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Regulation of endogenous erythropoietin production

  • David R. Mole
  • Peter J. Ratcliffe
Part of the Milestones in Drug Therapy book series (MDT)

Abstract

The principal function of the red cell is to convey oxygen from the lungs to the tissues through the oxygen transport molecule, haemoglobin, a concept finally established in the 19th Century after major advances in biology and chemistry over the preceding two centuries. The description of the blood circulation by William Harvey (1578–1657) in De Motu Cordis et Sanguinis in Animalibus in 1628 framed the question as to the purpose of moving such large volumes of fluid around the body. Richard Lower (1631–1691) working in Oxford with Robert Hooke (1635–1702) noted that whereas the blood leaving the heart for the lungs was blue, that returning from the lungs to the heart was red, concluding that ‘Nitrous spirit of the air, vital to life is mixed with the blood during transit through the lungs’. After the first consistent measurements of oxygen in blood, by Gustav Magnus, the role of the blood circulation in delivering oxygen to the tissues was confirmed by showing that there was more oxygen in arterial than venous blood [1]. Finally, a specific role for erythrocytes in oxygen transport was established by the demonstration of reversible binding of oxygen to the pigmented haemoglobin that accounted for the colour change [2, 3].

Keywords

Prolyl Hydroxylase Domain Vascular Endothelial Growth Factor Endogenous Erythropoietin Production Atrial Naturetic Peptide 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 1.
    Magnus G. Ueber die im Blute enthaltenen Gase, Sauerstoff, Stickstoff und Kohlensaeure. Ann Physik 1837;12:583–606.Google Scholar
  2. 2.
    Hoppe F. Ueber das Verhalten des Blutfarbstoffes im Spectrum des Sonnenlichtes. Virchows Arch 1862;23:446–449.CrossRefGoogle Scholar
  3. 3.
    Stokes GG. On the reduction and oxidation of the colouring matter of blood. Proc Roy Soc London 1864;13:355–364.Google Scholar
  4. 4.
    Carnot P, Deflandre C. Sur l’activité hémopoiétique du sérum au cours de la régénération du sang. CR Acad Sci Paris 1906;143:384–386.Google Scholar
  5. 5.
    Erslev A. Humoral regulation of red cell production. Blood 1953;8:349–357.PubMedGoogle Scholar
  6. 6.
    FitzGerald MP. The changes in the breathing and the blood at various high altitudes. Phil Trans R Soc Lond B, Containing Papers of a Biological Character. 1913;203:351–371.CrossRefGoogle Scholar
  7. 7.
    Abbrecht PH, Littell JK. Plasma erythropoietin in men and mice during acclimatization to different altitudes. J Appl Physiol 1972;32:54–58.PubMedGoogle Scholar
  8. 8.
    Jacobson LO, Goldwasser E, Fried W et al. Role of the kidney in erythropoiesis. Nature 1957;179:633–634.PubMedCrossRefGoogle Scholar
  9. 9.
    Erslev AJ. In vitro production of erythropoietin by kidneys perfused with a serum-free solution. Blood 1974;44:77–85.PubMedGoogle Scholar
  10. 10.
    Beru N, McDonald J, Lacombe C et al. Expression of the erythropoietin gene. Mol Cell Biol 1986;6:2571–2575.PubMedGoogle Scholar
  11. 11.
    Fandrey J, Bunn HF. In vitro and in vitro regulation of erythropoietin mRNA: measurement by competitive polymerase chain reaction. Blood 1993;81:617–623.PubMedGoogle Scholar
  12. 12.
    Bachmann S, Le Hir M, Eckardt KU. Co-localization of erythropoietin mRNA and ecto-5′-nucleotidase immunoreactivity in peritubular cells of rat renal cortex indicates that fibroblasts produce erythropoietin. J Histochem Cytochem 1993;41:335–341.PubMedGoogle Scholar
  13. 13.
    Maxwell PH, Osmond MK, Pugh CW et al. Identification of the renal erythropoietin-producing cells using transgenic mice. Kidney Int 1993;44:1149–1162.PubMedCrossRefGoogle Scholar
  14. 14.
    Koury ST, Koury MJ, Bondurant MC et al. Quantitation of erythropoietin-producing cells in kidneys of mice by in situ hybridization: correlation with hematocrit, renal erythropoietin mRNA, and serum erythropoietin concentration. Blood 1989;74:645–651.PubMedGoogle Scholar
  15. 15.
    Jacobs K, Shoemaker C, Rudersdorf R et al. Isolation and characterization of genomic and cDNA clones of human erythropoietin. Nature 1985;313:806–810.PubMedCrossRefGoogle Scholar
  16. 16.
    Lin FK, Suggs S, Lin CH et al. Cloning and expression of the human erythropoietin gene. Proc Natl Acad Sci USA 1985;82:7580–7584.PubMedCrossRefGoogle Scholar
  17. 17.
    Semenza GL, Wang GL. A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol Cell Biol 1992;12:5447–5454.PubMedGoogle Scholar
  18. 18.
    Makita T, Hernandez-Hoyos G, Chen TH et al. A developmental transition in definitive erythropoiesis: erythropoietin expression is sequentially regulated by retinoic acid receptors and HNF4. Genes Dev 2001;15:889–901.PubMedCrossRefGoogle Scholar
  19. 19.
    Wenger RH, Kvietikova I, Rolfs A et al. Oxygen-regulated erythropoietin gene expression is dependent on a CpG methylation-free hypoxia-inducible factor-1 DNA-binding site. Eur J Biochem 1998;253:771–777.PubMedCrossRefGoogle Scholar
  20. 20.
    Yin H, Blanchard KL. DNA methylation represses the expression of the human erythropoietin gene by two different mechanisms. Blood 2000;95:111–119.PubMedGoogle Scholar
  21. 21.
    Maxwell PH, Pugh CW, Ratcliffe PJ. Inducible operation of the erythropoietin 3′ enhancer in multiple cell lines: evidence for a widespread oxygen-sensing mechanism. Proc Natl Acad Sci USA 1993;90:2423–2427.PubMedCrossRefGoogle Scholar
  22. 22.
    Wenger RH, Stiehl DP, Camenisch G. Integration of oxygen signaling at the consensus HRE. Sci STKE 2005;2005:re 12.CrossRefGoogle Scholar
  23. 23.
    Wang GL, Jiang BH, Rue EA et al. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci USA 1995;92:5510–5514.PubMedCrossRefGoogle Scholar
  24. 24.
    Salceda S, Caro J. Hypoxia-inducible factor 1alpha (HIF-1alpha) protein is rapidly degraded by the ubiquitin-proteasome system under normoxic conditions. Its stabilization by hypoxia depends on redo x-induced changes. J Biol Chem 1997;272:22642–22647.PubMedCrossRefGoogle Scholar
  25. 25.
    Wiesener MS, Turley H, Allen WE et al. Induction of endothelial PAS domain protein-1 by hypoxia: characterization and comparison with hypoxia-inducible factor-1alpha. Blood 1998;92:2260–2268.PubMedGoogle Scholar
  26. 26.
    Pugh CW, O’Rourke JF, Nagao M et al. Activation of hypoxia-inducible factor-1; definition of regulatory domains within the alpha subunit. J Biol Chem 1997;272:11205–11214.PubMedCrossRefGoogle Scholar
  27. 27.
    Arany Z, Huang LE, Eckner R et al. An essential role for p300/CBP in the cellular response to hypoxia. Proc Natl Acad Sci USA 1996;93:12969–12973.PubMedCrossRefGoogle Scholar
  28. 28.
    Makino Y, Kanopka A, Wilson WJ et al. Inhibitory PAS domain protein (IPAS) is a hypoxia-inducible splicing variant of the hypoxia-inducible factor-3alpha locus. J Biol Chem 2002;277:32405–32408.PubMedCrossRefGoogle Scholar
  29. 29.
    Wiesener MS, Jurgensen JS, Rosenberger C et al. Widespread hypoxia-inducible expression of HIF-2alpha in distinct cell populations of different organs. FASEB J 2003;17:271–273.PubMedGoogle Scholar
  30. 30.
    Rosenberger C, Mandriota S, Jurgensen JS et al. Expression of hypoxia-inducible factor-1alpha and −2alpha in hypoxic and ischemic rat kidneys. J Am Soc Nephrol 2002;13:1721–1732.PubMedCrossRefGoogle Scholar
  31. 31.
    Iyer NV, Kotch LE, Agani F et al. Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1 alpha. Genes Dev 1998;12:149–162.PubMedCrossRefGoogle Scholar
  32. 32.
    Carmeliet P, Dor Y, Herbert JM et al. Role of HIF-1alpha in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. Nature 1998;394:485–490.PubMedCrossRefGoogle Scholar
  33. 33.
    Scortegagna M, Ding K, Oktay Y et al. Multiple organ pathology, metabolic abnormalities and impaired homeostasis of reactive oxygen species in Epas 1-/-mice. Nat Genet 2003;35:331–340.PubMedCrossRefGoogle Scholar
  34. 34.
    Tian H, Hammer RE, Matsumoto AM et al. The hypoxia-responsive transcription factor EPAS1 is essential for catecholamine homeostasis and protection against heart failure during embryonic development. Genes Dev 1998;12:3320–3324.PubMedCrossRefGoogle Scholar
  35. 35.
    Peng J, Zhang L, Drysdale L et al. The transcription factor EPAS-1/hypoxia-inducible factor 2alpha plays an important role in vascular remodeling. Proc Natl Acad Sci USA 2000;97:8386–8391.PubMedCrossRefGoogle Scholar
  36. 36.
    Compernolle V, Brusselmans K, Acker T et al. Loss of HIF-2alpha and inhibition of VEGF impair fetal lung maturation, whereas treatment with VEGF prevents fatal respiratory distress in premature mice. Nat Med 2002;8:702–710.PubMedGoogle Scholar
  37. 37.
    Gruber M, Hu CJ, Johnson RS et al. Acute postnatal ablation of Hif-2alpha results in anemia. Proc Natl Acad Sci USA 2007;104:2301–2306.PubMedCrossRefGoogle Scholar
  38. 38.
    Elvidge GP, Glenny L, Appelhoff RJ et al. Concordant regulation of gene expression by hypoxia and 2-oxoglutarate-dependent dioxygenase inhibition: the role of HIF-1alpha, HIF-2alpha, and other pathways. J Biol Chem 2006;281:15215–15226.PubMedCrossRefGoogle Scholar
  39. 39.
    Wang V, Davis DA, Haque M et al. Differential gene up-regulation by hypoxia-inducible factor-1alpha and hypoxia-inducible factor-2alpha in HEK293T cells. Cancer Res 2005;65:3299–3306.PubMedGoogle Scholar
  40. 40.
    Sowter HM, Raval RR, Moore JW et al. Predominant role of hypoxia-inducible transcription factor (Hif)-1alpha versus Hif-2alpha in regulation of the transcriptional response to hypoxia. Cancer Res 2003;63:6130–6134.PubMedGoogle Scholar
  41. 41.
    Greijer AE, van der Groep P, Kemming D et al. Up-regulation of gene expression by hypoxia is mediated predominantly by hypoxia-inducible factor 1 (HIF-1). J Pathol 2005;206:291–304.PubMedCrossRefGoogle Scholar
  42. 42.
    Hu CJ, Wang LY, Chodosh LA et al. Differential roles of hypoxia-inducible factor 1alpha (HIF-1alpha) and HIF-2alpha in hypoxic gene regulation. Mol Cell Biol 2003;23:9361–9374.PubMedCrossRefGoogle Scholar
  43. 43.
    Raval RR, Lau KW, Tran MG et al. Contrasting Properties of Hypoxia-Inducible Factor 1 (HIF-1) and HIF-2 in von Hippel-Lindau-Associated Renal Cell Carcinoma. Mol Cell Biol 2005;25:5675–5686.PubMedCrossRefGoogle Scholar
  44. 44.
    Grabmaier K, MC AdW, Verhaegh GW et al. Strict regulation of CAIX(G250/MN) by HIF-1alpha in clear cell renal cell carcinoma. Oncogene 2004;23:5624–5631.PubMedCrossRefGoogle Scholar
  45. 45.
    Warnecke C, Zaborowska Z, Kurreck J et al. Differentiating the functional role of hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha (EPAS-1) by the use of RNA interference: erythropoietin is a HIF-2alpha target gene in Hep 3B and Kelly cells. FASEB J 2004;18:1462–1464.PubMedGoogle Scholar
  46. 46.
    Baba M, Hirai S, Yamada-Okabe H et al. Loss of von Hippel-Lindau protein causes cell density dependent deregulation of CyclinD1 expression through hypoxia-inducible factor. Oncogene 2003;22:2728–2738.PubMedCrossRefGoogle Scholar
  47. 47.
    Gunaratnam L, Morley M, Franovic A et al. Hypoxia inducible factor activates the transforming growth factor-alpha/epidermal growth factor receptor growth stimulatory pathway in VHL(-/-) renal cell carcinoma cells. J Biol Chem 2003;278:44966–44974.PubMedCrossRefGoogle Scholar
  48. 48.
    Covello KL, Kehler J, Yu H et al. HIF-2alpha regulates Oct-4: effects of hypoxia on stem cell function, embryonic development, and tumor growth. Genes Dev 2006;20:557–570.PubMedCrossRefGoogle Scholar
  49. 49.
    Gort EH, van Haaften G, Verlaan I et al. The TWIST1 oncogene is a direct target of hypoxia-inducible factor-2alpha. Oncogene 2008;27:1501–1510.PubMedCrossRefGoogle Scholar
  50. 50.
    Hu CJ, Sataur A, Wang L et al. The N-terminal transactivation domain confers target gene specificity of hypoxia-inducible factors HIF-1alpha and HIF-2alpha. Mol Biol Cell 2007;18:4528–4542.PubMedCrossRefGoogle Scholar
  51. 51.
    Lau KW, Tian YM, Raval RR et al. Target gene selectivity of hypoxia-inducible factor-alpha in renal cancer cells is conveyed by post-DNA-binding mechanisms. Br J Cancer 2007;96:1284–1292.PubMedCrossRefGoogle Scholar
  52. 52.
    Elvert G, Kappel A, Heidenreich R et al. Cooperative interaction of hypoxia-inducible factor-2alpha (HIF-2alpha) and Ets-1 in the transcriptional activation of vascular end othelial growth factor receptor-2 (Flk-1). J Biol Chem 2003;278:7520–7530.PubMedCrossRefGoogle Scholar
  53. 53.
    Aprelikova O, Wood M, Tackett S et al. Role of ETS transcription factors in the hypoxia-inducible factor-2 target gene selection. Cancer Res 2006;66:5641–5647.PubMedCrossRefGoogle Scholar
  54. 54.
    Schofield CJ, Ratcliffe PJ. Oxygen sensing by HIF hydroxylases. Nat Rev Mol Cell Biol 2004;5:343–354.PubMedCrossRefGoogle Scholar
  55. 55.
    O’Rourke JF, Tian YM, Ratcliffe PJ et al. Oxygen-regulated and transactivating domains in endothelial PAS protein 1: comparison with hypoxia-inducible factor-1alpha. J Biol Chem 1999;274:2060–2071.PubMedCrossRefGoogle Scholar
  56. 56.
    Huang LE, Gu J, Schau M et al. Regulation of hypoxia-inducible factor 1alpha is mediated by an O2-dependent degradation domain via the ubiquitin-proteasome pathway. Proc Natl Acad Sci USA 1998;95:7987–7992.PubMedCrossRefGoogle Scholar
  57. 57.
    Jaakkola P, Mole DR, Tian YM et al. Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 2001;292:468–472.PubMedCrossRefGoogle Scholar
  58. 58.
    Ivan M, Kondo K, Yang H et al. HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science 2001;292:464–468.PubMedCrossRefGoogle Scholar
  59. 59.
    Masson N, Willam C, Maxwell PH et al. Independent function of two destruction domains in hypoxia-inducible factor-alpha chains activated by prolyl hydroxylation. EMBO J 2001;20:5197–5206.PubMedCrossRefGoogle Scholar
  60. 60.
    Hirsila M, Koivunen P, Gunzler V et al. Characterization of the human prolyl 4-hydroxylases that modify the hypoxia-inducible factor HIF. J Biol Chem 2003;278:30772–30780.PubMedCrossRefGoogle Scholar
  61. 61.
    Lando D, Peet DJ, Whelan DA et al. Asparagine hydroxylation of the HIF transactivation domain a hypoxic switch. Science 2002;295:858–861.PubMedCrossRefGoogle Scholar
  62. 62.
    Kallio PJ, Okamoto K, O’Brien S et al. Signal transduction in hypoxic cells: inducible nuclear translocation and recruitment of the CBP/p300 coactivator by the hypoxia-inducible factor-1alpha. EMBO J 1998;17:6573–6586.PubMedCrossRefGoogle Scholar
  63. 63.
    Groulx I, Lee S. Oxygen-dependent ubiquitination and degradation of hypoxia-inducible factor requires nuclear-cytoplasmic trafficking of the von Hippel-Lindau tumor suppressor protein. Mol Cell Biol 2002;22:5319–5336.PubMedCrossRefGoogle Scholar
  64. 64.
    Maynard MA, Qi H, Chung J et al. Multiple splice variants of the human HIF-3 alpha locus are targets of the von Hippel-Lindau E3 ubiquitin ligase complex. J Biol Chem 2003;278:11032–11040.PubMedCrossRefGoogle Scholar
  65. 65.
    Hara S, Hamada J, Kobayashi C et al. 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 2001;287:808–813.PubMedCrossRefGoogle Scholar
  66. 66.
    Myllyharju J. Prolyl 4-hydroxylases, the key enzymes of collagen biosynthesis. Matrix Biol 2003;22:15–24.PubMedCrossRefGoogle Scholar
  67. 67.
    Schofield CJ, Zhang Z. Structural and mechanistic studies on 2-oxoglutarate-dependent oxygenases and related enzymes. Curr Opin Struct Biol 1999;9:722–731.PubMedCrossRefGoogle Scholar
  68. 68.
    Knowles HJ, Mole DR, Ratcliffe PJ et al. Normoxic stabilization of hypoxia-inducible factor-1alpha by modulation of the labile iron pool in differentiating U937 macrophages: effect of natural resistance-associated macrophage protein 1. Cancer Res 2006;66:2600–2607.PubMedCrossRefGoogle Scholar
  69. 69.
    Knowles HJ, Raval RR, Harris AL et al. Effect of ascorbate on the activity of hypoxia-inducible factor in cancer cells. Cancer Res 2003;63:1764–1768.PubMedGoogle Scholar
  70. 70.
    Epstein AC, Gleadle JM, McNeill LA et al. C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell 2001;107:43–54.PubMedCrossRefGoogle Scholar
  71. 71.
    Bruick RK, McKnight SL. A conserved family of prolyl-4-hydroxylases that modify HIF. Science 2001;294:1337–1340.PubMedCrossRefGoogle Scholar
  72. 72.
    Hewitson KS, McNeill LA, Riodan MV et al. Hypoxia-inducible factor (HIF) asparagine hydroxylase is identical to factor inhibiting HIF (FIH) and is related to the cupin structural family. J Biol Chem 2002;277:26351–26355.PubMedCrossRefGoogle Scholar
  73. 73.
    Lando D, Peet DJ, Gorman JJ et al. FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor. Genes Dev 2002;16:1466–1471.PubMedCrossRefGoogle Scholar
  74. 74.
    Berra E, Benizri E, Ginouves A et al. HIF prolyl-hydroxylase 2 is the key oxygen sensor setting low steady-state levels of HIF-1 {alpha} in normoxia. EMBO J 2003;22:4082–4090.PubMedCrossRefGoogle Scholar
  75. 75.
    Takeda K, Ho VC, Takeda H et al. Placental but not heart defects are associated with elevated hypoxia-inducible factor alpha levels in mice lacking prolyl hydroxylase domain protein 2. Mol Cell Biol 2006;26:8336–8346.PubMedCrossRefGoogle Scholar
  76. 76.
    Metzen E, Berchner-Pfannschmidt U, Stengel P et al. Intracellular localisation of human HIF-1alpha hydroxylases: implications for oxygen sensing. J Cell Sci 2003;116:1319–1326.PubMedCrossRefGoogle Scholar
  77. 77.
    Appelhoff RJ, Tian Y-M, Raval RR et al. Differential function of the prolyl hydroxylases, PHD1, 2 and 3 in the regulation of Hypoxia inducible factor (HIF). J Biol Chem 2004;279:38458–38465.PubMedCrossRefGoogle Scholar
  78. 78.
    Cioffi CL, Qin Liu X, Kosinski PA et al. Differential regulation of HIF-1alpha prolyl-4-hydroxylase genes by hypoxia in human cardiovascular cells. Biochem Biophys Res Commun 2003;303:947–953.PubMedCrossRefGoogle Scholar
  79. 79.
    Nakayama K, Frew IJ, Hagensen M et al. Siah2 regulates stability of prolyl-hydroxylases, controls HIF1alpha abundance, and modulates physiological responses to hypoxia. Cell 2004;117:941–952.PubMedCrossRefGoogle Scholar
  80. 80.
    Hopfer U, Hopfer H, Jablonski K et al. The novel WD-repeat protein Morgl acts as a molecular scaffold for hypoxia-inducible factor prolyl hydroxylase 3 (PHD3). J Biol Chem 2006;281:8645–8655.PubMedCrossRefGoogle Scholar
  81. 81.
    Lieb ME, Menzies K, Moschella MC et al. Mammalian EGLN genes have distinct patterns of mRNA expression and regulation. Biochem Cell Biol 2002;80:421–426.PubMedCrossRefGoogle Scholar
  82. 82.
    Bhattacharya S, Michels CL, Leung MK et al. Functional role of p35srj, a novel p300/CBP binding protein, during transactivation by HIF-1. Genes Dev 1999;13:64–75.PubMedCrossRefGoogle Scholar
  83. 83.
    Latif F, Tory K, Gnarra J et al. Identification of the von Hippel-Lindau disease tumor suppressor gene. Science 1993;260:1317–1320.PubMedCrossRefGoogle Scholar
  84. 84.
    Maxwell PH, Wiesener MS, Chang GW et al. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 1999;399:271–275.PubMedCrossRefGoogle Scholar
  85. 85.
    Cockman ME, Masson N, Mole DR et al. Hypoxia inducible factor-alpha binding and ubiquitylation by the von Hippel-Lindau tumor suppressor protein. J Biol Chem 2000;275:25733–25741.PubMedCrossRefGoogle Scholar
  86. 86.
    Kamura T, Sato S, Iwai K et al. Activation of HIF1alpha ubiquitination by a reconstituted von Hippel-Lindau (VHL) tumor suppressor complex. Proc Natl Acad Sci USA 2000;97:10430–10435.PubMedCrossRefGoogle Scholar
  87. 87.
    Ohh M, Park CW, Ivan M et al. Ubiquitination of hypoxia-inducible factor requires direct binding to the beta-domain of the von Hippel-Lindau protein. Nat Cell Biol 2000;2:423–427.PubMedCrossRefGoogle Scholar
  88. 88.
    Tanimoto K, Makino Y, Pereira T et al. Mechanism of regulation of the hypoxia-inducible factor-1 alpha by the von Hippel-Lindau tumor suppressor protein. EMBO J 2000;19:4298–4309.PubMedCrossRefGoogle Scholar
  89. 89.
    Hon WC, Wilson MI, Harlos K et al. Structural basis for the recognition of hydroxyproline in HIF-1 alpha by pVHL. Nature 2002;417:975–978.PubMedCrossRefGoogle Scholar
  90. 90.
    Min JH, Yang H, Ivan M et al. Structure of an HIF-1 alpha-pVHL complex: hydroxyproline recognition in signaling. Science 2002;296:1886–1889.PubMedCrossRefGoogle Scholar
  91. 91.
    Selak MA, Armour SM, MacKenzie ED et al. Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. Cancer Cell 2005;7:77–85.PubMedCrossRefGoogle Scholar
  92. 92.
    Isaacs JS, Jung YJ, Mole DR et al. HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: Novel role of fumarate in regulation of HIF stability. Cancer Cell 2005;8:143–153.PubMedCrossRefGoogle Scholar
  93. 93.
    Brugarolas J, Kaelin WG Jr, Dysregulation of HIF and VEGF is a unifying feature of the familial hamartoma syndromes. Cancer Cell 2004;6:7–10.PubMedCrossRefGoogle Scholar
  94. 94.
    Gerald D, Berra E, Frapart YM et al. JunD reduces tumor angiogenesis by protecting cells from oxidative stress. Cell 2004;118:781–794.PubMedCrossRefGoogle Scholar
  95. 95.
    Maxwell PH, Ferguson DJ, Nicholls LG et al. The interstitial response to renal injury: fibroblast-like cells show phenotypic changes and have reduced potential for erythropoietin gene expression. Kidney Int 1997;52:715–724.PubMedCrossRefGoogle Scholar
  96. 96.
    Faquin WC, Schneider TJ, Goldberg MA. Effect of inflammatory cytokines on hypoxia-induced erythropoietin production. Blood 1992;79:1987–1994.PubMedGoogle Scholar
  97. 97.
    Jelkmann W, Pagel H, Wolff M et al. Monokines inhibiting erythropoietin production in human hepatoma cultures and in isolated perfused rat kidneys. Life Sci 1992;50:301–308.PubMedCrossRefGoogle Scholar
  98. 98.
    Hewitson KS, Schofield CJ. The HIF pathway as a therapeutic target. Drug Discov Today 2004;9:704–711.PubMedCrossRefGoogle Scholar
  99. 99.
    Elkins JM, Hewitson KS, McNeill LA et al. Structure of factor-inhibiting hypoxia-inducible factor (HIF) reveals mechanism of oxidative modification of HIF-1 alpha. J Biol Chem 2003;278:1802–1806.PubMedCrossRefGoogle Scholar

Copyright information

© Birkhäuser Verlag/Switzerland 2009

Authors and Affiliations

  • David R. Mole
    • 1
  • Peter J. Ratcliffe
    • 1
  1. 1.Headington CampusUniversity of OxfordOxfordUK

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