res 54:1425–1430

    PubMed  Google Scholar 

  48. Koong AC, Chen EY, Mivechi NF, Denko NC, Stambrook P, Giaccia AJ (1994) Hypoxic activation of nuclear factor-κB is mediated by a Ras and Raf signaling pathway and does not involve MAP kinase (ERK1 or ERK2). Cancer Res 54:5273–5279

    PubMed  Google Scholar 

  49. La Ferla K, Reimann C, Jelkmann W, Hellwig-Burgel T (2002) Inhibition of erythropoietin gene expression signaling involves the transcription factors GATA-2 and NF-kappaB. FASEB J 16:1811–1813

    PubMed  Google Scholar 

  50. Lavrovsky Y, Chatterjee B, Clark RA, Roy AK (2000) Role of redox-regulated transcription factors in inflammation, aging and age-related diseases. Exp Gerontol 35:521–532

    Article  PubMed  Google Scholar 

  51. Lee M, Bikram M, Oh S, Bull DA, Kim SW (2004) Sp1-dependent regulation of the RTP801 promoter and its application to hypoxia-inducible VEGF plasmid for ischemic disease. Pharm Res 21:736–741

    Article  PubMed  Google Scholar 

  52. Lee M, Hwang JT, Lee HJ, Jung SN, Kang I, Chi SG, Kim SS, Ha J (2003) AMP-activated protein kinase activity is critical for hypoxia-inducible factor-1 transcriptional activity and its target gene expression under hypoxic conditions in DU145 cells. J Biol Chem 278:39653–39661

    Article  PubMed  Google Scholar 

  53. Lee M, Song SU, Ryu JK, Suh JK (2004) Sp1-dependent regulation of the tissue inhibitor of metalloproteinases-1 promoter. J Cell Biochem 91:1260–1268

    Article  PubMed  Google Scholar 

  54. Leeper-Woodford SK, Detmer K (1999) Acute hypoxia increases alveolar macrophage tumor necrosis factor activity and alters NF-κB expression. Am J Physiol 276:L909–L916

    PubMed  Google Scholar 

  55. Leonard MO, Cottell DC, Godson C, Brady HR, Taylor CT (2003) The role of HIF-1α in transcriptional regulation of the proximal tubular epithelial cell response to hypoxia. J Biol Chem 278:40296–40304

    Article  PubMed  Google Scholar 

  56. Lo LW, Cheng JJ, Chiu JJ, Wung BS, Liu YC, Wang DL (2001) Endothelial exposure to hypoxia induces Egr-1 expression involving PKCalpha-mediated Ras/Raf-1/ERK1/2 pathway. J Cell Physiol 188:304–312

    Article  PubMed  Google Scholar 

  57. Mahon PC, Hirota K, Semenza GL (2001) FIH-1: a novel protein that interacts with HIF-1α and VHL to mediate repression of HIF-1 transcriptional activity. Genes Dev 15:2675–2686

    Article  PubMed  Google Scholar 

  58. Makino Y, Cao R, Svensson K, Bertilsson G, Asman M, Tanaka H, Cao Y, Berkenstam A, Poellinger L (2001) Inhibitory PAS domain protein is a negative regulator of hypoxia-inducible gene expression. Nature 414:550–554

    Article  PubMed  Google Scholar 

  59. Manalo DJ, Rowan A, Lavoie T, Natarajan L, Kelly BD, Ye SQ, Garcia JG, Semenza GL (2004) Transcriptional regulation of vascular endothelial cell responses to hypoxia by HIF-1. Blood 105: 659–669

    Article  PubMed  Google Scholar 

  60. Matsui H, Ihara Y, Fujio Y, Kunisada K, Akira S, Kishimoto T, Yamauchi-Takihara K (1999) Induction of interleukin (IL)-6 by hypoxia is mediated by nuclear factor (NF)-κB and NF-IL6 in cardiac myocytes. Cardiovasc Res 42:104–112

    Article  PubMed  Google Scholar 

  61. Mayr B, Montminy M (2001) Transcriptional regulation by the phosphorylation-dependent factor CREB. Nat Rev Mol Cell Biol 2:599–609

    Article  PubMed  Google Scholar 

  62. Mechta-Grigoriou F, Gerald D, Yaniv M (2001) The mammalian Jun proteins: redundancy and specificity. Oncogene 20:2378–2389

    Article  PubMed  Google Scholar 

  63. Meyer M, Schreck R, Baeuerle PA (1993) H2O2 and antioxidants have opposite effects on activation of NF-κB and AP-1 in intact cells: AP-1 as secondary antioxidant-responsive factor. EMBO J 12:2005–2015

    PubMed  Google Scholar 

  64. Miki N, Ikuta M, Matsui T (2004) Hypoxia-induced activation of the retinoic acid receptor-related orphan receptor α4 gene by an interaction between hypoxia-inducible factor-1 and Sp1. J Biol Chem 279:15025–15031

    Article  PubMed  Google Scholar 

  65. Millhorn DE, Raymond R, Conforti L, Zhu W, Beitner-Johnson D, Filisko T, Genter MB, Kobayashi S, Peng M (1997) Regulation of gene expression for tyrosine hydroxylase in oxygen sensitive cells by hypoxia. Kidney Int 51:527–535

    PubMed  Google Scholar 

  66. Minet E, Michel G, Mottet D, Piret JP, Barbieux A, Raes M, Michiels C (2001) c-JUN gene induction and AP-1 activity is regulated by a JNK-dependent pathway in hypoxic HepG2 cells. Exp Cell Res 265:114–124

    Article  PubMed  Google Scholar 

  67. Miyazaki K, Kawamoto T, Tanimoto K, Nishiyama M, Honda H, Kato Y (2002) Identification of functional hypoxia response elements in the promoter region of the DEC1 and DEC2 genes. J Biol Chem 277:47014–47021

    Article  PubMed  Google Scholar 

  68. Nishi H, Nishi KH, Johnson AC (2002) Early growth response-1 gene mediates up-regulation of epidermal growth factor receptor expression during hypoxia. Cancer Res 62:827–834

    PubMed  Google Scholar 

  69. Oikawa M, Abe M, Kurosawa H, Hida W, Shirato K, Sato Y (2001) Hypoxia induces transcription factor ETS-1 via the activity of hypoxia-inducible factor-1. Biochem Biophys Res Commun 289:39–43

    Article  PubMed  Google Scholar 

  70. Pan Y, Oprysko PR, Asham AM, Koch CJ, Simon MC (2004) p53 cannot be induced by hypoxia alone but responds to the hypoxic microenvironment. Oncogene 23:4975–4983

    Article  PubMed  Google Scholar 

  71. Premkumar DR, Adhikary G, Overholt JL, Simonson MS, Cherniack NS, Prabhakar NR (2000) Intracellular pathways linking hypoxia to activation of c-fos and AP-1. Adv Exp Med Biol 475:101–109

    PubMed  Google Scholar 

  72. Ravi R, Mookerjee B, Bhujwalla ZM, Sutter CH, Artemov D, Zeng Q, Dillehay LE, Madan A, Semenza GL, Bedi A (2000) Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1α. Genes Dev 14:34–44

    PubMed  Google Scholar 

  73. Rolfe DF, Brown GC (1997) Cellular energy utilization and molecular origin of standard metabolic rate in mammals. Physiol Rev 77:731–758

    PubMed  Google Scholar 

  74. Salnikow K, Kluz T, Costa M, Piquemal D, Demidenko ZN, Xie K, Blagosklonny MV (2002) The regulation of hypoxic genes by calcium involves c-Jun/AP-1, which cooperates with hypoxia-inducible factor 1 in response to hypoxia. Mol Cell Biol 22:1734–1741

    Article  PubMed  Google Scholar 

  75. Samson SL, Wong NC (2002) Role of Sp1 in insulin regulation of gene expression. J Mol Endocrinol 29:265–279

    Article  PubMed  Google Scholar 

  76. Sanchez-Elsner T, Botella LM, Velasco B, Corbi A, Attisano L, Bernabeu C (2001) Synergistic cooperation between hypoxia and transforming growth factor-β pathways on human vascular endothelial growth factor gene expression. J Biol Chem 276:38527–38535

    Article  PubMed  Google Scholar 

  77. Sanchez-Elsner T, Ramirez JR, Sanz-Rodriguez F, Varela E, Bernabeu C, Botella LM (2004) A cross-talk between hypoxia and TGF-β orchestrates erythropoietin gene regulation through SP1 and Smads. J Mol Biol 336:9–24

    Article  PubMed  Google Scholar 

  78. Schmedtje JF Jr, Ji YS, Liu WL, DuBois RN, Runge MS (1997) Hypoxia induces cyclooxygenase-2 via the NF-κB p65 transcription factor in human vascular endothelial cells. J Biol Chem 272:601–608

    Article  PubMed  Google Scholar 

  79. Schmid T, Zhou J, Kohl R, Brune B (2004) p300 relieves p53-evoked transcriptional repression of hypoxia-inducible factor-1 (HIF-1). Biochem J 380:289–295

    Article  PubMed  Google Scholar 

  80. Schofield CJ, Ratcliffe PJ (2004) Oxygen sensing by HIF hydroxylases. Nat Rev Mol Cell Biol 5:343–354

    Article  PubMed  Google Scholar 

  81. Semenza GL (2000) Oxygen-regulated transcription factors and their role in pulmonary disease. Respir Res 1:159–162

    Article  PubMed  Google Scholar 

  82. Semenza GL (2004) Hydroxylation of HIF-1: oxygen sensing at the molecular level. Physiology 19:176–182

    Article  PubMed  Google Scholar 

  83. Shaulian E, Karin M (2001) AP-1 in cell proliferation and survival. Oncogene 20:2390–2400

    Article  PubMed  Google Scholar 

  84. Shi Q, Le X, Abbruzzese JL, Wang B, Mujaida N, Matsushima K, Huang S, Xiong Q, Xie K (1999) Cooperation between transcription factor AP-1 and NF-κB in the induction of interleukin-8 in human pancreatic adenocarcinoma cells by hypoxia. J Interferon Cytokine Res 19:1363–1371

    Article  PubMed  Google Scholar 

  85. Shie JL, Wu G, Wu J, Liu FF, Laham RJ, Oettgen P, Li J (2004) RTEF-1, a novel transcriptional stimulator of vascular endothelial growth factor in hypoxic endothelial cells. J Biol Chem 279:25010–25016

    Article  PubMed  Google Scholar 

  86. Slee EA, O‘Connor DJ, Lu X (2004) To die or not to die: how does p53 decide? Oncogene 23:2809–2818

    Article  PubMed  Google Scholar 

  87. Suzuki H, Tomida A, Tsuruo T (2001) Dephosphorylated hypoxia-inducible factor 1α as a mediator of p53-dependent apoptosis during hypoxia. Oncogene 20:5779–5788

    Article  PubMed  Google Scholar 

  88. Takiguchi M (1998) The C/EBP family of transcription factors in the liver and other organs. Int J Exp Pathol 79:369–391

    Article  PubMed  Google Scholar 

  89. Taylor CT, Dzus AL, Colgan SP (1998) Autocrine regulation of epithelial permeability by hypoxia: role for polarized release of tumor necrosis factor alpha. Gastroenterology 114:657–668

    PubMed  Google Scholar 

  90. Taylor CT, Furuta GT, Synnestvedt K, Colgan SP (2000) Phosphorylation-dependent targeting of cAMP response element binding protein to the ubiquitin/proteasome pathway in hypoxia. Proc Natl Acad Sci USA 97:12091–12096

    Article  PubMed  Google Scholar 

  91. Thiel G, Cibelli G (2002) Regulation of life and death by the zinc finger transcription factor Egr-1. J Cell Physiol 193:287–292

    Article  PubMed  Google Scholar 

  92. Tian H, McKnight SL, Russell DW (1997) Endothelial PAS domain protein 1 (EPAS1), a transcription factor selectively expressed in endothelial cells. Genes Dev 11:72–82

    PubMed  Google Scholar 

  93. Vaux EC, Metzen E, Yeates KM, Ratcliffe PJ (2001) Regulation of hypoxia-inducible factor is preserved in the absence of a functioning mitochondrial respiratory chain. Blood 98:296–302

    Article  PubMed  Google Scholar 

  94. Wang GL, Jiang BH, Rue EA, Semenza GL (1995) Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci USA 92:5510–5514

    PubMed  Google Scholar 

  95. Wenger RH, Camenisch G, Desbaillets I, Chilov D, Gassmann M (1998) Up-regulation of hypoxia-inducible factor-1α is not sufficient for hypoxic/anoxic p53 induction. Cancer Res 58:5678–5680

    PubMed  Google Scholar 

  96. Xu Q, Ji YS, Schmedtje JF Jr (2000) Sp1 increases expression of cyclooxygenase-2 in hypoxic vascular endothelium Implications for the mechanisms of aortic aneurysm and heart failure. J Biol Chem 275:24583–24589

    Article  PubMed  Google Scholar 

  97. Yamashita K, Discher DJ, Hu J, Bishopric NH, Webster KA (2001) Molecular regulation of the endothelin-1 gene by hypoxia Contributions of hypoxia-inducible factor-1, activator protein-1, GATA-2, AND p300/CBP. J Biol Chem 276:12645–12653

    Article  PubMed  Google Scholar 

  98. Yan SF, Lu J, Xu L, Zou YS, Tongers J, Kisiel W, Mackman N, Pinsky DJ, Stern DM (2000) Pulmonary expression of early growth response-1: biphasic time course and effect of oxygen concentration. J Appl Physiol 88:2303–2309

    PubMed  Google Scholar 

  99. Yan SF, Lu J, Zou YS, Kisiel W, Mackman N, Leitges M, Steinberg S, Pinsky D, Stern D (2000) Protein kinase C-β and oxygen deprivation A novel Egr-1-dependent pathway for fibrin deposition in hypoxemic vasculature. J Biol Chem 275:11921–11928

    Article  PubMed  Google Scholar 

  100. Yan SF, Lu J, Zou YS, Soh-Won J, Cohen DM, Buttrick PM, Cooper DR, Steinberg SF, Mackman N, Pinsky DJ, Stern DM (1999) Hypoxia-associated induction of early growth response-1 gene expression. J Biol Chem 274:15030–15040

    Article  PubMed  Google Scholar 

  101. Yan SF, Mackman N, Kisiel W, Stern DM, Pinsky DJ (1999) Hypoxia/hypoxemia-Induced activation of the procoagulant pathways and the pathogenesis of ischemia-associated thrombosis. Arterioscler Thromb Vasc Biol 19:2029–2035

    PubMed  Google Scholar 

  102. Yan SF, Tritto I, Pinsky D, Liao H, Huang J, Fuller G, Brett J, May L, Stern D (1995) Induction of interleukin 6 (IL-6) by hypoxia in vascular cells. Central role of the binding site for nuclear factor-IL-6. J Biol Chem 270:11463–11471

    Article  PubMed  Google Scholar 

  103. Yan SF, Zou YS, Gao Y, Zhai C, Mackman N, Lee SL, Milbrandt J, Pinsky D, Kisiel W, Stern D (1998) Tissue factor transcription driven by Egr-1 is a critical mechanism of murine pulmonary fibrin deposition in hypoxia. Proc Natl Acad Sci USA 95:8298–8303

    Article  PubMed  Google Scholar 

  104. Yang Y, Li CC, Weissman AM (2004) Regulating the p53 system through ubiquitination. Oncogene 23:2096–2106

    Article  PubMed  Google Scholar 

  105. Zampetaki A, Mitsialis SA, Pfeilschifter J, Kourembanas S (2004) Hypoxia induces macrophage inflammatory protein-2 (MIP-2) gene expression in murine macrophages via NF-κB: the prominent role of p42/p44 and PI3 kinase pathways. FASEB J 18:1090–1092

    PubMed  Google Scholar 

  106. Zhang H, Akman HO, Smith EL, Zhao J, Murphy-Ullrich JE, Batuman OA (2003) Cellular response to hypoxia involves signaling via Smad proteins. Blood 101:2253–2260

    Article  PubMed  Google Scholar 

  107. Zhang L, Hill RP (2004) Hypoxia enhances metastatic efficiency by up-regulating Mdm2 in KHT cells and increasing resistance to apoptosis. Cancer Res 64:4180–4189

    PubMed  Google Scholar 

Download references

Acknowledgements

The authors are funded by research grants from the Science Foundation Ireland (CTT), The Wellcome Trust (CTT) and the Health Research Board of Ireland (EPC).

Author information

Authors and Affiliations

  1. Department of Medicine and Therapeutics, The Conway Institute for Biomolecular and Biomedical Research and the Dublin Molecular Medicine Centre, University College Dublin, Belfield, Dublin, 4, Ireland

    Eoin P. Cummins & Cormac T. Taylor

Authors
  1. Eoin P. Cummins
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Cormac T. Taylor
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Cormac T. Taylor.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cummins, E.P., Taylor, C.T. Hypoxia-responsive transcription factors. Pflugers Arch - Eur J Physiol 450, 363–371 (2005). https://doi.org/10.1007/s00424-005-1413-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00424-005-1413-7

Keywords

Search

Navigation