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Hypoxia and High Altitude

The molecular response

  • Conference paper
Hypoxia

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 543))

Abstract

Increased erythropoietin plasma levels and the consequent augmented production of red blood cells is the best known systemic adaptation to reduced oxygen partial pressure (pO2). Intensive research during the last years revealed that the molecular mechanism behind the regulation of erythropoietin is ubiquitous and has far more implications than first thought. Erythropoietin regulation results from the activation of the hypoxia-inducible factor-1 (HIF-1) pathway under hypoxic conditions. HIF-1 is a heterodimer consisting of an oxygen sensitive - HIF-1¦Á- and an oxygen-in-dependent subunit - HIF-1¦Â (also known as the aryl hydrocarbon receptor nuclear trans locator - ARNT). In addition to erythropoietin, more than 30 genes are now known to be up-regulated by HIF-1. Recently, the critical involvement of HIF-1¦Á post-translational modifications in the cellular oxygen sensing mechanism was discovered. In this review we will focus on the regulation of the HIF-1 pathway and the cellular oxygen sensor and discuss their implications in high altitude hypoxia.

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References

  1. Agani F and Semenza GL. Mersalyl is a novel inducer of vascular endothelial growth factor gene expression and hypoxia-inducible factor 1 activity. Mol Pharmacol 54: 749–754, 1998.

    CAS  PubMed  Google Scholar 

  2. Alfranca A, Gutierrez MD, Vara A, Aragones J, Vidal F, and Landazuri MO. c-Jun and hypoxia-inducible factor 1 functionally cooperate in hypoxia-induced gene transcription. Mol Cell Biol 22: 12–22, 2002.

    CAS  PubMed Central  PubMed  Google Scholar 

  3. Alvarez-Tejado M, Alfranca A, Aragones J, Vara A, Landazuri MO, and del Peso L. Lack of Evidence for the Involvement of the Phosphoinositide 3-Kinase/Akt Pathway in the Activation of Hypoxia-inducible Factors by Low Oxygen Tension. J Biol Chem 277: 13508–13517, 2002.

    CAS  PubMed  Google Scholar 

  4. Arany Z, Huang LE, Eckner R, Bhattacharya S, Jiang C, Goldberg MA, Bunn HF, and Livingston DM. An essential role for p300/CBP in the cellular response to hypoxia. Proc Natl Acad Sci USA 93: 12969–12973, 1996.

    CAS  PubMed Central  PubMed  Google Scholar 

  5. Arsham AM, Plas DR, Thompson CB, and Simon MC. Phosphatidylinositol 3-kinase/Akt signaling is neither required for hypoxic stabilization of HIF-1 alpha nor sufficient for HIF-1 - dependent target gene transcription. J Biol Chem 277: 15162–15170, 2002.

    CAS  PubMed  Google Scholar 

  6. Bhattacharya S, Michels CL, Leung MK, Arany ZP, Kung AL, and Livingston DM. Functional role of p35srj, a novel p300/CBP binding protein, during transactivation by HIF-1. Gene dev 13:64–75, 1999.

    CAS  PubMed Central  PubMed  Google Scholar 

  7. Brooks GA, Butterfield GE, Wolfe RR, Groves BM, Mazzeo RS, Sutton JR, Wolfel EE, and Reeves JT.Increased dependence on blood glucose after acclimatization to 4,300 m.J Appl Physiol 70: 919–927, 1991.

    CAS  PubMed  Google Scholar 

  8. Brown EJ, Albers MW, Shin TB, Ichikawa K, Keith CT, Lane WS, and Schreiber SL.A mammalian protein targeted by Gl-arresting rapamycin-receptor complex.Nature 369: 756–758, 1994.

    CAS  PubMed  Google Scholar 

  9. Brown EJ, Beal PA, Keith CT, Chen J, Shin TB, and Schreiber SL.Control of p70 s6 kinase by kinase activity of FRAP in vivo.Nature 311: 441–446, 1995.

    Google Scholar 

  10. Bruick RK.Expression of the gene encoding the proapoptotic Nip3 protein is induced by hypoxia.ProcNatl Acad Sci U S A 97: 9082–9087, 2000.

    CAS  PubMed Central  PubMed  Google Scholar 

  11. Bruick RK and McKnight SL.A conserved family of prolyl-4-hydroxylases that modify HIF.Science 294: 1337–1340, 2001.

    CAS  PubMed  Google Scholar 

  12. Camenisch G, Stroka DM, Gassmann M, and Wenger RH.Attenuation of HIF-1 DNA-binding activity limits hypoxia-inducible endothelin-1 expression.Eur J Physiol 443: 240–249, 2001.

    CAS  Google Scholar 

  13. Camenisch G, Tini M, Chilov D, Kvietikova I, Srinivas V, Caro J, Spielmann P, Wenger RH, and Gassmann M.General applicability of chicken egg yolk antibodies: the performance of IgY immunoglobulins raised against the hypoxia-inducible factor 1 alpha.Faseb J.13: 81–88, 1999.

    CAS  PubMed  Google Scholar 

  14. Cantley LC and Neel BG.New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway.Proc Natl Acad Sci U S A 96: 4240–4245, 1999.

    CAS  PubMed Central  PubMed  Google Scholar 

  15. 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, and Keshet E.Role of HIF-1 alpha in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis.Nature 394: 485–490, 1998.

    CAS  PubMed  Google Scholar 

  16. Carrero P, Okamoto K, Coumailleau P, O'Brien S, Tanaka H, and Poellinger L.Redox-regulated recruitment of the transcriptional coactivators CREB-binding protein and SRC-1 to hypoxiainducible factor 1 alpha.Mol Cell Biol 20: 402–415, 2000.

    CAS  PubMed Central  PubMed  Google Scholar 

  17. Chan HM and La Thangue NB.p300/CBP proteins: HATs for transcriptional bridges and scaffolds.J Cell Sci 114: 2363–2373, 2001.

    CAS  PubMed  Google Scholar 

  18. Chandel NS, Maltepe E, Goldwasser E, Mathieu CE, Simon MC, and Schumacker PT.Mitochondrial reactive oxygen species trigger hypoxia-induced transcription.Proc Natl Acad Sci U S A 95: 11715–11720, 1998.

    CAS  PubMed Central  PubMed  Google Scholar 

  19. Chandel NS, McClintock DS, Feliciano CE, Wood TM, Melendez JA, Rodriguez AM, and Schumacker PT.Reactive oxygen species generated at mitochondrial complex III stabilize hypoxia-inducible factor-1 alpha during hypoxia: a mechanism of 02 sensing.J Biol Chem 275:25130–25138, 2000.

    CAS  PubMed  Google Scholar 

  20. Chavez JC, Agani F, Pichiule P, and LaManna JC.Expression of hypoxia-inducible factor-1 alpha in the brain of rats during chronic hypoxia.J Appl Physiol 89: 1937–1942, 2000.

    CAS  PubMed  Google Scholar 

  21. Chen G, Cizeau J, Vande Velde C, Park JH, Bozek G, Bolton J, Shi L, Dubik D, and Greenberg A.Nix and Nip3 form a subfamily of pro-apoptotic mitochondrial proteins.J Biol Chem 274: 7–10, 1999.

    CAS  PubMed  Google Scholar 

  22. Chilov D, Camenisch G, Kvietikova I, Ziegler U, Gassmann M, and Wenger RH.Induction and nuclear translocation of hypoxia-inducible factor-1 (HIF-1): heterodimerization with ARNT is not necessary for nuclear accumulation of HIF-1 alpha.J Cell Sci 112: 1203–1212, 1999.

    CAS  PubMed  Google Scholar 

  23. Cockman ME, Masson N, Mole DR, Jaakkola P, Chang GW, Clifford SC, Maher ER, Pugh CW, Ratcliffe PJ, and Maxwell PH.Hypoxia inducible factor-alpha binding and ubiquitylation by the von Hippel-Lindau tumor suppressor protein.J Biol Chem 275: 25733–25741, 2000.

    CAS  PubMed  Google Scholar 

  24. Conrad PW, Rust RT, Han J, Millhorn DE, and Beitner-Johnson D.Selective activation of p38alpha and p38gamma by hypoxia.Role in regulation of cyclin D1 by hypoxia in PC 12 cells.J Biol Chem 274: 23570–23576, 1999.

    CAS  PubMed  Google Scholar 

  25. Cormier-Regard S, Nguyen SV, and Claycomb WC.Adrenomedullin gene expression is developmentally regulated and induced by hypoxia in rat ventricular cardiac myocytes.J Biol Chem 273: 17787–17792, 1998.

    CAS  PubMed  Google Scholar 

  26. Cowden KD and Simon MC.The bHLH/PAS factor MOP3 does not participate in hypoxia responses.Biochem Biophys Res Commun 290: 1228–1236, 2002.

    CAS  PubMed  Google Scholar 

  27. Dames SA, Martinez-Yamout M, De Guzman RN, Dyson HJ, and Wright PE.From the Cover: Structural basis for Hif-1 alpha /CBP recognition in the cellular hypoxic response.Proc Natl AcadSci U S A 99: 5271–5276, 2002.

    CAS  Google Scholar 

  28. Drutel G, Kathmann M, Heron A, Schwartz JC, and Arrang JM.Cloning and selective expression in brain and kidney of ARNT2 homologous to the Ah receptor nuclear translocator (ARNT).Biochem Biophys Res Commun 225: 333–339, 1996.

    CAS  Google Scholar 

  29. Ebert BL and Bunn HF.Regulation of transcription by hypoxia requires a multiprotein complex that includes hypoxia-inducible factor 1, an adjacent transcription factor, and p300/CREB binding protein.Mol Cell Biol 18: 4089–4096, 1998.

    CAS  PubMed Central  PubMed  Google Scholar 

  30. Eckhart AD, Yang N, Xin X, and Faber JE.Characterization of the alphal B-adrenergic receptor gene promoter region and hypoxia regulatory elements in vascular smooth muscle.Proc Natl AcadSci U S A 94: 9487–9492, 1997.

    CAS  Google Scholar 

  31. Ema M, Hirota K, Mimura J, Abe H, Yodoi J, Sogawa K, Poellinger L, and Fujii-Kuriyama Y.Molecular mechanisms of transcription activation by HLF and HIFI alpha in response to hypoxia: their stabilization and redox signal-induced interaction with CBP/p300.Embo J 18: 1905–1914, 1999.

    CAS  PubMed Central  PubMed  Google Scholar 

  32. 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, Schofleld CJ, and Ratcliffe PJ.C.elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation.Cell 107: 43–54, 2001.

    CAS  PubMed  Google Scholar 

  33. Epstein FH, Agmon Y, and Brezis M.Physiology of renal hypoxia.Ann N Y AcadSci 718: 72–81; discussion 81–72, 1994.

    CAS  Google Scholar 

  34. Feldser D, Agani F, Iyer NV, Pak B, Ferreira G, and Semenza GL.Reciprocal positive regulation of hypoxia-inducible factor lalpha and insulin-like growth factor 2.Cancer Res 59: 3915–3918, 1999.

    CAS  PubMed  Google Scholar 

  35. Ferrara N.Role of vascular endothelial growth factor in regulation of physiological angiogenesis.Am J Physiol Cell Physiol 280: C1358–1366, 2001.

    Google Scholar 

  36. Ferrara N, Carver-Moore K, Chen H, Dowd M, Lu L, KS OS, Powell-Braxton L, Hillan KJ, and Moore MW.Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene.Nature 380: 439–442, 1996.

    CAS  PubMed  Google Scholar 

  37. Fisher JW, Koury S, Ducey T, and Mendel S.Erythropoietin production by interstitial cells of hypoxic monkey kidneys.Br J Haematol 95: 27–32, 1996.

    CAS  PubMed  Google Scholar 

  38. Forsythe JA, Jiang BH, Iyer NV, Agani F, Leung SW, Koos RD, and Semenza GL.Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1.Mol Cell Biol 16:4604–4613, 1996.

    CAS  Google Scholar 

  39. Freedman SJ, Sun ZY, Poy F, Kung AL, Livingston DM, Wagner G, and Eck MJ.Structural basis for recruitment of CBP/p300 by hypoxia-inducible factor-1 alpha.Proc Natl AcadSci U S A 99: 5367–5372, 2002.

    CAS  Google Scholar 

  40. Fukuda R, Hirota K, Fan F, Jung YD, Ellis LM, and Semenza GL.Insulin-like Growth Factor 1 Induces Hypoxia-inducible Factor 1-mediated Vascular Endothelial Growth Factor Expression, Which is Dependent on MAP Kinase and Phosphatidylinositol 3-Kinase Signaling in Colon Cancer Cells.J Biol Chem 277: 38205–38211, 2002.

    CAS  PubMed  Google Scholar 

  41. Gao N, Jiang BH, Leonard SS, Corum L, Zhang Z, Roberts JR, Antonini J, Zheng JZ, Flynn DC, Castranova V, and Shi X.p38 Signaling-mediated Hypoxia-inducible Factor 1 alpha and Vascular Endothelial Growth Factor Induction by Cr(VI) in DU 145 Human Prostate Carcinoma Cells.J Biol Chem 211: 45041–45048, 2002.

    Google Scholar 

  42. Garayoa M, Martinez A, Lee S, Pio R, An WG, Neckers L, Trepel J, Montuenga LM, Ryan H, Johnson R, Gassmann M, and Cuttitta F.Hypoxia-inducible factor-1 (HIF-1) up-regulates adrenomedullin expression in human tumor cell lines during oxygen deprivation: a possible promotion mechanism of carcinogenesis.Mol Endocrinol 14: 848–862, 2000.

    CAS  PubMed  Google Scholar 

  43. Gerber HP, Condorelli F, Park J, and Ferrara N.Differential transcriptional regulation of the two vascular endothelial growth factor receptor genes.Flt-1, but not Flk-1/KDR, is up-regulated by hypoxia.J Biol Chem 272: 23659–23667, 1997.

    CAS  PubMed  Google Scholar 

  44. Gingras AC, Raught B, and Sonenberg N.Regulation of translation initiation by FRAP/mTOR.Genes Dev 15: 807–826, 2001.

    CAS  PubMed  Google Scholar 

  45. Gnaiger E.Bioenergetics at low oxygen: dependence of respiration and phosphorylation on oxygen and adenosine diphosphate supply.Respir Physiol 128: 277–297, 2001.

    CAS  PubMed  Google Scholar 

  46. Görlach A, Camenisch G, Kvietikova I, Vogt L, Wenger RH, and Gassmann M.Efficient translation of mouse hypoxia-inducible factor-1 alpha under normoxic and hypoxic conditions.Biochim Biophys Acta 1493: 125–134, 2000.

    PubMed  Google Scholar 

  47. Görlach A, Diebold I, Schini-Kerth VB, Berchner-Pfannschmidt U, Roth U, Brandes RP, Kietzmann T, and Busse R.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, 2001.

    PubMed  Google Scholar 

  48. Gradin K, McGuire J, Wenger RH, Kvietikova I, Whitelaw ML, Toftgard R, Tora L, Gassmann M, and Poellinger L.Functional interference between hypoxia and dioxin signal transduction pathways: competition for recruitment of the Arnt transcription factor.Mol Cell Biol 16: 5221– 5231, 1996.

    CAS  PubMed Central  PubMed  Google Scholar 

  49. Gu YZ, Moran SM, Hogenesch JB, Wartman L, and Bradfield CA.Molecular characterization and chromosomal localization of a third alpha-class hypoxia inducible factor subunit, HIF3alpha.Gene Expression 7: 205–213, 1998.

    CAS  PubMed  Google Scholar 

  50. Hackett PH.High altitude cerebral edema and acute mountain sickness.A pathophysiology update.Adv Exp Med Biol 474: 23–45, 1999.

    CAS  PubMed  Google Scholar 

  51. Haddad JJ and Land SC.A non-hypoxic, ROS-sensitive pathway mediates TNF-alpha-dependent regulation of HIF-1 alpha.FEBS Lett 505: 269–274, 2001.

    CAS  PubMed  Google Scholar 

  52. Haddad JJ and Land SC.0(2)-evoked regulation of HIF-1 alpha and NF-kappaB in perinatal lung epithelium requires glutathione biosynthesis.Am J Physiol Lung Cell Mol Physiol 278: L492–503, 2000.

    Google Scholar 

  53. Haddad JJ, Olver RE, and Land SC.Antioxidant/pro-oxidant equilibrium regulates HIF-1 alpha and NF-kappa B redox sensitivity.Evidence for inhibition by glutathione oxidation in alveolar epithelial cells.J Biol Chem 275: 21130–21139, 2000.

    CAS  PubMed  Google Scholar 

  54. Hagemann C and Blank JL.The ups and downs of MEK kinase interactions.Cell Signal 13: 863–875,2001.

    CAS  PubMed  Google Scholar 

  55. Hanaoka M, Droma Y, Naramoto A, Honda T, Kobayashi T, and Kubo K.Vascular endothelial growth factor in patients with high-altitude pulmonary edema.J Appl Physiol 10: 10, 2003.

    Google Scholar 

  56. Hara S, Hamada J, Kobayashi C, Kondo Y, and Imura N.Expression and characterization of hypoxia-inducible factor (HIF)-3alpha in human kidney: suppression of HIF-mediated gene expression by HIF-3alpha.Biochem Biophys Res Commun 287: 808–813, 2001.

    CAS  PubMed  Google Scholar 

  57. Heinicke K, Prommer N, Cajigal J, Viola T, Behn C, and Schmidt W.Long-term exposure to intermittent hypoxia results in increased hemoglobin mass, reduced plasma volume, and elevated erythropoietin plasma levels in man.Eur J Appl Physiol 88: 535–543, 2003.

    CAS  PubMed  Google Scholar 

  58. Hellwig-Burgel T, Rutkowski K, Metzen E, Fandrey J, and Jelkmann W.Interleukin-lbeta and tumor necrosis factor-alpha stimulate DNA binding of hypoxia-inducible factor-1.Blood 94: 1561–1567, 1999.

    CAS  PubMed  Google Scholar 

  59. Hirose K, Morita M, Ema M, Mimura J, Hamada H, Fujii H, Saijo Y, Gotoh O, Sogawa K, and Fujii-Kuriyama Y.cDNA cloning and tissue-specific expression of a novel basic helix- loop-helix/PAS factor (Arnt2) with close sequence similarity to the aryl hydrocarbon receptor nuclear translocator (Arnt).Mol Cell Biol 16: 1706–1713, 1996.

    CAS  PubMed Central  PubMed  Google Scholar 

  60. Hochachka PW, Rupert JL, and Monge C.Adaptation and conservation of physiological systems in the evolution of human hypoxia tolerance.Comp Biochem Physiol A Mol Integr Physiol 124: 1–17, 1999.

    CAS  PubMed  Google Scholar 

  61. Hofer T, Desbaillets I, Hopfl G, Gassmann M, and Wenger RH.Dissecting hypoxia-dependent and hypoxia-independent steps in the HIF-1 alpha activation cascade: implications for HIF- 1 alpha gene therapy.Faseb J 15: 2715–2717, 2001.

    CAS  PubMed  Google Scholar 

  62. Hofer T, Wenger RH, Kramer MF, Ferreira GC, and Gassmann M.Hypoxic up-regulation of erythroid 5-aminolevulinate synthase.Blood 101: 348–350, 2003.

    CAS  PubMed  Google Scholar 

  63. Hogenesch JB, Chan WK, Jackiw VH, Brown RC, Gu YZ, Pray-Grant M, Perdew GH, and Bradfield CA.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: 8581–8593, 1997.

    CAS  PubMed  Google Scholar 

  64. Hogenesch JB, Gu YZ, Jain S, and Bradfield CA.The basic-helix-loop-helix-PAS orphan MOP3 forms transcriptionally active complexes with circadian and hypoxia factors.Proc Natl AcadSci U S A 95: 5474–5479, 1998.

    CAS  Google Scholar 

  65. Hoppeler H and Vogt M.Muscle tissue adaptations to hypoxia.J Exp Biol 204: 3133–3139, 2001.

    CAS  PubMed  Google Scholar 

  66. Hu J, Discher DJ, Bishopric NH, and Webster KA.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: 894–899, 1998.

    CAS  PubMed  Google Scholar 

  67. Huang LE, Arany Z, Livingston DM, and Bunn HF.Activation of hypoxia-inducible transcription factor depends primarily upon redox-sensitive stabilization of its alpha subunit.J Biol Chem 271: 32253–32259, 1996.

    CAS  PubMed  Google Scholar 

  68. Huang LE, Gu J, Schau M, and Bunn HF.Regulation of hypoxia-inducible factor 1 alpha is mediated by an 02-dependent degradation domain via the ubiquitin-proteasome pathway.Proc Natl Acad Sci 95: 7987–7992, 1998.

    CAS  PubMed Central  PubMed  Google Scholar 

  69. Hur E, Chang KY, Lee E, Lee SK, and Park H.Mitogen-activated protein kinase kinase inhibitor PD98059 blocks the trans-activation but not the stabilization or DNA binding ability of hypoxia-inducible factor-1 alpha.Mol Pharmacol 59: 1216–1224, 2001.

    CAS  PubMed  Google Scholar 

  70. Ikeda M and Nomura M.cDNA cloning and tissue-specific expression of a novel basic helix-loop-helix/PAS protein (BMAL1) and identification of alternatively spliced variants with alternative translation initiation site usage.Biochem Biophys Res Commun 233: 258–264, 1997.

    CAS  PubMed  Google Scholar 

  71. Ivan M, Kondo K, Yang H, Kim W, Valiando J, Ohh M, Salic A, Asara JM, Lane WS, and Kaelin WG.HIF {alpha} Targeted for VHL-Mediated Destruction by Proline Hydroxylation: Implications for 02 Sensing.Science 5: 5, 2001.

    Google Scholar 

  72. Iyer NV, Kotch LE, Agani F, Leung SW, Laughner E, Wenger RH, Gassmann M, Gearhart JD, Lawler AM, Yu AY, and Semenza GL.Cellular and developmental control of 02 homeostasis by hypoxia-inducible factor 1 alpha.Genes Dev 12: 149–162, 1998.

    CAS  PubMed Central  PubMed  Google Scholar 

  73. Iyer NV, Leung SW, and Semenza GL.The human hypoxia-inducible factor 1 alpha gene: HIF 1A structure and evolutionary conservation.Genomics 52: 159–165, 1998.

    CAS  PubMed  Google Scholar 

  74. Jaakkola P, Mole DR, Tian YM, Wilson MI, Gielbert J, Gaskell SJ, Kriegsheim A, Hebestreit HF, Mukherji M, Schofield CJ, Maxwell PH, Pugh CW, and Ratcliffe PJ.Targeting of HIF- alpha to the von Hippel-Lindau ubiquitylation complex by 02-regulated prolyl hydroxylation.Science 292: 468–472, 2001.

    CAS  PubMed  Google Scholar 

  75. Jain S, Maltepe E, Lu MM, Simon C, and Bradfield CA.Expression of ARNT, ARNT2, HIFI alpha, HIF2 alpha and Ah receptor mRNAs in the developing mouse.Mechanisms of Development 73: 117–123, 1998.

    CAS  PubMed  Google Scholar 

  76. Jeong JW, Bae MK, Ahn MY, Kim SH, Sohn TK, Bae MH, Yoo MA, Song EJ, Lee KJ, and Kim KW.Regulation and Destabilization of HIF-1 alpha by ARD1-Mediated Acetylation.Cell 111: 709–720, 2002.

    CAS  PubMed  Google Scholar 

  77. Jewell UR, Kvietikova I, Scheid A, Bauer C, Wenger RH, and Gassmann M.Induction of HIF-1 alpha in response to hypoxia is instantaneous.Faseb J 15: 1312–1314, 2001.

    CAS  PubMed  Google Scholar 

  78. Jiang BH, Agani F, Passaniti A, and Semenza GL.V-SRC induces expression of hypoxia-inducible factor 1 (HIF-1) and transcription of genes encoding vascular endothelial growth factor andenolase 1: involvement of HIF-1 in tumor progression.Cancer Res 57: 5328–5335, 1997.

    CAS  PubMed  Google Scholar 

  79. Jiang BH, Rue E, Wang GL, Roe R, and Semenza GL.Dimerization, DNA binding, and transactivation properties of hypoxia-inducible factor 1.J Biol Chem 271: 17771–17778, 1996.

    CAS  PubMed  Google Scholar 

  80. Jiang BH, Semenza GL, Bauer C, and Marti HH.Hypoxia-inducible factor 1 levels vary exponentially over a physiologically relevant range of 02 tension.Am J Physiol 271: C 1172–1180, 1996.

    CAS  PubMed  Google Scholar 

  81. Kallio PJ, Okamoto K, O'Brien S, Carrero P, Makino Y, Tanaka H, and Poellinger L.Signal transduction in hypoxic cells: inducible nuclear translocation and recruitment of the CBP/ p300 coactivator by the hypoxia-inducible factor-1 alpha.Embo J 17: 6573–6586, 1998.

    CAS  PubMed Central  PubMed  Google Scholar 

  82. Kallio PJ, Wilson WJ, O'Brien S, Makino Y, and Poellinger L.Regulation of the hypoxia-in-ducible transcription factor 1 alpha by the ubiquitin-proteasome pathway.J Biol Chem 274: 6519–6525, 1999.

    CAS  PubMed  Google Scholar 

  83. Kamura T, Sato S, Iwai K, Czyzyk-Krzeska M, Conaway RC, and Conaway JW.Activation of HIF 1 alpha ubiquitination by a reconstituted von Hippel-Lindau (VHL) tumor suppressor complex.Proc Natl Acad Sci U S A 97: 10430–10435, 2000.

    CAS  PubMed Central  PubMed  Google Scholar 

  84. Keith B, Adelman DM, and Simon MC.Targeted mutation of the murine arylhydrocarbon receptor nuclear translocator 2 (Arnt2) gene reveals partial redundancy with Arnt.Proc Natl Acad Sci U S A 98: 6692–6697, 2001.

    CAS  PubMed Central  PubMed  Google Scholar 

  85. Kemp PJ, Lewis A, Hartness ME, Searle GJ, Miller P, O'Kelly I, and Peers C.Airway chemotransduction: from oxygen sensor to cellular effector.Am J Respir Crit Care Med 166: S17–24, 2002.

    Google Scholar 

  86. Kietzmann T, Roth U, and Jungermann K.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: 4177–4185, 1999.

    CAS  PubMed  Google Scholar 

  87. Klausen T, Christensen H, Hansen JM, Nielsen OJ, Fogh-Andersen N, and Olsen NV.Human erythropoietin response to hypocapnic hypoxia, normocapnic hypoxia, and hypocapnic nor- moxia.Eur J Appl Physiol Occup Physiol 74: 475–480, 1996.

    CAS  PubMed  Google Scholar 

  88. Kline DD, Peng YJ, Manalo DJ, Semenza GL, and Prabhakar NR.Defective carotid body function and impaired ventilatory responses to chronic hypoxia in mice partially deficient for hypoxia-inducible factor lalpha.Proc Natl Acad Sci U S A 99: 821–826, 2002.

    CAS  PubMed Central  PubMed  Google Scholar 

  89. Koury ST, Bondurant MC, and Koury MJ.Localization of erythropoietin synthesizing cells in murine kidneys by in situ hybridization.Blood 71: 524–527, 1988.

    CAS  PubMed  Google Scholar 

  90. Krek W.VHL takes HIF's breath away.Nat Cell Biol 2: E121–123, 2000.

    Google Scholar 

  91. Krieg M, Haas R, Brauch H, Acker T, Flamme I, and Plate KH.Up-regulation of hypoxia-inducible factors HIF-1 alpha and HIF-2alpha under normoxic conditions in renal carcinoma cells by von Hippel-Lindau tumor suppressor gene loss of function.Oncogene 19: 5435–5443, 2000.

    CAS  PubMed  Google Scholar 

  92. Lacombe C, Da Silva JL, Bruneval P, Fournier JG, Wendling F, Casadevall N, Camilleri JP, Bariety J, Varet B, and Tambourin P.Peritubular cells are the site of erythropoietin synthesis in the murine hypoxic kidney.J Clin Invest 81: 620–623, 1988.

    CAS  PubMed Central  PubMed  Google Scholar 

  93. Lando D, Peet DJ, Whelan DA, Gorman JJ, and Whitelaw ML.Asparagine hydroxylation of the HIF transactivation domain a hypoxic switch.Science 295: 858–861, 2002.

    CAS  PubMed  Google Scholar 

  94. Lando D, Pongratz I, Poellinger L, and Whitelaw ML.A redox mechanism controls differential DNA binding activities of hypoxia-inducible factor (HIF) 1 alpha and the HIF-like factor.J Biol Chem 275: 4618–4627, 2000.

    CAS  PubMed  Google Scholar 

  95. Laughner E, Taghavi P, Chiles K, Mahon PC, and Semenza GL.HER2 (neu) signaling increases the rate of hypoxia-inducible factor 1 alpha (HIF-1 alpha) synthesis: novel mechanism for HIF-1-mediated vascular endothelial growth factor expression.Mol Cell Biol 21: 3995–4004, 2001.

    CAS  PubMed Central  PubMed  Google Scholar 

  96. Lee PJ, Jiang BH, Chin BY, Iyer NV, Alam J, Semenza GL, and Choi AM.Hypoxia-inducible factor-1 mediates transcriptional activation of the heme oxygenase-1 gene in response to hy- poxia.J Biol Chem 272: 5375–5381, 1997.

    CAS  PubMed  Google Scholar 

  97. Levy AP, Levy NS, Wegner S, and Goldberg MA.Transcriptional regulation of the rat vascular endothelial growth factor gene by hypoxia.J Biol Chem 270: 13333–13340, 1995.

    CAS  PubMed  Google Scholar 

  98. Liu Y, Cox SR, Morita T, and Kourembanas S.Hypoxia regulates vascular endothelial growth factor gene expression in endothelial cells.Identification of a 5' enhancer.Circ Res 77: 638– 643, 1995.

    CAS  PubMed  Google Scholar 

  99. Lok CN and Ponka P.Identification of a hypoxia response element in the transferrin receptor gene.J Biol Chem 274: 24147–24152, 1999.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  101. Makino Y, Kanopka A, Wilson WJ, Tanaka H, and Poellinger L.Inhibitory PAS domain protein (IPAS) is a hypoxia-inducible splicing variant of the hypoxia-inducible factor-3alpha locus.J Biol Chem 277: 32405–32408, 2002.

    CAS  PubMed  Google Scholar 

  102. Maloney J, Wang D, Duncan T, Voelkel N, and Ruoss S.Plasma vascular endothelial growth factor in acute mountain sickness.Chest 118: 47–52, 2000.

    CAS  PubMed  Google Scholar 

  103. Maltepe E, Keith B, Arsham AM, Brorson JR, and Simon MC.The role of ARNT2 in tumor angiogenesis and the neural response to hypoxia.Biochem Biophys Res Commun 273: 231–238, 2000.

    CAS  PubMed  Google Scholar 

  104. Marti HH and Risau W.Systemic hypoxia changes the organ-specific distribution of vascular endothelial growth factor and its receptors.Proc Natl Acad Sci 95: 15809–15814, 1998.

    CAS  PubMed Central  PubMed  Google Scholar 

  105. Masuda S, Chikuma M, and Sasaki R.Insulin-like growth factors and insulin stimulate erythro-poietin production in primary cultured astrocytes.Brain Res 746: 63–70, 1997.

    CAS  PubMed  Google Scholar 

  106. Melillo G, Musso T, Sica A, Taylor LS, Cox GW, and Varesio L.A hypoxia-responsive element mediates a novel pathway of activation of the inducible nitric oxide synthase promoter.J Exp Med 182: 1683–1693, 1995.

    CAS  PubMed  Google Scholar 

  107. Milledge JS and Cotes PM.Serum erythropoietin in humans at high altitude and its relation to plasma renin.JAppl Physiol 59: 360–364, 1985.

    CAS  Google Scholar 

  108. Minchenko A, Leshchinsky I, Opentanova I, Sang N, Srinivas V, Armstead V, and Caro J.Hypoxia-inducible factor-1-mediated expression of the 6-phosphofructo-2-kinase/fructose- 2,6-bisphosphatase-3 (PFKFB3) gene.Its possible role in the Warburg effect.J Biol Chem 277:6183–6187, 2002.

    CAS  PubMed  Google Scholar 

  109. Minet E, Michel G, Mottet D, Piret JP, Barbieux A, Raes M, and Michiels C.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, 2001.

    CAS  PubMed  Google Scholar 

  110. Moore LG, Armaza F, Villena M, and Vargas E.Comparative aspects of high-altitude adaptation in human populations.Adv Exp Med Biol 475: 45–62, 2000.

    CAS  PubMed  Google Scholar 

  111. Mukhopadhyay CK, Mazumder B, and Fox PL.Role of hypoxia-inducible factor-1 in transcrip- tional activation of ceruloplasmin by iron deficiency.J Biol Chem 275: 21048–21054, 2000.

    CAS  PubMed  Google Scholar 

  112. Nguyen SV and Claycomb WC.Hypoxia regulates the expression of the adrenomedullin and HIF-1 genes in cultured HL-1 cardiomyocytes.Biochem Biophys Res Commun 265: 382–386, 1999.

    CAS  PubMed  Google Scholar 

  113. Ogunshola OO, Stewart WB, Mihalcik V, Solli T, Madri JA, and Ment LR.Neuronal VEGF expression correlates with angiogenesis in postnatal developing rat brain.Brain Res Dev Brain Res 119: 139–153, 2000.

    CAS  PubMed  Google Scholar 

  114. Ohh M, Park CW, Ivan M, Hoffman MA, Kim TY, Huang LE, Pavletich N, Chau V, and Kaelin WG.Ubiquitination of hypoxia-inducible factor requires direct binding to the beta-domain of the von Hippel-Lindau protein.Nat Cell Biol 2: 423–427, 2000.

    CAS  PubMed  Google Scholar 

  115. Palmer LA, Semenza GL, Stoler MH, and Johns RA.Hypoxia induces type II NOS gene expression in pulmonary artery endothelial cells via HIF-1.Am J Physiol 274: L212–219, 1998.

    Google Scholar 

  116. Pugh CW, O’Rourke JF, Nagao M, Gleadle JM, and Ratcliffe PJ.Activation of hypoxia-inducible factor-1; definition of regulatory domains within the alpha subunit.J Biol Chem 272: 11205–11214, 1997.

    CAS  PubMed  Google Scholar 

  117. Raught B, Gingras AC, and Sonenberg N.The target of rapamycin (TOR) proteins.Proc Natl AcadSci USA 98: 7037–7044, 2001.

    CAS  Google Scholar 

  118. Richard DE, Berra E, Gothie E, Roux D, and Pouyssegur J.p42/p44 mitogen-activated protein kinases phosphorylate hypoxia-inducible factor 1 alpha (HIF-1 alpha) and enhance the tran- scriptional activity of HIF-1.J Biol Chem 274: 32631–32637, 1999.

    CAS  PubMed  Google Scholar 

  119. Richard DE, Berra E, and Pouyssegur J.Nonhypoxic pathway mediates the induction of hypoxia-inducible factor 1 alpha in vascular smooth muscle cells.J Biol Chem 275: 26765–26771, 2000.

    CAS  PubMed  Google Scholar 

  120. Roach RC and Hackett PH.Frontiers of hypoxia research: acute mountain sickness.J Exp Biol 204:3161–3170, 2001.

    CAS  PubMed  Google Scholar 

  121. Rolfs A, Kvietikova I, Gassmann M, and Wenger RH.Oxygen-regulated transferrin expression is mediated by hypoxia-inducible factor-1.J Biol Chem 272: 20055–20062, 1997.

    CAS  PubMed  Google Scholar 

  122. Rosenberger C, Mandriota S, Jurgensen JS, Wiesener MS, Horstrup JH, Frei U, Ratcliffe PJ, Maxwell PH, Bachmann S, and Eckardt KU.Expression of hypoxia-inducible factor-1 alpha and -2alpha in hypoxic and ischemic rat kidneys.J Am Soc Nephrol 13: 1721–1732, 2002.

    CAS  PubMed  Google Scholar 

  123. Russo D, Damante G, Foti D, Costante G, and Filetti S.Different molecular mechanisms are involved in the multihormonal control of glucose transport in FRTL5 rat thyroid cells.J Endocrinol Invest 17: 323–327, 1994.

    CAS  PubMed  Google Scholar 

  124. Ryan HE, Lo J, and Johnson RS.HIF-1 alpha is required for solid tumor formation and embryonic vascularization.Embo J 17: 3005–3015, 1998.

    CAS  PubMed Central  PubMed  Google Scholar 

  125. Salceda S and Caro J.Hypoxia-inducible factor 1 alpha (HIF-1 alpha) 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: 22642–22647, 1997.

    CAS  PubMed  Google Scholar 

  126. Sandau KB, Zhou J, Kietzmann T, and Brune B.Regulation of the hypoxia-inducible factor 1 alpha by the inflammatory mediators nitric oxide and tumor necrosis factor-alpha in contrast to desferoxamine and phenylarsine oxide.J Biol Chem 276: 39805–39811, 2001.

    CAS  PubMed  Google Scholar 

  127. Sang N, Fang J, Srinivas V, Leshchinsky I, and Caro J.Carboxyl-Terminal Transactivation Activity of Hypoxia-Inducible Factor 1 alpha Is Governed by a von Hippel-Lindau Protein- Independent, Hydroxylation-Regulated Association with p300/CBP.Mol Cell Biol 22: 2984– 2992, 2002.

    PubMed Central  PubMed  Google Scholar 

  128. Schmelzle T and Hall MN.TOR, a central controller of cell growth.Cell 103: 253–262, 2000.

    CAS  PubMed  Google Scholar 

  129. Schoch HJ, Fischer S, and Marti HH.Hypoxia-induced vascular endothelial growth factor expression causes vascular leakage in the brain.Brain 125: 2549–2557, 2002.

    PubMed  Google Scholar 

  130. Schurek HJ, Jost U, Baumgartl H, Bertram H, and Heckmann U.Evidence for a preglomerular oxygen diffusion shunt in rat renal cortex.Am J Physiol 259: F910–915, 1990.

    Google Scholar 

  131. Scott PH, Paul A, Belham CM, Peacock AJ, Wadsworth RM, Gould GW, Welsh D, and Plevin R.Hypoxic stimulation of the stress-activated protein kinases in pulmonary artery fibroblasts.Am J Respir Crit Care Med 158: 958–962, 1998.

    CAS  PubMed  Google Scholar 

  132. Seagroves TN, Ryan HE, Lu H, Wouters BG, Knapp M, Thibault P, Laderoute K, and Johnson RS.Transcription factor HIF-1 is a necessary mediator of the pasteur effect in mammalian cells.Mol Cell Biol 21: 3436–3444, 2001.

    CAS  PubMed Central  PubMed  Google Scholar 

  133. Seko Y, Takahashi N, Tobe K, Kadowaki T, and Yazaki Y.Hypoxia and hypoxia/reoxygenation activate p65PAK, p38 mitogen-activated protein kinase (MAPK), and stress-activated protein kinase (SAPK) in cultured rat cardiac myocytes.Biochem Biophys Res Commun 239: 840– 844, 1997.

    CAS  PubMed  Google Scholar 

  134. Severinghaus JW.Hypothetical roles of angiogenesis, osmotic swelling, and ischemia in high-altitude cerebral edema.J Appl Physiol 79: 375–379, 1995.

    CAS  PubMed  Google Scholar 

  135. Shemirani B and Crowe DL.Hypoxic induction of HIF-1 alpha and VEGF expression in head and neck squamous cell carcinoma lines is mediated by stress activated protein kinases.Oral Oncol 38: 251–257, 2002.

    CAS  Google Scholar 

  136. Shimoda LA, Manalo DJ, Sham JS, Semenza GL, and Sylvester JT.Partial HIF-1 alpha deficiency impairs pulmonary arterial myocyte electrophysiological responses to hypoxia.Am J Physiol Lung Cell Mol Physiol 281: L202–208, 2001.

    Google Scholar 

  137. Shoshani T, Faerman A, Mett I, Zelin E, Tenne T, Gorodin S, Moshel Y, Elbaz S, Budanov A, Chajut A, Kalinski H, Kamer I, Rozen A, Mor O, Keshet E, Leshkowitz D, Einat P, Skaliter R, and Feinstein E.Identification of a Novel Hypoxia-Inducible Factor 1-Responsive Gene, RTP801, Involved in Apoptosis.Mol Cell Biol 22: 2283–2293, 2002.

    CAS  PubMed Central  PubMed  Google Scholar 

  138. Srinivas V, Leshchinsky I, Sang N, King MP, Minchenko A, and Caro J.Oxygen sensing and HIF-1 activation does not require an active mitochondrial respiratory chain electron-transfer pathway.J Biol Chem 276: 21995–21998, 2001.

    CAS  PubMed  Google Scholar 

  139. Srinivas V, Zhang LP, Zhu XH, and Caro J.Characterization of an oxygen/redox-dependent degradation domain of hypoxia-inducible factor alpha (HIF-alpha) proteins.Biochem Biophys Res Commun 260: 557–561, 1999.

    CAS  PubMed  Google Scholar 

  140. Stiehl DP, Jelkmann W, Wenger RH, and Hellwig-Burgel T.Normoxic induction of the hypoxia-inducible factor 1 alpha by insulin and interleukin-lbeta involves the phosphatidylinositol 3-kinase pathway.FEBS Lett 512: 157–162, 2002.

    CAS  PubMed  Google Scholar 

  141. Stroka DM, Burkhardt T, Desbaillets I, Wenger RH, Neil DA, Bauer C, Gassmann M, and Candinas D.HIF-1 is expressed in normoxic tissue and displays an organ-specific regulation under systemic hypoxia.Faseb 715: 2445–2453, 2001.

    Google Scholar 

  142. Sutter CH, Laughner E, and Semenza GL.Hypoxia-inducible factor 1 alpha protein expression is controlled by oxygen-regulated ubiquitination that is disrupted by deletions and missense mutations.Proc Natl Acad Sci 97: 4748–4753, 2000.

    CAS  PubMed Central  PubMed  Google Scholar 

  143. Tacchini L, Bianchi L, Bernelli-Zazzera A, and Cairo G.Transferrin receptor induction by hypoxia.HIF-1-mediated transcriptional activation and cell-specific post-transcriptional regulation.J Biol Chem 274: 24142–24146, 1999.

    CAS  PubMed  Google Scholar 

  144. Takahashi Y, Takahashi S, Shiga Y, Yoshimi T, and Miura T.Hypoxic induction of prolyl 4-hydroxylase alpha (I) in cultured cells.J Biol Chem 275: 14139–14146, 2000.

    CAS  PubMed  Google Scholar 

  145. Takahata S, Sogawa K, Kobayashi A, Ema M, Mimura J, Ozaki N, and Fujii-Kuriyama Y.Transcriptionally active heterodimer formation of an Arnt-like PAS protein, Arnt3, with HIF-1 a, HLF, and clock.Biochem Biophys Res Commun 248: 789–794, 1998.

    CAS  PubMed  Google Scholar 

  146. Tazuke SI, Mazure NM, Sugawara J, Carland G, Faessen GH, Suen LF, Irwin JC, Powell DR, Giaccia AJ, and Giudice LC.Hypoxia stimulates insulin-like growth factor binding protein 1 (IGFBP-1) gene expression in HepG2 cells: a possible model for IGFBP-1 expression in fetal hypoxia.Proc Natl Acad Sci U S A 95: 10188–10193, 1998.

    CAS  PubMed Central  PubMed  Google Scholar 

  147. Thornton RD, Lane P, Borghaei RC, Pease EA, Caro J, and Mochan E.Interleukin 1 induces hypoxia-inducible factor 1 in human gingival and synovial fibroblasts.Biochem J 350: 307– 312, 2000.

    CAS  PubMed Central  PubMed  Google Scholar 

  148. Tian H, Hammer RE, Matsumoto AM, Russell DW, and McKnight SL.The hypoxia-responsive transcription factor EPAS1 is essential for catecholamine homeostasis and protection against heart failure during embryonic development.Genes Dev 12: 3320–3324, 1998.

    CAS  PubMed Central  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  150. Vivanco I and Sawyers CL.The phosphatidylinositol 3-Kinase AKT pathway in human cancer.Nat Rev Cancer 2: 489–501, 2002.

    CAS  PubMed  Google Scholar 

  151. Vogt M, Puntschart A, Geiser J, Zuleger C, Billeter R, and Hoppeler H.Molecular adaptations in human skeletal muscle to endurance training under simulated hypoxic conditions.J Appl Physiol 91: 173–182, 2001.

    CAS  PubMed  Google Scholar 

  152. Walter R, Maggiorini M, Scherrer U, Contesse J, and Reinhart WH.Effects of high-altitude exposure on vascular endothelial growth factor levels in man.Eur J Appl Physiol 85: 113–117, 2001.

    CAS  PubMed  Google Scholar 

  153. Wang GL, Jiang BH, Rue EA, and Semenza GL.Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular 02 tension.Proc Natl Acad Sci U S A 92: 5510–5514, 1995.

    CAS  PubMed Central  PubMed  Google Scholar 

  154. Wang GL, Jiang BH, and Semenza GL.Effect of altered redox states on expression and DNA-binding activity of hypoxia-inducible factor 1.Biochem Biophys Res Commun 212: 550–556, 1995.

    CAS  PubMed  Google Scholar 

  155. Wang GL and Semenza GL.Characterization of hypoxia-inducible factor 1 and regulation of DNA binding activity by hypoxia.J Biol Chem 268: 21513–21518, 1993.

    CAS  PubMed  Google Scholar 

  156. Warren RS, Yuan H, Matli MR, Ferrara N, and Donner DB.Induction of vascular endothelial growth factor by insulin-like growth factor 1 in colorectal carcinoma.J Biol Chem 271: 29483–29488, 1996.

    CAS  PubMed  Google Scholar 

  157. Wenger RH.Mammalian oxygen sensing, signalling and gene regulation.J Exp Biol 203: 1253–1263, 2000.

    CAS  PubMed  Google Scholar 

  158. Wenger RH and Gassmann M.Oxygen(es) and the hypoxia-inducible factor-1.Biol Chem 378: 609–616, 1997.

    CAS  PubMed  Google Scholar 

  159. Whalen WJ, Ganfield R, and Nair P.Effects of breathing O 2 or O 2 +CO 2 and of the injection of neurohumors on the PO 2 of cat cerebral cortex.Stroke 1: 194–200, 1970.

    CAS  PubMed  Google Scholar 

  160. Wiesener MS, Jurgensen JS, Rosenberger C, Scholze C, Horstrup JH, Warnecke C, Mandriota S, Bechmann I, Frei UA, Pugh CW, Ratcliffe PJ, Bachmann S, Maxwell PH, and Eckardt KU.Widespread, hypoxia-inducible expression of HIF-2alpha in distinct cell populations of different organs.Faseb J 17: 17, 2002.

    Google Scholar 

  161. Wood SM, Wiesener MS, Yeates KM, Okada N, Pugh CW, Maxwell PH, and Ratcliffe PJ.Selection and analysis of a mutant cell line defective in the hypoxia-inducible factor-1 alpha-subunit (HIF-1 alpha).Characterization of hif-1 alpha-dependent and -independent hypoxia-inducible gene expression.J Biol Chem 273: 8360–8368, 1998.

    CAS  PubMed  Google Scholar 

  162. Wykoff CC, Beasley NJ, Watson PH, Turner KJ, Pastorek J, Sibtain A, Wilson GD, Turley H, Talks KL, Maxwell PH, Pugh CW, Ratcliffe PJ, and Harris AL.Hypoxia-inducible expression of tumor-associated carbonic anhydrases.Cancer Res 60: 7075–7083, 2000.

    CAS  PubMed  Google Scholar 

  163. Xu F and Severinghaus JW.Rat brain VEGF expression in alveolar hypoxia: possible role in high-altitude cerebral edema.J Appl Physiol 85: 53–57, 1998.

    CAS  Google Scholar 

  164. Yu AY, Shimoda LA, Iyer NV, Huso DL, Sun X, McWilliams R, Beaty T, Sham JS, Wiener CM, Sylvester JT, and Semenza GL.Impaired physiological responses to chronic hypoxia in mice partially deficient for hypoxia-inducible factor 1 alpha.J Clin Invest 103: 691–696, 1999.

    CAS  PubMed Central  PubMed  Google Scholar 

  165. Yu F, White SB, Zhao Q, and Lee FS.Dynamic, site-specific interaction of hypoxia-inducible factor-1 alpha with the von Hippel-Lindau tumor suppressor protein.Cancer Res 61: 4136–4142,2001.

    CAS  PubMed  Google Scholar 

  166. Zelzer E, Levy Y, Kahana C, Shilo BZ, Rubinstein M, and Cohen B.Insulin induces transcription of target genes through the hypoxia-inducible factor HIF-1 alpha/ARNT.Embo J 17: 5085–5094, 1998.

    CAS  PubMed Central  PubMed  Google Scholar 

  167. Zhong H, Chiles K, Feldser D, Laughner E, Hanrahan C, Georgescu MM, Simons JW, and Semenza GL.Modulation of hypoxia-inducible factor 1 alpha 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– 1545, 2000.

    CAS  PubMed  Google Scholar 

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Höpfl, G., Ogunshola, O., Gassmann, M. (2003). Hypoxia and High Altitude. In: Roach, R.C., Wagner, P.D., Hackett, P.H. (eds) Hypoxia. Advances in Experimental Medicine and Biology, vol 543. Springer, Boston, MA. https://doi.org/10.1007/978-1-4419-8997-0_7

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