Abstract
Recombinant erythropoietin is a 165-amino acid glycoprotein hormone with a molecular weight of 30.4 kDa that contains 39% carbohydrate [1, 2] and has the same biologic function as the endogenous product of a human gene located on chromosome 7q22 [3, 4]. Both the endogenous material (eEPO), and recombinant human glycoprotein (rHuEPO) bind a single receptor (EPOR) [5–7]. Although data from one group challenge this concept by suggesting signaling through a heterodimeric receptor including the beta-common cytokine receptor [8], these data have yet to be confirmed by other groups. For some years it had been widely accepted that EPOR was expressed broadly within the body in both normal and diseased tissues (e.g., [9]), but as discussed elsewhere in this book, methodological flaws in almost all of the published data draw this conclusion into doubt. To date, it is possible only to conclude with certainty that EPOR is expressed at effective levels in erythroid tissues in the bone marrow and spleen, so our discussion will focus only on the function of EPOR in that context.
Keywords
- Darbepoetin Alfa
- Recombinant Human Erythropoietin
- Erythropoietin Receptor
- Erythropoietic Agent
- Hemoglobin Response
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.
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsPreview
Unable to display preview. Download preview PDF.
References
Lai PH, Everett R, Wang FF et al. Structural characterization of human erythropoietin. J Biol Chem 1986;261:3116–3121.
Browne JK, Cohen AM, Egrie JC. Erythropoietin: Gene cloning protein structure and biological properties. Cold Spring Harbor Symp Quant Biol 1986;51:693–702.
Davis JM, Arakawa T, Strickland TW et al. Characterization of recombinant human erythropoietin produced in Chinese hamster ovary cells. Biochemistry 1987;26:2633–2638.
Law ML, Cai GY, Lin FK et al. Chromosomal assignment of the human erythropoietin gene and its DNA polymorphism. Proc Natl Acad Sci USA 1986;83:6920–6924.
D’Andrea AD, Lodish HF, Wong GG. Expression cloning of the murine erythropoietin receptor. Cell 1989;57:277–285.
Noguchi CT, Bae KS, Chin K et al. Cloning of the human erythropoietin receptor gene. Blood 1991;78:2548–2556.
Maouche L, Tournamille C, Hattab C et al. Cloning of the gene encoding the human erythropoietin receptor. Blood 1991;78:2557–2563.
Brines M, Grasso G, Fiordaliso F et al. Erythropoietin mediates tissue protection through an erythropoietin and common β-subunit heteroreceptor. Proc Natl Acad Sci USA 2004;101:14907–14912.
Juul SE, Yachnis AT, Christensen RD. Tissue distribution of erythropoietin and erythropoietin receptor in the developing human fetus. Early Human Dev 1998;52:235–249
Wagner KF, Katschinski DM, Hasegawa J et al. Chronic inborn erythrocytosis leads to cardiac dysfunction and premature death in mice overexpressing erythropoietin. Blood 2001;97:536–542.
Wu H, Liu X, Jaenisch R et al. Generation of committed erythroid BFU-E and CFU-E progenitors does not require erythropoietin or the erythropoietin receptor. Cell 1995;83:59–67.
Lin CS, Lim SK, D’Agati V et al. Differential effects of an erythropoietin receptor gene disruption on primitive and definitive erythropoiesis. Genes Dev 1996;10:154–164.
Wu H, Lee SH, Gao J et al. Inactivation of erythropoietin leads to detects in cardiac morphogenesis. Development 1999;126:3597–3605.
Suzuki N, Ohneda O, Takahashi S et al. Erythroid-specific expression of the erythropoietin receptor rescued its null mutant mice from lethality. Blood 2002;100:2279–2288.
Chen ZY, Asavaritikrai P, Prchal JT et al. Endogenous erythropoietin signaling is required for normal neural progenitor cell proliferation. J Biol Chem 2007;282:25875–25883.
Tsai PT, Ohab JJ, Kertesz N et al. A critical role of erythropoietin receptor in neurogenesis and post-stroke recovery. J Neurosci 2006;26:1269–1274.
Hsieh MM, Linde NS, Wynter A et al. HIF-prolyl hydroxylase inhibition results in endogenous erythropoietin induction, erythrocytosis, and modest fetal hemoglobin expression in rhesus macaques. Blood 2007;110:2140–2147.
Sasaki H, Bothner B, Dell A et al. Carbohydrate structure of erythropoietin expressed in Chinese hamster ovary cells by a human erythropoietin cDNA. J Biol Chem 1987;262:12059–12076.
Kawasaki N, Haishima Y, Ohta M et al. Structural analysis of sulfated N-linked oligosaccharides in erythropoietin. Glycobiology 2001;11: 1043–1049.
Lu X, Gross AW, Lodish HF. Active conformation of the erythropoietin receptor: Random and cysteine-scanning mutagenesis of the extracellular juxtamembrane and transmembrane domains. J Biol Chem 2006;281:7002–7011.
Cheetham JC, Smith DM, Aoki KH et al. NMR structure of human erythropoietin and a comparison with its receptor bound conformation. Nat Struct Biol 2006;5:861–866.
Sawyer ST, Hankins WD. The functional form of the erythropoietin receptor is a 78-kDa protein: correlation with cell surface expression, endocytosis and phosphorylation. Proc Nat Acad Sci USA 1993;90:6849–6853.
Gross AW, Lodish HF. Cellular trafficking and degradation of erythropoietin and novel erythropoiesis stimulating protein (NESP). J Biol Chem 2006;281:2024–2032.
Liu Z, Stoll VS, DeVries PJ et al. A potent erythropoietin-mimicking human antibody interacts through a novel binding site. Blood 2007;110:2408–2413.
Broudy VC, Lin N, Brice M et al. Erythropoietin receptor characteristics on primary human erythroid cells. Blood 1991;77:2583–2590.
Constantinescu SN, Keren T, Socolovsky M et al. Ligand-independent oligomerization of cell-surface erythropoietin receptor is mediated by the transmembrane domain. Proc Natl Acad Sci USA 2001;98:4379–4384.
Frank SJ. Receptor dimerization in GH and erythropoietin action — it takes two to tango, but how? Endocrinology 2002;143:2–10.
Cheung JY, Miller BA. Molecular mechanisms of erythropoietin signaling. Nephron 2001;87:215–222.
Wojchowski DM, Gregory RC, Miller CP et al. Signal transduction in the erythropoietin receptor system. Exp Cell Res 1999;253:143–156.
Chen C, Sytkowski AJ. Erythropoietin activates two distinct signaling pathways required for the initiation and the elongation of c-myc. J Biol Chem 2001;276:38518–38526.
von Lindern M, Parren-van Amelsvoort M, van Dijk T et al. Protein kinase C alpha controls erythropoietin receptor signaling. J Biol Chem 2000;275:34719–34727.
Koury MJ, Bondurant MC. Erythropoietin retards DNA breakdown and prevents programmed death in erythroid progenitor cells. Science 1990;248:378–381.
Koury MJ, Bondurant MC. Control of red cell production: the roles of programmed cell death (apoptosis) and erythropoietin. Transfusion 1990;30:673–674.
Spivak JL, Pham T, Isaacs M et al. Erythropoietin is both a mitogen and a survival factor. Blood 1991;77:1228–1233.
Krantz SB. Erythropoietin. Blood 1991;77:419–434.
Cynshi O, Satoh K, Higuchi M et al. Effects of recombinant human erythropoietin on anaemic W/Wv and Sl/Sld mice. Br J Haematol 1990;75:319–324.
Pharr PN, Hofbauer A, Worthington RE et al. Residual erythroid progenitors in W/W mice respond to erythropoietin in the absence of steel factor signals. Int J Hematol 2000;72:178–185
Kapur R, Zhang L. A novel mechanism of cooperation between c-Kit and erythropoietin receptor. Stem cell factor induces the expression of Stat5 and erythropoietin receptor, resulting in efficient proliferation and survival by erythropoietin. J Biol Chem 2001;276:1099–1106.
Woo S, Jusko WJ. Interspecies comparisons of pharacokinetics and pharmacodynamics of recombinant human erythropoietin. Drug Metab Dispos 2007;35:1672–1678.
Rice L, Ruiz W, Driscoll T et al. Neocytolysis on descent from altitude: a newly recognized mechanism for the control of red cell mass. Ann Intern Med 2001;134:652–656.
Rice L, Alfrey CP. Modulation of red cell mass by neocytolysis in space and on Earth. Pflügers Arch 2000;441:R91–R94.
Trial J, Rice L, Alfrey CP. Erythropoietin withdrawal alters interactions between young red blood cells, splenic endothelial cells, and macrophages: an in vitro model of neocytolysis. J Investig Med 2001;49:335–345.
Cotes PM, Bangham DR. Bio-assay of erythropoietin in mice male polycythaemic by exposure to air at reduced pressure. Nature 1961;191:1065–1067.
Elliott S, Egrie J, Browne J et al. Control of rHuEPO biological activity: The role of carbohydrate. Exp Hematol 2004;32:1146–1155.
Goldwasser E, White WF. Fed Proc 1959;18:236
Ebert BL, Bunn HF. Regulation of the erythropoietin gene. Blood 1999;94:1864–1877
Jacobson LO, Goldwasser E, Gurney CW. Transfusion induced polycythemia as a model for studying factors influencing erythropoiesis. In: CIBA Foundation Symposium on Haemopoiesis. GEW Wolstenhome & M O’Connor, Eds: 1960;423. Little Brown and Co Boston, Mass.
Cotes PM, Bangham DR. An international reference preparation for bioassay of erythropoietin. Bull Wld Hlth Org 1966;35:751
Sasu BJ, Hartley C, Schultz H et al. Comparison of Epoetin alfa and darbepoetin alfa biological activity under different administration schedules in normal mice. Acta Haematologica 2005;113:163–174.
Macdougall IC. Role of uremic toxins in exacerbating anemia in renal failure. Kidney Int Suppl 2001;78:S67–S72.
Macdougall IC, Cooper A. The inflammatory response and epoetin sensitivity. Nephrol Dial Transplant 2002;17:48–52.
Casadevall N, Dupuy E, Molho-Sabatier P et al. Autoantibodies against erythropoietin in a patient with pure red-cell aplasia. N Engl J Med 1996;334:630–633.
Voulgarelis M, Kokori SI, Ioannidis JP et al. Anaemia in systemic lupus erythematosus: aetiological profile and the role of erythropoietin. Ann Rheum Dis 2000;59:217–222.
Tzioufas AG, Kokori SI, Petrovas CI et al. Autoantibodies to human recombinant erythropoietin in patients with systemic lupus erythematosus: correlation with anemia. Arthritis Rheum 1997;40:2212–2216.
Sipsas NV, Kokori SI, Ioannidis JP et al. Circulating autoantibodies to erythropoietin are associated with human immunodeficiency virus type 1-related anemia. J Infect Dis 1999;180:2044–2047.
Kuramochi S, Ikawa Y, Todokoro K. Characterization of murine erythropoietin receptor genes. J Mol Biol 1990;216:567–575.
Hercberg S, Preziosi P, Galan P. Iron deficiency in Europe. Public Health Nutr 2001;4:537–545.
Bayoumeu F, Subiran-Buisset C, Baka NE et al. Iron therapy in iron deficiency anemia in pregnancy: intravenous route versus oral route. Am J Obstet Gynecol 2002;186:518–522.
Stoves J, Inglis H, Newstead CG. A randomized study of oral versus intravenous iron supplementation in patients with progressive renal insufficiency treated with erythropoietin. Nephrol Dial Transplant 2001;16:967–974.
Bayoumeu F, Subiran-Buisset C, Baka NE et al. Iron therapy in iron deficiency anemia in pregnancy: intravenous route versus oral route. Am J Obstet Gynecol 2002;186:518–522.
Stoves J, Inglis H, Newstead CG. A randomized study of oral versus intravenous iron supplementation in patients with progressive renal insufficiency treated with erythropoietin. Nephrol Dial Transplant 2001;16:967–974.
Pak M, Lopez MA, Gabayan V et al. Suppression of hepcidin during anemia requires erythropoietic activity. Blood 2006;108:3730–3735.
Wen D, Boissel JP, Tracy TE et al. Erythropoietin structure-function relationships: high degree of sequence homology among mammals. Blood 1993;82:1507–1516.
David RB, Blom AK, Sjaastad OV et al. The porcine erythropoietin gene: cDNA sequence, genomic sequence and expression analyses in piglets. Domest Anim Endocrinol 2001;20:137–147.
Arai M, Darman J, Lewis A et al. The use of human hematopoietic growth factors (rhGM-CSF and rhEPO) as a supportive therapy for FIV-infected cats. Vet Immunol Immunopathol 2000;77:71–92.
Manire CA, Rhinehart HL. Use of human recombinant erythropoietin for the treatment of nonregenerative anemia in a rough-toothed dolphin (Steno bredanensis). J Zoo Wildl Med 2000;31:57–163.
McKeever KH. Erythropoietin: a new form of blood doping in horses. Proceedings of the 11th International Conference of Racing Analysts and Veterinarians. 1996;79–84. R&W Press, Newmarket, UK.
Catania MA, Marciano MC, Parisi A et al. Erythropoietin prevents cognition impairment induced by transient brain ischemia in gerbils. Eur J Pharmacol 2002;437:147–150.
Grasso G, Passalacqua M, Sfacteria A et al. Does administration of recombinant human erythropoietin attenuate the increase of S-100 protein observed in cerebrospinal fluid after experimental subarachnoid hemorrhage? J Neurosurg 2002;96:565–570.
Chapel SH, Veng-Pedersen P, Schmidt RL et al. A pharmacodynamic analysis of erythropoietinstimulated reticulocyte response in phlebotomized sheep. J Pharmacol Exp Ther 2000;295:346–351.
Piercy RJ, Swardson CJ, Hinchcliff KW. Erythroid hypoplasia and anemia following administration of recombinant human erythropoietin to two horses. J Am Vet Med Assoc 1998;212:244–247.
Winearls CG, Oliver DO, Pippard MJ et al. Effect of human erythropoietin derived from recombinant DNA on the anaemia of patients maintained by chronic haemodialysis. Lancet 1986;2:1175–1178.
Eschbach JW, Egrie JC, Downing MR et al. Correction of the anemia of end-stage renal disease with recombinant human erythropoietin. Results of a combined phase I and II clinical trial. N Engl J Med 1987;316:73–78.
Adamson JW, Eschbach JW. Treatment of the anemia of chronic renal failure with recombinant human erythropoietin. Annu Rev Med 1990;41:349–360.
The US Recombinant Human Erythropoietin Predialysis Study Group. Double-blind, placebocontrolled study of the therapeutic use of recombinant human erythropoietin for anemia associated with chronic renal failure in predialysis patients. Am J Kidney Dis 1991;18:50–59.
Mohini R. Clinical efficacy of recombinant human erythropoietin in hemodialysis patients. Semin Nephrol 1991;9:16–21.
Satoh K, Masuda T, Ikeda Y et al. Hemodynamic changes by recombinant erythropoietin therapy in hemodialyzed patients. Hypertension 1990;15:262–266.
Brown WS, Marsh JT, Wolcott D et al. Cognitive function, mood and P3 latency: effects of the amelioration of anemia in dialysis patients. Neuropsychologia 1991;29:35–45.
Chmielewski CM. Case study of the anemic patient: epoetin alfa — focus on erythrokinetics. ANNA J 1995;22:420–423.
Nowrousian MR. Definition, classification and characterization of anemia in cancer. Recombinant Human Erythropoietin (rhEPO) in Clinical Oncology. Springer-Verlag/Wien, New York 2008;5:117–148.
Beguin Y. Erythropoietin and the anemia of cancer. Acta Clin Belg 1996;51:36–52.
Ludwig H, Fritz E. Anemia of cancer patients: patient selection and patient stratification for epoetin treatment. Semin Oncol 1998;25:35–38.
Ludwig H, Fritz E. Anemia in cancer patients. Semin Oncol 1998;25:2–6.
Bron D, Meuleman N, Mascaux C. Biological basis of anemia. Semin Oncol 2001;28:1–6.
Ludwig H, Pecherstorfer M, Leitgeb C et al. Recombinant human erythropoietin for the treatment of chronic anemia in multiple myeloma and squamous cell carcinoma. Stem Cells 1993;11:348–355.
DeGowin RL, Gibson DP. Erythropoietin and the anemia of mice bearing extramedullary tumor. J Lab Clin Med 1979;94:303–311.
Zarrabi MH, Lysik R, DiStefano J et al. The anaemia of chronic disorders: studies of iron reutilization in the anaemia of experimental malignancy and chronic inflammation. Br J Haematol 1977;35:647–658.
Leng HM, Albrecht CF, Kidson SH et al. Erythropoietin production in anemia associated with experimental cancer. Exp Hematol 1999;27:806–810.
Fisher JW, Roh BL. Influence of alkylating agents on kidney erythropoietin production. Cancer Res 1964;24:983–988.
Magid E, Hausen P. The erythropoietin content of plasma from sheep treated with nitrogen mustard. Scand J Clin Lab Invest 1966;18:347–352.
Barcelo AC, Bozzini CE. Erythropoietin formation during hypoxia in mice with impaired responsiveness to erythropoietin induced by irradiation or 5-fluorouracil injection. Experientia 1982;38:504–505.
Zucker S, Friedman S, Lysik RM. Bone marrow erythropoiesis in the anemia of infection, inflammation, and malignancy. J Clin Invest 1974;53:1132–1138.
Lockner D. Iron absorption and serum erythropoietin concentration in patients with cancer of the uterine cervix. Acta Med Scand 1966;180:651–655.
Schreuder WO, Ting WC, Smith S et al. Testosterone, erythropoietin and anaemia in patients with disseminated bronchial cancer. Br J Haematol 1984;57:521–526.
Miller CB, Jones RJ, Piantadosi S et al. Decreased erythropoietin response in patients with the anemia of cancer. N Engl J Med 1990;322:1689–1692.
Smith DH, Goldwasser E, Vokes EE. Serum immunoerythropoietin levels in patients with cancer receiving cisplatin-based chemotherapy. Cancer 1991;68:1101–1105.
Greendyke RM, Sharma K, Gifford FR. Serum levels of erythropoietin and selected other cytokines in patients with anemia of chronic disease. Am J Clin Pathol 1994;101:338–341.
Ponchio L, Beguin Y, Farina G et al. Evaluation of erythroid marrow response to recombinant human erythropoietin in patients with cancer anaemia. Haematologica 1992;77:494–501.
Ozguroglu M, Arun B, Demir G et al. Serum erythropoietin level in anemic cancer patients. Med Oncol 2000;17:29–34.
Groopman JE, Itri LM. Chemotherapy-induced anemia in adults: incidence and treatment. J Natl Cancer Inst 1999;91:1616–1634.
Corazza F, Beguin Y, Bergmann P et al. Anemia in children with cancer is associated with decreased erythropoietic activity and not with inadequate erythropoietin production. Blood 1998;92:1793–1798.
Itri LM. The use of epoetin alfa in chemotherapy patients: a consistent profile of efficacy and safety. Semin Oncol 2002;29:81–87.
Migliaccio AR, Migliaccio G, D’Andrea A et al. Response to erythropoietin in erythroid subclones of the factor-dependent cell line 32D is determined by translocation of the erythropoietin receptor to the cell surface. Proc Natl Acad Sci USA 1991;88:11086–11090.
Huang LJ, Constantinescu SN, Lodish HF. The N-terminal domain of Janus kinase 2 is required for Golgi processing and cell surface expression of erythropoietin receptor. Mol Cells 2001;8:1327–1338.
Nakamura Y, Komatsu N, Nakauchi H. A truncated erythropoietin receptor that fails to prevent programmed cell death of erythroid cells. Science 1992;257:1138–1141.
Sinclair AM, Rogers N, Busse L et al. Erythropoietin receptor transcription is neither elevated nor predictive of surface expression in human tumour cells. Br J Cancer 2008;98:1059–1067.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2009 Birkhäuser Verlag/Switzerland
About this chapter
Cite this chapter
Molineux, G., Sinclair, A.M. (2009). Biology of erythropoietin. In: Elliott, S.G., Foote, M.A., Molineux, G. (eds) Erythropoietins, Erythropoietic Factors, and Erythropoiesis. Milestones in Drug Therapy. Birkhäuser Basel. https://doi.org/10.1007/978-3-7643-8698-6_3
Download citation
DOI: https://doi.org/10.1007/978-3-7643-8698-6_3
Publisher Name: Birkhäuser Basel
Print ISBN: 978-3-7643-8694-8
Online ISBN: 978-3-7643-8698-6
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)