Preferences help
enabled [disable] Abstract
Number of results
2004 | 51 | 3 | 563-585
Article title

HIF-1: the knowns and unknowns of hypoxia sensing.

Title variants
Languages of publication
Hypoxia-inducible factor-1 (HIF-1) is a transcriptional activator that functions as a master regulator of cellular and systemic oxygen homeostasis. It consists of two constitutively produced subunits: HIF-1α and HIF-1β. Under normoxic conditions HIF-1α undergoes hydroxylation at specific prolyl residues which leads to an immediate ubiquitination and subsequent proteasomal degradation of the α subunit. Additionally, hydroxylation of an asparaginyl residue blocks the transcriptional activity of HIF-1 due to inhibition of its interaction with co-activators. In contrast, under hypoxic conditions, abolition of prolyl hydroxylation results in HIF-1α stabilization, whereas the lack of asparaginyl hydroxylation allows the transcriptional activity. Additionally, the transcriptional activity may be modulated by phosphorylation or redox modification of HIF-1. Despite its name, HIF-1 is induced not only in response to reduced oxygen availability but also by other stimulants, such as nitric oxide, various growth factors, or direct inhibitors of prolyl and asparaginyl hydroxylases. Therefore, it seems to be a crucial transcription factor elicited by a wide range of stresses such as impaired oxygenation, inflammation, energy deprivation, or intensive proliferation. However, the mechanisms of normoxic activation, as well as of oxygen sensing, are not yet fully known. Further understanding of the processes that control HIF-1 activity will be crucial for the development of new diagnostic and therapeutic strategies.
Physical description
  • Department of Cell Biochemistry, Faculty of Biotechnology, Jagiellonian University, Kraków, Poland
  • Department of Cell Biochemistry, Faculty of Biotechnology, Jagiellonian University, Kraków, Poland
  • Agani FH, Pichiule P, Chavez JC, LaManna JC. (2000) The role of mitochondria in the regulation of hypoxia-inducible factor 1 expression during hypoxia. J Biol Chem.; 275: 35863-7.
  • Archer SL, Reeve HL, Michelakis E, Puttagunta L, Waite R, Nelson DP, Dinauer MC, Weir EK. (1999) O2 sensing is preserved in mice lacking the gp91 phox subunit of NADPH oxidase. Proc Natl Acad Sci USA.; 96: 7944-9.
  • Bhattacharya S, Michels CL, Leung MK, Arany ZP, Kung AL, Livingston DM. (1999) Functional role of p35srj, a novel p300/CBP binding protein, during transactivation by HIF-1. Genes Dev.; 13: 64-75.
  • Bonicalzi ME, Groulx I, de Paulsen N, Lee S. (2001) Role of exon 2-encoded beta-domain of the von Hippel-Lindau tumor suppressor protein. (2001) J Biol Chem.; 276: 1407-16.
  • Bruick RK. (2000) Expression of the gene encoding the proapoptotic Nip3 protein is induced by hypoxia. Proc Natl Acad Sci USA.; 97: 9082-7.
  • Brüick RK, McKnight SL. (2001) A conserved family of prolyl-4-hydroxylases that modify HIF. Science.; 294: 1337-40.
  • Bruick RK, McKnight SL. (2002) Transcription. Oxygen sensing gets a second wind. Science.; 295: 807-8.
  • Brune B, von Knethen A, Sandau KB. (2001) Transcription factors p53 and HIF-1alpha as targets of nitric oxide. Cell Signal.; 13: 525-33.
  • Caniggia I, Mostachfi H, Winter J, Gassmann M, Lye SJ, Kuliszewski M, Post M. (2000) Hypoxia-inducible factor-1 mediates the biological effects of oxygen on human trophoblast differentiation through TGFbeta(3). J Clin Invest.; 105: 577-87.
  • 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, Keshet E. (1998) Role of HIF-1alpha in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. Nature.; 394: 485-90. Erratum in: Nature.; 395: 525.
  • 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: 11715-20.
  • Chun YS, Kim MS, Park JW. (2002) Oxygen-dependent and -independent regulation of HIF-1alpha. J Korean Med Sci.; 17: 581-8.
  • Cormier-Regard S, Nguyen SV, Claycomb WC. (1998) Adrenomedullin gene expression is developmentally regulated and induced by hypoxia in rat ventricular cardiac myocytes. J Biol Chem.; 273: 17787-92.
  • D'Angelo G, Duplan E, Boyer N, Vigne P, Frelin C. (2003) Hypoxia upregulates prolyl hydroxylase activity: a feedback mechanism that limits HIF-1 responses during reoxygenation. J Biol Chem.; 278: 38183-7.
  • Dioum EM, Rutter J, Tuckerman JR, Gonzalez G, Gilles-Gonzalez MA, McKnight SL. (2002) NPAS2: a gas-responsive transcription factor. Science.; 298: 2385-7.
  • Dulak J, Jozkowicz A. (2003a) Carbon monoxide - a new gaseous modulator of gene expression. Acta Biochim Polon.; 50: 31-47.
  • Dulak J, Jozkowicz A. (2003b) Regulation of vascular endothelial growth factor synthesis by nitric oxide: facts and controversies. Antioxid Redox Signal.; 5: 123-32.
  • Dulak J, Łoboda A, Zagórska A, Józkowicz A. (2004) Compex role of heme oxygenase-1 in angiogenesis. Antioxid Redox Signal.; 6: 858-66.
  • Dulak J, Józkowicz A, Dembinska-Kiec A, Guevara I, Zdzienicka A, Zmudzinska-Grochot D, Florek I, Wójtowicz A, Szuba A, Cooke JP. (2000) Nitric oxide induces the synthesis of vascular endothelial growth factor by rat vascular smooth muscle cells. Arterioscler Thromb Vasc Biol.; 20: 659-66.
  • Dulak J, Jozkowicz A, Foresti R, Kasza A, Frick M, Huk I, Green CJ, Pachinger O, Weidinger F, Motterlini R. (2002) Heme oxygenase activity modulates vascular endothelial growth factor synthesis in vascular smooth muscle cells. Antioxid Redox Signal.; 4: 229-40.
  • Eckhart AD, Yang N, Xin X, Faber JE. (1997) Characterization of the alpha1B-adrenergic receptor gene promoter region and hypoxia regulatory elements in vascular smooth muscle. Proc Natl Acad Sci USA.; 94: 9487-92.
  • Ema M, Hirota K, Mimura J, Abe H, Yodoi J, Sogawa K, Poellinger L, Fujii-Kuriyama Y. (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: 1905-14.
  • Epstein AC, Gleadle JM, McNeill LA, Hewitson KS, O'Rourke J, Mole DR, Mukherji M, Metzen E, Wilson MI, Dhanda A, Tian YM, Masson N, Hamilton DL, Jaakkola P, Barstead R, Hodgkin J, Maxwell PH, Pugh CW, Schofield CJ, Ratcliffe PJ. (2001) C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell.; 107: 43-54.
  • Feldser D, Agani F, Iyer NV, Pak B, Ferreira G, Semenza GL. (1999) Reciprocal positive regulation of hypoxia-inducible factor 1alpha and insulin-like growth factor 2. Cancer Res.; 59: 3915-8.
  • Firth JD, Ebert BL, Pugh CW, Ratcliffe PJ. (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: 6496-500.
  • Forsythe JA, Jiang BH, Iyer NV, Agani F, Leung SW, Koos RD, Semenza GL. (1996) Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol.; 16: 4604-13.
  • Gerber H-P, Condorelli F, Park J, Ferrara N. (1997) Differential transcriptional regulation of the two vascular endothelial growth factor receptor genes: Flt-1, but not Flk-1/KDR, is upregulated by hypoxia. J Biol Chem.; 272: 23659-67.
  • Giaccia AJ, Kastan MB. (1998) The complexity of p53 modulation: emerging patterns from divergent signals. Genes Dev.; 12: 2973-83.
  • Gleadle JM, Ebert BL, Ratcliffe PJ. (1995) Diphenylene iodonium inhibits the induction of erythropoietin and other mammalian genes by hypoxia. Implications for the mechanism of oxygen sensing. Eur J Biochem.; 234: 92-9.
  • Gleadle JM, Ratcliffe PJ. (1997) Induction of hypoxia-inducible factor-1, erythropoietin, vascular endothelial growth factor, and glucose transporter-1 by hypoxia: evidence against a regulatory role for Src kinase. Blood.; 89: 503-9.
  • Gorlach A, Diebold I, Schini-Kerth VB, Berchner-Pfannschmidt U, Roth U, Brandes RP, Kietzmann T, Busse R. (2001) Thrombin activates the hypoxia-inducible factor-1 signaling pathway in vascular smooth muscle cells: Role of the p22(phox)-containing NADPH oxidase. Circ Res.; 89: 47-54.
  • Gothie E, Richard DE, Berra E, Pages G, Pouyssegur J. (2000) Identification of alternative spliced variants of human hypoxia-inducible factor-1alpha. J Biol Chem.; 275: 6922-7.
  • Grzenkowicz-Wydra J, Cisowski J, Nakonieczna J, Zarębski A, Udilova N, Nohl H, Józkowicz A, Podhajska A, Dulak J. (2004) Gene transfer of CuZn superoxide dismutase enhances the synthesis of vascular endothelial growth factor. Mol Cell Biochem.; in press.
  • Gu J, Milligan J, Huang LE. (2001) Molecular mechanism of hypoxia-inducible factor 1alpha-p300 interaction. A leucine-rich interface regulated by a single cysteine. J Biol Chem.; 276: 3550-4.
  • Hofer T, Desbaillets I, Hopfl G, Gassmann M, Wenger RH. (2001) Dissecting hypoxia-dependent and hypoxia-independent steps in the HIF-1alpha activation cascade: implications for HIF-1alpha gene therapy. FASEB J.; 15: 2715-7.
  • Hu J, Discher DJ, Bishopric NH, Webster KA. (1998) Hypoxia regulates expression of the endothelin-1 gene through a proximal hypoxia-inducible factor-1 binding site on the antisense strand. Biochem Biophys Res Commun.; 245: 894-9.
  • Huang LE, Ho V, Arany Z, Krainc D, Galson D, Tendler D, Livingston DM, Bunn HF. (1997) Erythropoietin gene regulation depends on heme-dependent oxygen sensing and assembly of interacting transcription factors. Kidney Int.; 51: 548-52.
  • Huang LE, Gu J, Schau M, Bunn HF. (1998) Regulation of hypoxia-inducible factor 1alpha is mediated by an O2-dependent degradation domain via the ubiquitin-proteasome pathway. Proc Natl Acad Sci USA.; 95: 7987-92.
  • Huang LE, Willmore WG, Gu J, Goldberg MA, Bunn HF. (1999) Inhibition of hypoxia-inducible factor 1 activation by carbon monoxide and nitric oxide. Implications for oxygen sensing and signaling. J Biol Chem.; 274: 9038-44.
  • Ivan M, Kondo K, Yang H, Kim W, Valiando J, Ohh M, Salic A, Asara JM, Lane WS, Kaelin WG Jr. (2001) HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science.; 292: 464-8.
  • Iyer NV, Kotch LE, Agani F, Leung SW, Laughner E, Wenger RH, Gassmann M, Gearhart JD, Lawler AM, Yu AY, Semenza GL. (1998) Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1 alpha. Genes Dev.; 12: 149-62.
  • Jaakkola P, Mole DR, Tian YM, Wilson MI, Gielbert J, Gaskell SJ, Kriegsheim Av, Hebestreit HF, Mukherji M, Schofield CJ, Maxwell PH, Pugh CW, Ratcliffe PJ. (2001) Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science.; 292: 468-72.
  • Jiang BH, Rue E, Wang GL, Roe R, Semenza GL. (1996a) Dimerization, DNA binding, and transactivation properties of hypoxia-inducible factor 1. J Biol Chem.; 271: 17771-8.
  • Jiang BH, Semenza GL, Bauer C, Marti HH. (1996b) Hypoxia-inducible factor 1 levels vary exponentially over a physiologically relevant range of O2 tension. Am J Physiol.; 271: C1172-80.
  • Jozkowicz A, Cooke JP, Guevara I, Huk I, Funovics P, Pachinger O, Weidinger F, Dulak J. (2001) Genetic augmentation of nitric oxide synthase increases the vascular generation of VEGF. Cardiovasc Res.; 51: 773-83.
  • Jozkowicz A, Huk I, Nigisch A, Weigel G, Dietrich W, Motterlini R, Dulak J. (2003) Heme oxygenase and angiogenic activity of endothelial cells: stimulation by carbon monoxide and inhibition by tin protoporphyrin-IX. Antioxid Redox Signal.; 5: 155-62.
  • Jozkowicz A, Nigisch A, Węgrzyn J, Weigel G, Huk I, Dulak J. (2004) Opposite effects of prostaglandin-J(2) on VEGF in normoxia and hypoxia: role of HIF-1. Biochem Biophys Res Commun.; 314: 31-38.
  • Kallio PJ, Pongratz I, Gradin K, McGuire J, Poellinger L. (1997) Activation of hypoxia-inducible factor 1alpha: posttranscriptional regulation and conformational change by recruitment of the Arnt transcription factor. Proc Natl Acad Sci USA.; 94: 5667-72.
  • Kallio PJ, Okamoto K, O'Brien S, Carrero P, Makino Y, Tanaka H, Poellinger L. (1998) Signal transduction in hypoxic cells: inducible nuclear translocation and recruitment of the CBP/p300 coactivator by the hypoxia-inducible factor-1alpha. EMBO J.; 17: 6573-86.
  • Kallio PJ, Wilson WJ, O'Brien S, Makino Y, Poellinger L. (1999) Regulation of the hypoxia-inducible transcription factor 1alpha by the ubiquitin-proteasome pathway. J Biol Chem.; 274: 6519-25.
  • Kasuno K, Takabuchi S, Fukuda K, Kizaka-Kondoh S, Yodoi J, Adachi T, Semenza GL, Hirota K. (2004) Nitric oxide induces hypoxia-inducible factor 1 activation that is dependent on MAPK and phosphatidylinositol 3-kinase signaling. J Biol Chem.; 279: 2550-8.
  • Katschinski DM, Le L, Heinrich D, Wagner KF, Hofer T, Schindler SG, Wenger RH. (2002) Heat induction of the unphosphorylated form of hypoxia-inducible factor-1alpha is dependent on heat shock protein-90 activity. J Biol Chem.; 277: 9262-7.
  • Kietzmann T, Roth U, Jungermann K. (1999) Induction of the plasminogen activator inhibitor-1 gene expression by mild hypoxia via a hypoxia response element binding the hypoxia-inducible factor-1 in rat hepatocytes. Blood.; 94: 4177-85.
  • Kim CH, Cho YS, Chun YS, Park JW, Kim MS. (2002) Early expression of myocardial HIF-1alpha in response to mechanical stresses: regulation by stretch-activated channels and the phosphatidylinositol 3-kinase signaling pathway. Circ Res.; 90: E25-33.
  • Kimura H, Weisz A, Kurashima Y, Hashimoto K, Ogura T, D'Acquisto F, Addeo R, Makuuchi M, Esumi H. (2000) Hypoxia response element of the human vascular endothelial growth factor gene mediates transcriptional regulation by nitric oxide: control of hypoxia-inducible factor-1 activity by nitric oxide. Blood.; 95: 189-97.
  • Kimura H, Weisz A, Ogura T, Hitomi Y, Kurashima Y, Hashimoto K, D'Acquisto F, Makuuchi M, Esumi H. (2001) Identification of hypoxia-inducible factor 1 ancillary sequence and its function in vascular endothelial growth factor gene induction by hypoxia and nitric oxide. J Biol Chem.; 276: 2292-8.
  • Kuwahara F, Kai H, Tokuda K, Shibata R, Kusaba K, Tahara N, Niiyama H, Nagata T, Imaizumi T. (2002) Hypoxia-inducible factor-1alpha/vascular endothelial growth factor pathway for adventitial vasa vasorum formation in hypertensive rat aorta. Hypertension.; 39: 46-50.
  • Lando D, Peet DJ, Whelan DA, Gorman JJ, Whitelaw ML. (2002a) Asparagine hydroxylation of the HIF transactivation domain a hypoxic switch. Science.; 295: 858-61.
  • Lando D, Peet DJ, Gorman JJ, Whelan DA, Whitelaw ML, Bruick RK. (2002b) FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor. Genes Dev.; 16: 1466-71.
  • Lee PJ, Jiang BH, Chin BY, Iyer NV, Alam J, Semenza GL, Choi AM. (1997) Hypoxia-inducible factor-1 mediates transcriptional activation of the heme oxygenase-1 gene in response to hypoxia. J Biol Chem.; 272: 5375-81.
  • Leung MK, Jones T, Michels CL, Livingston DM, Bhattacharya S. (1999) Molecular cloning and chromosomal localization of the human CITED2 gene encoding p35srj/Mrg1. Genomics.; 61: 307-13.
  • Liu Y, Christou H, Morita T, Laughner E, Semenza GL, Kourembanas S. (1998) Carbon monoxide and nitric oxide suppress the hypoxic induction of vascular endothelial growth factor gene via the 5' enhancer. J Biol Chem.; 273: 15257-62.
  • Lok CN, Ponka P. (1999) Identification of a hypoxia response element in the transferrin receptor gene. J Biol Chem.; 274: 24147-52.
  • Lu S, Gu X, Hoestje S, Epner DE. (2002) Identification of an additional hypoxia responsive element in the glyceraldehyde-3-phosphate dehydrogenase gene promoter. Biochim Biophys Acta.; 1574: 152-6.
  • 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: 550-4.
  • Maxwell PH, Wiesener MS, Chang GW, Clifford SC, Vaux EC, Cockman ME, Wykoff CC, Pugh CW, Maher ER, Ratcliffe PJ. (1999) The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature.; 399: 271-5.
  • Melillo G, Musso T, Sica A, Taylor LS, Cox GW, Varesio L. (1995) A hypoxia-responsive element mediates a novel pathway of activation of the inducible nitric oxide synthase promoter. J Exp Med.; 182: 1683-93.
  • Metzen E, Berchner-Pfannschmidt U, Stengel P, Marxsen JH, Stolze I, Klinger M, Huang WQ, Wotzlaw C, Hellwig-Burgel T, Jelkmann W, Acker H, Fandrey J. (2003a) Intracellular localisation of human HIF-1 alpha hydroxylases: implications for oxygen sensing. J Cell Sci.; 116: 1319-26.
  • Metzen E, Zhou J, Jelkmann W, Fandrey J, Brune B. (2003b) Nitric oxide impairs normoxic degradation of HIF-1alpha by inhibition of prolyl hydroxylases. Mol Biol Cell.; 14: 3470-81.
  • Michiels C, Minet E, Mottet D, Raes M. (2002) Regulation of gene expression by oxygen: NF-kappaB and HIF-1, two extremes. Free Radic Biol Med.; 33: 1231-42.
  • Mukhopadhyay CK, Mazumder B, Fox PL. (2000) Role of hypoxia-inducible factor-1 in transcriptional activation of ceruloplasmin by iron deficiency. J Biol Chem.; 275: 21048-54.
  • Natarajan R, Fisher BJ, Fowler AA 3rd. (2003) Regulation of hypoxia inducible factor-1 by nitric oxide in contrast to hypoxia in microvascular endothelium. FEBS Lett.; 549: 99-104.
  • Norris ML, Millhorn DE. (1995) Hypoxia-induced protein binding to O2-responsive sequences on the tyrosine hydroxylase gene. J Biol Chem.; 270: 23774-9.
  • O'Rourke JF, Pugh CW, Bartlett SM, Ratcliffe PJ. (1996) Identification of hypoxically inducible mRNAs in HeLa cells using differential-display PCR. Role of hypoxia-inducible factor-1. Eur J Biochem.; 241: 403-10.
  • Oehme F, Ellinghaus P, Kolkhof P, Smith TJ, Ramakrishnan S, Hutter J, Schramm M, Flamme I. (2002) Overexpression of PH-4, a novel putative proline 4-hydroxylase, modulates activity of hypoxia-inducible transcription factors. Biochem Biophys Res Commun.; 296: 343-9.
  • Page EL, Robitaille GA, Pouyssegur J, Richard DE. (2002) Induction of hypoxia-inducible factor-1alpha by transcriptional and translational mechanisms. J Biol Chem.; 277: 48403-9.
  • Palmer LA, Semenza GL, Stoler MH, Johns RA. (1998) Hypoxia induces type II NOS gene expression in pulmonary artery endothelial cells via HIF-1. Am J Physiol Lung Cell Mol Physiol.; 274: L212-9.
  • Pugh CW, O'Rourke JF, Nagao M, Gleadle JM, Ratcliffe PJ. (1997) Activation of hypoxia-inducible factor-1; definition of regulatory domains within the alpha subunit. J Biol Chem.; 272: 11205-14.
  • 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 1alpha. Genes Dev.; 14: 34-44.
  • Rechsteiner M, Rogers SW. (1996) PEST sequences and regulation by proteolysis. Trends Biochem Sci.; 21: 267-71.
  • Richard DE, Berra E, Gothie E, Roux D, Pouyssegur J. (1999) p42/p44 mitogen-activated protein kinases phosphorylate hypoxia-inducible factor 1alpha (HIF-1alpha) and enhance the transcriptional activity of HIF-1. J Biol Chem.; 274: 32631-7.
  • Richard DE, Berra E, Pouyssegur J. (2000) Nonhypoxic pathway mediates the induction of hypoxia-inducible factor 1alpha in vascular smooth muscle cells. J Biol Chem.; 275: 26765-71.
  • Rolfs A, Kvietikova I, Gassmann M, Wenger RH. (1997) Oxygen-regulated transferrin expression is mediated by hypoxia-inducible factor-1. J Biol Chem.; 272: 20055-62.
  • Rutter J, Reick M, Wu LC, McKnight SL. (2001) Regulation of clock and NPAS2 DNA binding by the redox state of NAD cofactors. Science.; 293: 510-4.
  • Salceda S, Caro J. (1997) Hypoxia-inducible factor 1alpha (HIF-1alpha) protein is rapidly degraded by the ubiquitin-proteasome system under normoxic conditions. Its stabilization by hypoxia depends on redox-induced changes. J Biol Chem.; 272: 22642-7.
  • Sandau KB, Fandrey J, Brune B. (2001a) Accumulation of HIF-1alpha under the influence of nitric oxide. Blood.; 97: 1009-15.
  • Sandau KB, Zhou J, Kietzmann T, Brune B. (2001b) Regulation of the hypoxia-inducible factor 1alpha by the inflammatory mediators nitric oxide and tumor necrosis factor-alpha in contrast to desferroxamine and phenylarsine oxide. J Biol Chem.; 276: 39805-11.
  • Schmid T, Callapina M, Zhou J, Brune B. (2003) p53 and HIF-1: transcription factors communicating at multiple levels. Oxygen and the Cell, Abstract Book, Berlin, poster No. 17.
  • Schroedl C, McClintock DS, Budinger GR, Chandel NS. (2002) Hypoxic but not anoxic stabilization of HIF-1alpha requires mitochondrial reactive oxygen species. Am J Physiol Lung Cell Mol Physiol.; 283: L922-31.
  • Semenza GL. (2000a) HIF-1 and human disease: one highly involved factor. Genes Dev.; 14: 1983-91.
  • Semenza GL. (2000b) HIF-1: mediator of physiological and pathophysiological responses to hypoxia. J Appl Physiol.; 88: 1474-80.
  • Semenza GL. (2000c) Expression of hypoxia-inducible factor 1: mechanisms and consequences. Biochem Pharmacol.; 59: 47-53.
  • Semenza GL. (2001) HIF-1, O(2), and the 3 PHDs: how animal cells signal hypoxia to the nucleus. Cell.; 107: 1-3.
  • Semenza GL, Roth PH, Fang HM, Wang GL. (1994) Transcriptional regulation of genes encoding glycolytic enzymes by hypoxia-inducible factor 1. J Biol Chem.; 269: 23757-63.
  • Semenza GL, Jiang BH, Leung SW, Passantino R, Concordet JP, Maire P, Giallongo A. (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: 32529-37.
  • Sogawa K, Numayama-Tsuruta K, Ema M, Abe M, Abe H, Fujii-Kuriyama Y. (1998) Inhibition of hypoxia-inducible factor 1 activity by nitric oxide donors in hypoxia. Proc Natl Acad Sci USA.; 95: 7368-73.
  • Sowter HM, Ratcliffe PJ, Watson P, Greenberg AH, Harris AL. (2001) HIF-1-dependent regulation of hypoxic induction of the cell death factors BNIP3 and NIX in human tumors. Cancer Res.; 61: 6669-73.
  • Tacchini L, Bianchi L, Bernelli-Zazzera A, Cairo G. (1999) Transferrin receptor induction by hypoxia: HIF-1-mediated transcriptional activation and cell-specific posttranscriptional regulation. J Biol Chem.; 274: 24142-6.
  • Takahashi Y, Takahashi S, Shiga Y, Yoshimi T, Miura T. (2000) Hypoxic induction of prolyl 4-hydroxylase alpha (I) in cultured cells. J Biol Chem.; 275: 14139-46.
  • 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.
  • Wang GL, Semenza GL. (1993) Desferrioxamine induces erythropoietin gene expression and hypoxia-inducible factor 1 DNA-binding activity: implications for models of hypoxia signal transduction. Blood.; 82: 3610-5.
  • Wang GL, Jiang BH, Rue EA, Semenza GL. (1995a) Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci USA.; 92: 5510-4.
  • Wang GL, Jiang BH, Semenza GL. (1995b) Effect of protein kinase and phosphatase inhibitors on expression of hypoxia-inducible factor 1. Biochem Biophys Res Commun.; 216: 669-75.
  • Wang F, Sekine H, Kikuchi Y, Takasaki C, Miura C, Heiwa O, Shuin T, Fujii-Kuriyama Y, Sogawa K. (2002) HIF-1alpha-prolyl hydroxylase: molecular target of nitric oxide in the hypoxic signal transduction pathway. Biochem Biophys Res Commun.; 295: 657-62.
  • Wenger RH, Kvietikova I, Rolfs A, Camenisch G, Gassmann M. (1998) Oxygen-regulated erythropoietin gene expression is dependent on a CpG methylation-free hypoxia-inducible factor-1 DNA-binding site. Eur J Biochem.; 253: 771-7.
  • Wenger RH. (2002) Cellular adaptation to hypoxia: O2-sensing protein hydroxylases, hypoxia-inducible transcription factors, and O2-regulated gene expression. FASEB J.; 16: 1151-62.
  • Wiener CM, Booth G, Semenza GL. (1996) In vivo expression of mRNAs encoding hypoxia-inducible factor 1. Biochem Biophys Res Commun.; 225: 485-8.
  • Wykoff CC, Beasley NJ, Watson PH, Turner KJ, Pastorek J, Sibtain A, Wilson GD, Turley H, Talks KL, Maxwell PH, Pugh CW, Ratcliffe PJ, Harris AL. (2000) Hypoxia-inducible expression of tumor-associated carbonic anhydrases. Cancer Res.; 60: 7075-83.
  • Yu AY, Frid MG, Shimoda LA, Wiener CM, Stenmark K, Semenza GL. (1998) Temporal, spatial, and oxygen-regulated expression of hypoxia-inducible factor-1 in the lung. Am J Physiol.; 275: L818-26.
  • Yu AY, Shimoda LA, Iyer NV, Huso DL, Sun X, McWilliams R, Beaty T, Sham JS, Wiener CM, Sylvester JT, Semenza GL. (1999) Impaired physiological responses to chronic hypoxia in mice partially deficient for hypoxia-inducible factor 1alpha. J Clin Invest.; 103: 691-6.
  • Zhong H, Chiles K, Feldser D, Laughner E, Hanrahan C, Georgescu MM, Simons JW, Semenza GL. (2000) Modulation of hypoxia- inducible factor 1alpha expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/AKT/FRAP pathway in human prostate cancer cells: implications for tumor angiogenesis and therapeutics. Cancer Res.; 60: 1541-5.
  • Zundel W, Schindler C, Haas-Kogan D, Koong A, Kaper F, Chen E, Gottschalk AR, Ryan HE, Johnson RS, Jefferson AB, Stokoe D, Giaccia AJ. (2000) Loss of PTEN facilitates HIF-1-mediated gene expression. Genes Dev.; 14: 391-6.
Document Type
Publication order reference
YADDA identifier
JavaScript is turned off in your web browser. Turn it on to take full advantage of this site, then refresh the page.