The molecular biology of erythropoietin.

Erythropoietin (Epo) controls the proliferation, differentiation and survival of the erythroid progenitors. Epo exerts its effects by binding to a cell surface receptor. The Epo receptor includes a p66 chain, which is dimerized upon Epo activation, and two accessory proteins, which have been defined by cross-linking. Epo binding induces stimulation of the Jak2 tyrosine kinase. Jak2 activation leads to the tyrosine phosphorylation of several proteins, including the Epo receptor itself. Different intracellular pathways are activated: Ras/MAP kinase, phosphatidylinositol 3-kinase and STAT transcription factors. However, the exact mechanisms by which the proliferation and/or differentiation of erythroid cells are regulated after Epo stimulation are not known. Target disruption of both Epo and Epo receptors showed that Epo is not involved in the commitment of the erythroid lineage; it seems to act mainly as a survival factor. Epo is synthesized largely by the kidney and the liver, and sequences required for tissue-specific expression have been localized in the Epo gene. A 3' enhancer is responsible for hypoxia-inducible Epo gene expression. Hypoxia-induced factor-1 (HIF-1) protein binds to this enhancer. In addition to anaemia of renal failure, the indication for treatment with epoetin has been extended to the anaemia of chronic diseases.

[1]  M. Goldsmith,et al.  Redundant and selective roles for erythropoietin receptor tyrosines in erythropoiesis in vivo. , 1998, Blood.

[2]  M. Gassmann,et al.  Oxygen(es) and the hypoxia-inducible factor-1. , 1997, Biological chemistry.

[3]  W. Vainchenker,et al.  Ectopic expression of the erythropoietin receptor in a murine interleukin-6-dependent plasmacytoma cell line (TEPC-2027) confers proliferative responsiveness to erythropoietin. , 1997, Blood.

[4]  S. Bhattacharya,et al.  An essential role for p300/CBP in the cellular response to hypoxia. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[5]  J. Krosl,et al.  Interleukin-3 (IL-3) Inhibits Erythropoietin-induced Differentiation in Ba/F3 Cells via the IL-3 Receptor α Subunit* , 1996, The Journal of Biological Chemistry.

[6]  Ronald W. Barrett,et al.  Small Peptides as Potent Mimetics of the Protein Hormone Erythropoietin , 1996, Science.

[7]  R. O. Poyton,et al.  Oxygen sensing and molecular adaptation to hypoxia. , 1996, Physiological reviews.

[8]  J. Ihle,et al.  Erythropoietin induces activation of Stat5 through association with specific tyrosines on the receptor that are not required for a mitogenic response , 1996, Molecular and cellular biology.

[9]  V. D’Agati,et al.  Differential effects of an erythropoietin receptor gene disruption on primitive and definitive erythropoiesis. , 1996, Genes & development.

[10]  J. Ihle.  Cytokine receptor signalling , 1995, Nature.

[11]  Rudolf Jaenisch,et al.  Generation of committed erythroid BFU-E and CFU-E progenitors does not require erythropoietin or the erythropoietin receptor , 1995, Cell.

[12]  H. Lodish,et al.  Interaction of the erythropoietin and stem-cell-factor receptors , 1995, Nature.

[13]  B. Groner,et al.  Interleukin-3, Erythropoietin, and Prolactin Activate a STAT5-like Factor in Lymphoid Cells (*) , 1995, The Journal of Biological Chemistry.

[14]  H. Lodish,et al.  Activation and inhibition of erythropoietin receptor function: role of receptor dimerization , 1994, Molecular and cellular biology.

[15]  M. Goldberg,et al.  Physiology of erythropoietin production. , 1994, Seminars in hematology.

[16]  G. Semenza,et al.  Characterization of hypoxia-inducible factor 1 and regulation of DNA binding activity by hypoxia. , 1993, The Journal of biological chemistry.

[17]  W. Vainchenker,et al.  Granulocyte-macrophage colony-stimulating factor and erythropoietin act competitively to induce two different programs of differentiation in the human pluripotent cell line UT-7. , 1992, Blood.

[18]  A. Wickrema,et al.  Differentiation and erythropoietin receptor gene expression in human erythroid progenitor cells. , 1992, Blood.

[19]  S. Krantz,et al.  Progress in understanding the pathogenesis of the anemia of chronic disease. , 1992, Blood.

[20]  T. Chiba,et al.  Functionally essential cytoplasmic domain of the erythropoietin receptor. , 1992, Biochemical and biophysical research communications.

[21]  H. Lodish,et al.  Homodimerization and constitutive activation of the erythropoietin receptor. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[22]  H. Lodish,et al.  An activating mutation in the murine erythropoietin receptor induces erythroleukemia in mice: A cytokine receptor superfamily oncogene , 1991, Cell.

[23]  J. Ihle,et al.  Induction of tyrosine phosphorylation by the erythropoietin receptor correlates with mitogenesis , 1991, Molecular and cellular biology.

[24]  S. Antonarakis,et al.  Hypoxia-inducible nuclear factors bind to an enhancer element located 3' to the human erythropoietin gene. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[25]  U. Reinhold.  Interferon‐Gamma , 1991, International journal of dermatology.

[26]  V. Broudy,et al.  Erythropoietin receptor characteristics on primary human erythroid cells. , 1991, Blood.

[27]  D. Quelle,et al.  Localized cytosolic domains of the erythropoietin receptor regulate growth signaling and down-modulate responsiveness to granulocyte-macrophage colony-stimulating factor. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[28]  O. Hankinson,et al.  Cloning of a factor required for activity of the Ah (dioxin) receptor. , 1991, Science.

[29]  L. Zon,et al.  The cytoplasmic region of the erythropoietin receptor contains nonoverlapping positive and negative growth-regulatory domains , 1991, Molecular and cellular biology.

[30]  J. Spivak,et al.  Erythropoietin is both a mitogen and a survival factor. , 1991, Blood.

[31]  L. Zon,et al.  Erythropoietin receptor. Subunit structure and activation. , 1990, The Journal of clinical investigation.

[32]  P. Sperryn,et al.  Blood. , 1989, British journal of sports medicine.

[33]  J. Adamson,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. , 1987, The New England journal of medicine.

[34]  C. H. Lin,et al.  Cloning and expression of the human erythropoietin gene. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[35]  A. Eaves,et al.  Three stages of erythropoietic progenitor cell differentiation distinguished by a number of physical and biologic properties. , 1978, Blood.

[36]  E. Goldwasser,et al.  Purification of human erythropoietin. , 1977, The Journal of biological chemistry.

[37]  A. Eaves,et al.  Human marrow cells capable of erythropoietic differentiation in vitro: definition of three erythroid colony responses. , 1977, Blood.

[38]  Robert H. Taylor,et al.  Immune checkpoint inhibitor therapy and outcomes from SARS-CoV-2 infection in patients with cancer: a joint analysis of OnCovid and ESMO-CoCARE registries , 2022, Immuno-Oncology and Technology.

[39]  H. Nakauchi,et al.  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. , 1991, Cancer research.

[40]  V. Broudy,et al.  Erythropoietin receptor characteristics on primary human erythroid cells. , 1991, Blood.

[41]  R. Weinmann,et al.  Stimulation of erythropoietin gene transcription during hypoxia and cobalt exposure. , 1989, Blood.

[42]  E. Fritsch,et al.  Isolation and characterization of genomic and cDNA clones of human erythropoietin , 1985, Nature.