Skip to main content
SpringerLink
Log in

Biology of erythropoietin

  • Chapter
Recombinant Human Erythropoietin (rhEPO) in Clinical Oncology

  • 149 Accesses

Abstract

Patients undergoing chemotherapy for cancer are at risk of developing anemia, and recombinant human erythropoietin (Epo) is an alternative to replace transfusions of allogenic red blood cells in this setting. This article will review the regulation of the Epo gene, the structure of the Epo receptor (EpoR) and the Epo-induced intracellular signaling events. Finally, we will describe other compounds and mechanisms which mimic Epo action, thereby also leading to intracellular signalling albeit with a decreased efficiency when compared to Epo.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 74.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Anagnostou A, Liu Z, Steiner M, Chin K, Lee ES, Kessimian N, Noguchi CT (1994) Erythropoietin receptor mRNA expression in human endothelial cells. Proc Natl Acad Sci U S A 91: 3974–3978

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  3. Bachmann S, Le Hir M, Eckardt KU (1993) Co-localization of erythropoietin mRNA and ecto-5’-nucleotidase immunoreactivity in peritubular cells of ratrenal cortex indicates that fibroblasts produce erythropoietin. J Histochem Cytochem 41: 335–341

    Article  PubMed  CAS  Google Scholar 

  4. Beck I, Ramirez S, Weinmann R, Caro J (1991) Enhancer element at the 3’-flanking region controls transcriptional response to hypoxia in the human erythropoietin gene. J Biol Chem 266: 15563–15566

    PubMed  CAS  Google Scholar 

  5. Beck I, Weinmann R, Caro J (1993) Characterization of hypoxia-responsive enhancer in the human erythropoietin gene shows presence of hypoxiainducible 120-Kd nuclear DNA-binding protein in erythropoietin-producing and nonproducing cells. Blood 82: 704–711

    PubMed  CAS  Google Scholar 

  6. Ben-David Y, Bernstein A (1991) Friend virus-induced erythroleukemia and the multistage nature of cancer. Cell 66: 831–834

    Article  PubMed  CAS  Google Scholar 

  7. Beru N, McDonald J, Lacombe C, Goldwasser E (1986) Expression of the erythropoietin gene. Mol Cell Biol 6: 2571–2575

    PubMed  CAS  Google Scholar 

  8. Blau CA, Peterson KR, Drachman JG, Spencer DM (1997) A proliferation switch for genetically modified cells. Proc Natl Acad Sci U S A 94: 3076–3081

    Article  PubMed  CAS  Google Scholar 

  9. Boissel JP, Lee WR, Presnell SR, Cohen FE, Bunn HF (1993) Erythropoietin structure-function relationships. Mutant proteins that test a model of tertiary structure. J Biol Chem 268: 15983–15993

    Google Scholar 

  10. Bondurant MC, Koury MJ (1986) Anemia induces accumulation of erythropoietin mRNA in the kidney and liver. Mol Cell Biol 6: 2731–2733

    PubMed  CAS  Google Scholar 

  11. Brines ML, Ghezzi P, Keenan S, Agnello D, de Lanerolle NC, Cerami C, Itri LM, Cerami A (2000) Erythropoietin crosses the blood-brain barrier to protect against experimental brain injury. Proc Natl Acad Sci U S A 97: 10526–10531

    Article  PubMed  CAS  Google Scholar 

  12. Broudy VC, Lin N, Brice M, Nakamoto B, Papayannopoulou T (1991) Erythropoietin receptor characteristics on primary human erythroid cells. Blood 77: 2583–2590

    PubMed  CAS  Google Scholar 

  13. Bunn HF, Poyton RO (1996) Oxygen sensing and molecular adaptation to hypoxia. Physiol Rev 76: 839–885

    PubMed  CAS  Google Scholar 

  14. Casadevall N, Lacombe C, Muller O, Gisselbrecht S, Mayeux P (1991) Multimeric structure of the membrane erythropoietin receptor of murine erythroleukemia cells (Friend cells): cross-linking of erythropoietin with the Spleen Focus-forming Virus envelope protein. J Biol Chem 266: 6952–6956

    Google Scholar 

  15. Chrétien S, Varlet P, Verdier F, Gobert S, Cartron J-P, Gisselbrecht S, Mayeux P, Lacombe C (1996) Erythropoietin-induced differentiation of the human erythroleukemia cell line TF-1 correlates with impaired STAT5 activation. EMBO J 15: 4174–4181

    PubMed  Google Scholar 

  16. Da Silva JL, Lacombe C, Bruneval P, Casadevall N, Leporrier M, Camilleri JP, Bariety J, Tambourin P, Varet B (1990) Tumor cells are the site of erythropoietin synthesis in human renal cancers associated with polycythemia. Blood 75: 577–582

    PubMed  Google Scholar 

  17. Damen J, Cutler RL, Jiao H, Yi T, Krystal G (1995) Phosphorylation of tyrosine 503 in the erythropoietin receptor (EpR) is essential for binding the p85 subunit of phosphatidylinositol (PI) 3-kinase and for EpR-associated PI 3-kinase activity. J Biol Chem 270: 23402–23406

    Article  PubMed  CAS  Google Scholar 

  18. Damen JE, Krystal G (1996) Early events in erythropoietin-induced signaling. Exp Hematol 24: 1455–1459

    PubMed  CAS  Google Scholar 

  19. D’Andrea AD, Lodish HF, Wong GG (1989) Expression cloning of the murine erythropoietin receptor. Cell 57: 277–285

    Article  PubMed  Google Scholar 

  20. D’Andrea AD, Yoshimura A, Youssoufian H, Zon L, Koo J, Lodish HF (1991) The cytoplasmic region of the erythropoietin receptor contains non overlapping positive and negative growth-regulatory domains. Mol Cell Biol 11: 1980–1987

    PubMed  Google Scholar 

  21. D’Andrea AD, Zon LI (1990) Erythropoietin receptor: subunit structure and activation. J Clin Invest 86: 681–687

    Article  PubMed  Google Scholar 

  22. De La Chapelle A, Traskelin A, Juvonen E (1993) Truncated erythropoietin receptor causes dominantly inherited benign human erythrocytosis. Proc Natl Acad Sci U S A 90: 4495–11199

    Article  PubMed  Google Scholar 

  23. Digicaylioglu M, Bichet S, Marti HH, Wenger RH, Rivas LA, Bauer C, Gassmann M (1995) Localization of specific erythropoietin binding sites in defined areas of the mouse brain. Proc Natl Acad Sci U S A 92: 3717–3720

    Article  PubMed  CAS  Google Scholar 

  24. Dusanter-Fourt I, Casadevall N, Lacombe C, Muller O, Billat C, Fischer S, Mayeux P (1992) Erythropoietin induces the tyrosine phosphorylation of its own receptor in human erythropoietin-responsive cells. J Biol Chem 267: 10670–10675

    PubMed  CAS  Google Scholar 

  25. Dusanter-Fourt I, Mayeux P, Gisselbrecht S (1994) Transduction du signal par les récepteurs de cytokines. Médecine et Sciences 10: 825–835

    Google Scholar 

  26. Ebert BL, Bunn HF (1999) Regulation of the erythropoietin gene. Blood 94: 1864–1877

    PubMed  CAS  Google Scholar 

  27. Elliott S, Lorenzini T, Chang D, Barzilay J, Delorme E (1997) Mapping of the active site of recombinant human erythropoietin. Blood 89: 493–502

    PubMed  CAS  Google Scholar 

  28. Fandrey J, Bunn HF (1993) In vivo and in vitro regulation of erythropoietin mRNA: measurement by competitive polymerase chain reaction. Blood 81: 617–623

    PubMed  CAS  Google Scholar 

  29. Franke TF, Kaplan DR, Cantley LC (1997) PI3K: downstream AKTion blocks apoptosis. Cell 88: 435–437

    Article  PubMed  CAS  Google Scholar 

  30. Fraser JK, Tan AS, Lin FJ, Berridge MV (1989) Expression of high affinity binding sites for erythropoietin on rat and mouse megakaryocytes. Exp Hematol 17: 10–16

    PubMed  CAS  Google Scholar 

  31. Galson DL, Tsuchiya T, Tendler DS, Huang LE, Ren Y, Ogura T, Bunn HF (1995) The orphan receptor hepatic nuclear factor 4 functions as a transcriptional activator for tissue-specific and hypoxia-specific erythropoietin gene expression and is antagonized by EAR3/COUP-TF1. Mol Cell Biol 15: 2135–2144

    PubMed  CAS  Google Scholar 

  32. Gobert S, Chrétien S, Gouilleux F, Muller O, Pallard C, Dusanter-Fourt I, Groner B, Lacombe C, Gisselbrecht S, Mayeux P (1996) Identification of tyrosine residues within the intracellular domain of the erythropoietin receptor crucial for STATS activation. EMBO J 15: 2434–2441

    PubMed  CAS  Google Scholar 

  33. Gobert S, Duprez V, Lacombe C, Gisselbrecht S, Mayeux P (1995a) Erythropoietin activates three forms of MAP kinase in UT7 erythroleukemia cells. Eur J Biochem 234: 75–83

    Article  PubMed  CAS  Google Scholar 

  34. Gobert S, Porteu F, Pallu S, Muller O, Sabbah M, Dusanter-Fourt I, Courtois G, Lacombe C, Gisselbrecht S, Mayeux P (1995b) Tyrosine phosphorylation of the erythropoietin receptor: role for differentiation and mitogenic signal transduction. Blood 86: 598–606

    PubMed  CAS  Google Scholar 

  35. Goldberg MA, Dunning SP, Bunn HF (1988) Regulation of the erythropoietin gene: evidence that the oxygen sensor is a heme protein. Science 242: 1412–1415

    Article  PubMed  CAS  Google Scholar 

  36. Gouilleux F, Pallard C, Dusanter-Fourt I, Wakao H, Haldosen L-A, Norstedt G, Levy D, Groner B (1995) Prolactin, growth hormone, erythropoietin and granulocyte-macrophage colony stimulating factor induce MGF-STAT5 DNA binding activity. EMBO J 14: 2005–2013

    PubMed  CAS  Google Scholar 

  37. Gregory CJ, Eaves AC (1978) Three stages of erythropoietic progenitor cell differentiation distinguished by a number of physical and biologic properties. Blood 51: 527–537

    PubMed  CAS  Google Scholar 

  38. 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: 548–552

    Article  PubMed  CAS  Google Scholar 

  39. Ihle JN (1995) Cytokine receptor signalling. Nature 377: 591–594

    Article  PubMed  CAS  Google Scholar 

  40. Jacobs K, Shoemaker C, Rudersdorf R, Neill SD, Kaufman RJ, Mufson A, Seehra J, Jones SS, Hewick R, Fritsch EF, Kawakita M, Shimizú T, Miyake T (1985) Isolation and characterization of genomic and cDNA clones of human erythropoietin. Nature 313: 806–810

    Article  PubMed  CAS  Google Scholar 

  41. Jacobson LO, Goldwasser E, Fried W, Plzak L (1957) Role of the kidney in erythropoiesis. Nature 179: 633–634

    Article  PubMed  CAS  Google Scholar 

  42. Kallio PJ, Pongratz I, Gradin K, McGuire J, Poellinger L (1997) Activation of hypoxia-inducible factor lalpha: posttranscriptional regulation and conformational change by recruitment of the Amt transcription factor. Proc Natl Acad Sci U S A 94: 5667–5672

    Article  PubMed  CAS  Google Scholar 

  43. Klingmüller U, Lorenz U, Cantley LC, Neel BC, Lodish HF (1995) Specific recruitment of SH-PTP1 to the erythropoietin receptor causes inactivation of JAK2 and termination of proliferative signals. Cell 80: 729–738

    Article  PubMed  Google Scholar 

  44. Komatsu N, Nakauchi H, Miwa A, Ishihara T, Eguchi M, Moroi M, Okada M, Sato Y, Wada H, Yawata Y, Suda T, Miura Y (1991) Establishment and characterization of a human leukemic cell line with megakaryocytic features: dependency on granulocyte-macrophage colony-stimulating factor, interleukin 3, or erythropoietin for growth and survival. Cancer Res 51: 341–348

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  46. Koury ST, Bondurant MC, Koury MJ, Semenza GL (1991) Localization of cells producing erythropoietin in murine liver by in situ hybridization. Blood 77: 2497–2503

    PubMed  CAS  Google Scholar 

  47. Kralovics R, Indrak K, Stopka T, Berman BW, Prchal JF, Prchal JT (1997) Two new EPO receptor mutations: truncated EPO receptors are most frequently associated with primary familial and congenital polycythemias. Blood 90: 2057–2061

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  49. Lecoq-Lafon C, Verdier F, Fichelson S, Chretien S, Gisselbrecht S, Lacombe C, Mayeux P (1999) Erythropoietin induces the tyrosine phosphorylation of GAB1 and its association with SHC, SHP2, SHIP, and phosphatidylinositol 3-kinase. Blood 93: 2578–2585

    PubMed  CAS  Google Scholar 

  50. Li JP, Hu HO, Niu QT, Fang C (1995) Cell surface activation of the erythropoietin receptor by Friend spleen focus-forming virus gp55. J Virol 69: 1714–1719

    PubMed  CAS  Google Scholar 

  51. Li J-P, D’Andrea AD, Lodish HF, Baltimore D (1990) Activation of cell growth by binding of friend spleen focus-forming virus gp55 glycoprotein to the erythropoietin receptor. Nature 343: 762–764

    Article  PubMed  CAS  Google Scholar 

  52. Lin C-S, Lim SK, D’Agati V, Costantini F (1996) Differential effects of an erythropoietin receptor gene disruption on primitive and definitive erythropoiesis. Genes Dev 10: 154–164

    Article  PubMed  CAS  Google Scholar 

  53. Lin FK, Suggs S, Lin CH, Browne JK, Smalling R, Egrie JC, Chen KK, Fox GM, Martin F, Stabinsky Z, et al (1985) Cloning and expression of the human erythropoietin gene. Proc Natl Acad Sci U S A 82: 7580–7584

    Article  PubMed  CAS  Google Scholar 

  54. Livnah O, Stura EA, Johnson DL, Middleton SA, Mulcahy LS, Wrighton NC, Dower WJ, Jolliffe LK, Wilson IA (1996) Functional mimicry of a protein hormone by a peptide agonist: the EPO receptor complex at 2.8 A. Science 273: 464–471

    Article  PubMed  CAS  Google Scholar 

  55. Livnah O, Stura EA, Middleton SA, Johnson DL, Jolliffe LK, Wilson IA (1999) Crystallographic evidence for preformed dimers of erythropoietin receptor before ligand activation. Science 283: 987–990

    Article  PubMed  CAS  Google Scholar 

  56. Longmore GD, Lodish HF (1991) An activating mutation in the murine erythropoietin receptor induces erythroleukemia in mice: A cytokine receptor superfamily oncogene. Cell 67: 1089–1102

    Google Scholar 

  57. Marine JC, McKay C, Wang D, Topham DJ, Parganas E, Nakajima H, Pendeville H, Yasukawa H, Sasaki A, Yoshimura A, Ihle JN (1999) SOCS3 is essential in the regulation of fetal liver erythropoiesis. Cell 98: 617–627

    Article  PubMed  CAS  Google Scholar 

  58. Masuda S, Nagao M, Takahata K, Konishi Y, Gallyas F Jr, Tabira T, Sasaki R (1993) Functional erythropoietin receptor of the cells with neural characteristics. Comparison with receptor properties of erythroid cells. J Biol Chem 268: 11208–11216

    Google Scholar 

  59. Masuda S, Okano M, Yamagishi K, Nagao M, Ueda M, Sasaki R (1994) A novel site of erythropoietin production. Oxygen-dependent production in cultured rat astrocytes. J Biol Chem 269: 19488–19493

    Google Scholar 

  60. Matthews DJ, Topping RS, Cass RT, Giebel LB (1996) A sequential dimerization mechanism for erythropoietin receptor activation. Proc Natl Acad Sci U S A 93: 9471–9476

    Article  PubMed  CAS  Google Scholar 

  61. Maxwell PH, Ferguson DJ, Osmond MK, Pugh CW, Heryet A, Doe BG, Johnson MH, Ratcliffe PJ (1994) Expression of a homologously recombined erythropoietin-SV40 T antigen fusion gene in mouse liver: evidence for erythropoietin production by Ito cells. Blood 84: 1823–1830

    PubMed  CAS  Google Scholar 

  62. Maxwell PH, Osmond MK, Pugh CW, Heryet A, Nicholls LG, Tan CC, Doe BG, Ferguson DJ, Johnson MH, Ratcliffe PJ (1993a) Identification of the renal erythropoietin-producing cells using transgenic mice. Kidney Int 44: 1149–1162

    Article  PubMed  CAS  Google Scholar 

  63. Maxwell PH, Pugh CW, Ratcliffe PJ (1993b) Inducible operation of the erythropoietin 3’ enhancer in multiple cell lines: evidence for a widespread oxygen-sensing mechanism. Proc Natl Acad Sci U S A 90: 2423–2427

    Article  PubMed  CAS  Google Scholar 

  64. 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: 271–275

    Article  PubMed  CAS  Google Scholar 

  65. Mayeux P, Billat C, Jacquot R (1987) The erythropoietin receptor of rat erythroid progenitor cell: Characterization and affinity cross-linkage. J Biol Chem 262: 13985–13990

    Google Scholar 

  66. Mayeux P, Lacombe C, Casadevall N, Chretien S, Dusanter I, Gisselbrecht S (1991) Structure of the murine erythropoietin receptor complex. Characterization of the erythropoietin cross-linked proteins. J Biol Chem 266: 23380–23385

    Google Scholar 

  67. Mayeux P, Dusanter-Fourt I, Muller O, Mauduit P, Sabbah M, Druker B, Vainchenker W, Fischer S, Lacombe C, Gisselbrecht S (1993) Erythropoietin induces the association of phosphatidylinositol 3’-kinase with a tyrosinephosphorylated protein complex containing the erythropoietin receptor. Eur J Biochem 216: 821–828

    Article  PubMed  CAS  Google Scholar 

  68. Middleton SA, Barbone FP, Johnson DL, Thurmond RL, You Y, McMahon FJ, Jin R, Livnah O, Tullai J, Farrell FX, Goldsmith MA, Wilson IA, Jolliffe LK (1999) Shared and unique determinants of the erythropoietin ( EPO) receptor are important for binding EPO and EPO mimetic peptide. J Biol Chem 274: 14163–14169

    Google Scholar 

  69. Middleton SA, Johnson DL, Jin R, McMahon FJ, Collins A, Tullai J, Gruninger RH, Jolliffe LK, Mulcahy LS (1996) Identification of a critical ligand binding determinant of the human erythropoietin receptor. Evidence for common ligand binding motifs in the cytokine receptor family. J Biol Chem 271: 14045–14054

    Google Scholar 

  70. Morishita E, Masuda S, Nagao M, Yasuda Y, Sasaki R (1997) Erythropoietin receptor is expressed in rat hippocampal and cerebral cortical neurons, and erythropoietin prevents in vitro glutamate-induced neuronal death. Neuroscience 76: 105–116

    Article  PubMed  CAS  Google Scholar 

  71. Ogilvie M, Yu X, Nicolas-Metral V, Pulido SM, Liu C, Ruegg UT, Noguchi CT (2000) Erythropoietin stimulates proliferation and interferes with differentiation of myoblasts. J Biol Chem 275: 39754–39761

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  73. Pollard C, Fabrice G, Martine C, Groner B, Gisselbrecht S, Dusanter-Fourt I (1995) Interleukin-3, erythropoietin, and prolactin activate a STATS like factor in lymphoid cells. J Biol Chem 270: 15942–15945

    Article  Google Scholar 

  74. Pugh CW, Ebert BL, Ebrahim O. Ratcliffe PJ (1994) Characterisation of functional domains within the mouse erythropoietin 3’ enhancer conveying oxygen-regulated responses in different cell lines. Biochim Biophys Acta 1217: 297–306

    PubMed  CAS  Google Scholar 

  75. Qiu H, Belanger A, Yoon HW, Bunn HF (1998) Homodimerization restores biological activity to an inactive erythropoietin mutant. J Biol Chem 273: 11173–11176

    Article  PubMed  CAS  Google Scholar 

  76. Quelle DE, Wojchowski DM (1991) Localized cytosolic domains of the erythropoietin receptor regulate growth signaling and down-modulate responsiveness to granulocyte-macrophage colony-stimulating factor. Proc Natl Acad Sci U S A 88: 4801–4805

    Article  PubMed  CAS  Google Scholar 

  77. Qureshi SA, Kim RM, Konteatis Z, Biazzo DE, Motamedi H, Rodrigues R, Boice JA, Calaycay JR, Bednarek MA, Griffin P, Gao YD, Chapman K, Mark DF (1999) Mimicry of erythropoietin by a nonpeptide molecule. Proc Natl Acad Sci U S A 96: 12156–12161

    Article  PubMed  CAS  Google Scholar 

  78. Ratcliffe PJ, Jones RW, Phillips RE, Nicholls LG, Bell JI (1990) Oxygen-dependent modulation of erythropoietin mRNA levels in isolated rat kidneys studied by RNase protection. J Exp Med 172: 657–660

    Article  PubMed  CAS  Google Scholar 

  79. Remy I, Wilson IA, Michnick SW (1999) Erythropoietin receptor activation by a ligand-induced conformation change. Science 283: 990–993

    Article  PubMed  CAS  Google Scholar 

  80. Salceda S, Caro J (1997) Hypoxia-inducible factor lalpha (HIF-lalpha) 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

    Google Scholar 

  81. Schneider H, Chaovapong W, Matthews DJ, Karkaria C, Cass RT, Zhan H, Boyle M, Lorenzini T, Elliott SG, Giebel LB (1997) Homodimerization of the erythropoietin receptor by a divalent monoclonal antibody triggers cell proliferation and differentiation of erythroid precursors. Blood 89: 473–482

    PubMed  CAS  Google Scholar 

  82. Schuster SJ, Badiavas EV, Costa-Giorni P, Weinmann R, Erslev AJ, Caro J (1989) Stimulation of erythropoietin gene transcription during hypoxia and cobalt exposure. Blood 73: 13–16

    PubMed  CAS  Google Scholar 

  83. Semenza GL, Dureza RC, Traystman MD, Gearhart JD, Antonarakis SE (1990) Human erythropoietin gene expression in transgenic mice: multiple transcription initiation sites and cis-acting regulatory elements. Mol Cell Biol 10: 930–938

    PubMed  CAS  Google Scholar 

  84. Semenza GL, Koury ST, Nejfelt MK, Gearhart JD, Antonarakis SE (1991a) Cell-type-specific and hypoxia-inducible expression of the human erythropoietin gene in transgenic mice. Proc Natl Acad Sci U S A 88: 8725–8729

    Article  PubMed  CAS  Google Scholar 

  85. Semenza GL, Nejfelt MK, Chi SM, Antonarakis SE (1991b) Hypoxia-inducible nuclear factors bind to an enhancer element located 3’ to the human erythropoietin gene. Proc Natl Acad Sci U S A 88: 5680–5684

    Article  PubMed  CAS  Google Scholar 

  86. Semenza GL, Traystman MD, Gearhart JD, Antonarakis SE (1989) Polycythemia in transgenic mice expressing the human erythropoietin gene. Proc Natl Acad Sci U S A 86: 2301–2305

    Article  PubMed  CAS  Google Scholar 

  87. Semenza GL, Wang GL (1992) A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol Cell Biol 12: 5447–5454

    PubMed  CAS  Google Scholar 

  88. Silva M, Grillot D, Benito A, Richard C, Nunez G, Fernandez-Luna JL (1996) Erythropoietin can promote erythroid progenitor survival by repressing apoptosis through Bcl-XL and Bc1–2. Blood 88: 1576–1582

    PubMed  CAS  Google Scholar 

  89. Socolovsky M, Fallon AE, Wang S, Brugnara C, Lodish HF (1999) Fetal anemia and apoptosis of red cell progenitors in Stat5a-/-5b-/- mice: a direct role for Stat5 in Bcl-X(L) induction. Cell 98: 181–191

    Article  PubMed  CAS  Google Scholar 

  90. Spivak JL, Pham T, Isaacs M, Hankins WD (1991) Erythropoietin is both a mitogen and a survival factor. Blood 77: 1228–1233

    PubMed  CAS  Google Scholar 

  91. Syed RS, Reid SW, Li C, Cheetham JC, Aoki KH, Liu B, Zhan H, Osslund TD, Chirino AJ, Zhang J, Finer-Moore J, Elliott S, Sitney K, Katz BA, Matthews DJ, Wendoloski JJ, Egrie J, Stroud RM (1998) Efficiency of signalling through cytokine receptors depends critically on receptor orientation. Nature 395: 511–516

    Article  PubMed  CAS  Google Scholar 

  92. Tamura K, Sudo T, Senftleben U, Dadak AM, Johnson R, Karin M (2000) Requirement for p38alpha in erythropoietin expression: a role for stress kinases in erythropoiesis. Cell 102: 221–231

    Article  PubMed  CAS  Google Scholar 

  93. Tan CC, Eckardt KU, Ratcliffe PJ (1991) Organ distribution of erythropoietin messenger RNA in normal and uremic rats. Kidney Int 40: 69–76

    Article  PubMed  CAS  Google Scholar 

  94. Teglund S, McKay C, Schuetz E, van Deursen JM, Stravopodis D, Wang D, Brown M, Bodner S, Grosveld G, Ihle JN (1998) Stat5a and Stat5b proteins have essential and nonessential, or redundant, roles in cytokine responses. Cell 93: 841–850

    Article  PubMed  CAS  Google Scholar 

  95. Van Zant G, Shultz L (1989) Hematological abnormalities of the immunodeficient mouse mutant, viable motheaten (me“). Exp Hematol 17: 81–87

    PubMed  Google Scholar 

  96. Verdier F, Chretien S, Billat C, Gisselbrecht S, Lacombe C, Mayeux P (1997) Erythropoietin induces the tyrosine phosphorylation of insulin receptor substrate-2: an alternate pathway for erythropoietin-induced phosphatidylinositol 3-kinase activation. J Biol Chem 272: 26173–26178

    Article  PubMed  CAS  Google Scholar 

  97. Verdier F, Chretien S, Muller O, Varlet P, Yoshimura A, Gisselbrecht S, Lacombe C, Mayeux P (1998) Proteasomes regulate erythropoietin receptor and signal transducer and activator of transcription 5 (STAT5) activation. Possible involvement of the ubiquitinated cis protein. J Biol Chem 273: 28185–28190

    Google Scholar 

  98. Verdier F, Walrafen P, Hubert N, Chretien S, Gisselbrecht S, Lacombe C, Mayeux P (2000) Proteasomes regulate the duration of erythropoietin receptor activation by controlling down-regulation of cell surface receptors. J Biol Chem 275: 18375–18381

    Article  PubMed  CAS  Google Scholar 

  99. Wakao H, Chida D, Damen JE, Krystal G, Miyajima A (1997) A possible involvement of Stat5 in erythropoietin-induced hemoglobin synthesis. Biochem Biophys Res Commun 234: 198–205

    Article  PubMed  CAS  Google Scholar 

  100. Wang GL, Jiang BH, Rue EA, Semenza GL (1995) 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

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  102. Wang GL, Semenza GL (1993b) General involvement of hypoxia-inducible factor 1 in transcriptional response to hypoxia. Proc Natl Acad Sci U S A 90: 4304–4308

    Article  PubMed  CAS  Google Scholar 

  103. Wang GL, Semenza GL (1995) Purification and characterization of hypoxiainducible factor 1. J Biol Chem 270: 1230–1237

    Article  PubMed  CAS  Google Scholar 

  104. Watowich SS, Yoshimura A, Longmore GD, Hilton DJ, Yoshimura Y, Lodish HF (1992) Homodimerization and constitutive activation of the erythropoietin receptor. Proc Nati Acad Sci U S A 89: 2140–2144

    Article  CAS  Google Scholar 

  105. Wen D, Boissel JP, Showers M, Ruch BC, Bunn HF (1994) Erythropoietin structure-function relationships: Identification of functionally important domains. J Biol Chem 269: 22839–22846

    Google Scholar 

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

    PubMed  CAS  Google Scholar 

  107. Witthuhn B, Quelle FW, Silvennoinen O, Yi T, Tang B, Muira O, Ihle.IN (1993) JAK2 associates with the erythropoietin receptor and is tyrosine phosphorylated and activated following Epo stimulation. Cell 74: 227–236

    CAS  Google Scholar 

  108. Wrighton NC, Farrell FX, Chang R, Kashyap AK, Barbone FP, Mulcahy LS, Johnson DL, Barrett RW, Jolliffe LK, Dower WJ (1996) Small peptides as potent mimetics of the protein hormone erythropoietin. Science 273: 458–464

    Article  PubMed  CAS  Google Scholar 

  109. Wu H, Liu X, Jaenisch R, Lodish HF (1995) Generation of committed erythroid BFU-E and CFU-E progenitors does not require erythropoietin or the erythropoietin receptor. Cell 83: 59–67

    Article  PubMed  CAS  Google Scholar 

  110. Yoshimura A, Longmore G, Lodish HF (1990) Point mutation in the exoplasmic domain of the erythropoietin receptor resulting in hormone-independent activation and tumorigenicity. Nature 348: 647–649

    Article  PubMed  CAS  Google Scholar 

  111. Yoshimura A, Ohkubo T, Kigushi T, Jenkins NA, Gilbert DJ, Copeland NG, Hara T, Miyajima A (1995) A novel cytokine-inducible gene CIS encodes an SH2-containing protein that binds to tyrosine-phosphorylated interleukin 3 and erythropoietin receptors. EMBO J 14: 2816–2826

    PubMed  CAS  Google Scholar 

  112. Zanjani ED, Ascensao JL, McGlave PB, Banisadre M, Ash RC (1981) Studies on the liver to kidney switch of erythropoietin production. J Clin Invest 67: 1183–1188

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institut National de la Santé et de la Recherche Médicale, ICGM, Université René Descartes, France

    Catherine Lacombe MD, PhD & P. Mayeux

  2. Service d’Hématologie, AP-HP, Hôpital Cochin, Paris, France

    Catherine Lacombe MD, PhD

Authors
  1. Catherine Lacombe MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. P. Mayeux
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Catherine Lacombe MD, PhD .

Editor information

Editors and Affiliations

  1. Innere Klinik und Poliklinik (Tumorforschung), Westdeutsches Tumorzentrum, Essen, Universitätsklinikum, Essen, Deutschland

    M. R. Nowrousian

Rights and permissions

Reprints and permissions

Copyright information

© 2002 Springer-Verlag/Wien

About this chapter

Cite this chapter

Lacombe, C., Mayeux, P. (2002). Biology of erythropoietin. In: Nowrousian, M.R. (eds) Recombinant Human Erythropoietin (rhEPO) in Clinical Oncology. Springer, Vienna. https://doi.org/10.1007/978-3-7091-7658-0_1

Download citation

  • DOI: https://doi.org/10.1007/978-3-7091-7658-0_1

  • Publisher Name: Springer, Vienna

  • Print ISBN: 978-3-7091-7660-3

  • Online ISBN: 978-3-7091-7658-0

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation