Survival and proliferative roles of erythropoietin beyond the erythroid lineage

Constance Tom Noguchi; Li Wang; Heather M. Rogers; Ruifeng Teng; Yi Jia

doi:10.1017/S1462399408000860

Survival and proliferative roles of erythropoietin beyond the erythroid lineage

Published online by Cambridge University Press: 01 December 2008

Constance Tom Noguchi ,

Li Wang ,

Heather M. Rogers ,

Ruifeng Teng and

Yi Jia

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Constance Tom Noguchi*: Affiliation:
Molecular Medicine Branch, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda MD, USA.
Li Wang: Affiliation:
Molecular Medicine Branch, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda MD, USA.
Heather M. Rogers: Affiliation:
Molecular Medicine Branch, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda MD, USA.
Ruifeng Teng: Affiliation:
Molecular Medicine Branch, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda MD, USA.
Yi Jia: Affiliation:
Molecular Medicine Branch, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda MD, USA.
*: *Corresponding author: Constance Tom Noguchi, Molecular Medicine Branch, NIDDK, National Institutes of Health, Building 10, Room 9N319, 10 CENTER DR MSC-1822, Bethesda, MD 20892-1822, USA. Tel: +1 301 496 1163; Fax: +1 301 402 0101; E-mail: [email protected]

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Abstract

Since the isolation and purification of erythropoietin (EPO) in 1977, the essential role of EPO for mature red blood cell production has been well established. The cloning of the EPO gene and production of recombinant human EPO led to the widespread use of EPO in treating patients with anaemia. However, the biological activity of EPO is not restricted to regulation of erythropoiesis. EPO receptor (EPOR) expression is also found in endothelial, brain, cardiovascular and other tissues, although at levels considerably lower than that of erythroid progenitor cells. This review discusses the survival and proliferative activity of EPO that extends beyond erythroid progenitor cells. Loss of EpoR expression in mouse models provides evidence for the role of endogenous EPO signalling in nonhaematopoietic tissue during development or for tissue maintenance and/or repair. Determining the extent and distribution of receptor expression provides insights into the potential protective activity of EPO in brain, heart and other nonhaematopoietic tissues.

Type: Review Article
Information: Expert Reviews in Molecular Medicine , Volume 10 , October 2008 , e36

DOI: https://doi.org/10.1017/S1462399408000860 [Opens in a new window]
Copyright: Published by Cambridge University Press. Work by a US government employee - not in copyright in the USA.

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References

1Miyake, T., Kung, C.K. and Goldwasser, E. (1977) Purification of human erythropoietin. J Biol Chem 252, 5558-5564CrossRef Google Scholar PubMed

2Lin, F.K. et al. (1985) Cloning and expression of the human erythropoietin gene. Proc Natl Acad Sci U S A 82, 7580-7584CrossRef Google Scholar PubMed

3Jacobs, K. et al. (1985) Isolation and characterization of genomic and cDNA clones of human erythropoietin. Nature 313, 806-810CrossRef Google Scholar PubMed

4Lai, P.H. et al. (1986) Structural characterization of human erythropoietin. J Biol Chem 261, 3116-3121CrossRef Google Scholar PubMed

5Wen, D. et al. (1994) Erythropoietin structure-function relationships. Identification of functionally important domains. J Biol Chem 269, 22839-22846Google Scholar PubMed

6Sasaki, H. et al. (1987) Carbohydrate structure of erythropoietin expressed in Chinese hamster ovary cells by a human erythropoietin cDNA. J Biol Chem 262, 12059-12076CrossRef Google Scholar PubMed

7Wasley, L.C. et al. (1991) The importance of N- and O-linked oligosaccharides for the biosynthesis and in vitro and in vivo biologic activities of erythropoietin. Blood 77, 2624-2632CrossRef Google Scholar

8Higuchi, M. et al. (1992) Role of sugar chains in the expression of the biological activity of human erythropoietin. J Biol Chem 267, 7703-7709CrossRef Google Scholar PubMed

9Fukuda, M.N. et al. (1989) Survival of recombinant erythropoietin in the circulation: the role of carbohydrates. Blood 73, 84-89CrossRef Google Scholar PubMed

10Tsuda, E. et al. (1990) The role of carbohydrate in recombinant human erythropoietin. Eur J Biochem 188, 405-411CrossRef Google Scholar PubMed

11Zanjani, E.D. et al. (1981) Studies on the liver to kidney switch of erythropoietin production. J Clin Invest 67, 1183-1188CrossRef Google Scholar PubMed

12Dame, C. et al. (1998) Erythropoietin mRNA expression in human fetal and neonatal tissue. Blood 92, 3218-3225CrossRef Google Scholar PubMed

13Obara, N. et al. (2008) Repression via the GATA box is essential for tissue-specific erythropoietin gene expression. Blood 111, 5223-5232CrossRef Google Scholar PubMed

14Juul, S.E., Yachnis, A.T. and Christensen, R.D. (1998) Tissue distribution of erythropoietin and erythropoietin receptor in the developing human fetus. Early Hum Dev 52, 235-249CrossRef Google Scholar PubMed

15Koury, S.T. et al. (1991) Localization of cells producing erythropoietin in murine liver by in situ hybridization. Blood 77, 2497-2503CrossRef Google Scholar PubMed

16Kochling, J., Curtin, P.T. and Madan, A. (1998) Regulation of human erythropoietin gene induction by upstream flanking sequences in transgenic mice. Br J Haematol 103, 960-968CrossRef Google Scholar PubMed

17Bondurant, M.C. and Koury, M.J. (1986) Anemia induces accumulation of erythropoietin mRNA in the kidney and liver. Mol Cell Biol 6, 2731-2733Google Scholar PubMed

18Tan, C.C., Eckardt, K.U. and Ratcliffe, P.J. (1991) Organ distribution of erythropoietin messenger RNA in normal and uremic rats. Kidney Int 40, 69-76CrossRef Google Scholar PubMed

19Fandrey, J. and Bunn, H.F. (1993) In vivo and in vitro regulation of erythropoietin mRNA: measurement by competitive polymerase chain reaction. Blood 81, 617-623CrossRef Google Scholar PubMed

20Maxwell, P.H. et al. (1993) Identification of the renal erythropoietin-producing cells using transgenic mice. Kidney Int 44, 1149-1162CrossRef Google Scholar PubMed

21Koury, S.T., Bondurant, M.C. and Koury, M.J. (1988) Localization of erythropoietin synthesizing cells in murine kidneys by in situ hybridization. Blood 71, 524-527CrossRef Google Scholar PubMed

22Eckardt, K.U. et al. (1993) Distribution of erythropoietin producing cells in rat kidneys during hypoxic hypoxia. Kidney Int 43, 815-823CrossRef Google Scholar PubMed

23Semenza, G.L. et al. (1991) Cell-type-specific and hypoxia-inducible expression of the human erythropoietin gene in transgenic mice. Proc Natl Acad Sci U S A 88, 8725-8729CrossRef Google Scholar PubMed

24Semenza, G.L. and Wang, G.L. (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, 5447-5454Google Scholar

25Galson, D.L. et al. (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, 2135-2144CrossRef Google Scholar PubMed

26Ebert, B.L. and Bunn, H.F. (1999) Regulation of the erythropoietin gene. Blood 94, 1864-1877CrossRef Google Scholar PubMed

27Metzen, E. and Ratcliffe, P.J. (2004) HIF hydroxylation and cellular oxygen sensing. Biol Chem 385, 223-230CrossRef Google Scholar PubMed

28Smith, T.G., Robbins, P.A. and Ratcliffe, P.J. (2008) The human side of hypoxia-inducible factor. Br J Haematol 141, 325-334CrossRef Google Scholar PubMed

29Hu, C.J. et al. (2007) The N-terminal transactivation domain confers target gene specificity of hypoxia-inducible factors HIF-1alpha and HIF-2alpha. Mol Biol Cell 18, 4528-4542CrossRef Google Scholar PubMed

30Percy, M.J. et al. (2006) A family with erythrocytosis establishes a role for prolyl hydroxylase domain protein 2 in oxygen homeostasis. Proc Natl Acad Sci U S A 103, 654-659CrossRef Google Scholar PubMed

31Ang, S.O. et al. (2002) Disruption of oxygen homeostasis underlies congenital Chuvash polycythemia. Nat Genet 32, 614-621CrossRef Google Scholar PubMed

32Warnecke, C. et al. (2004) 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 Hep3B and Kelly cells. FASEB J 18, 1462-1464CrossRef Google Scholar PubMed

33Rankin, E.B. et al. (2007) Hypoxia-inducible factor-2 (HIF-2) regulates hepatic erythropoietin in vivo. J Clin Invest 117, 1068-1077CrossRef Google Scholar PubMed

34Chavez, J.C. et al. (2006) The transcriptional activator hypoxia inducible factor 2 (HIF-2/EPAS-1) regulates the oxygen-dependent expression of erythropoietin in cortical astrocytes. J Neurosci 26, 9471-9481CrossRef Google Scholar PubMed

35Gruber, M. et al. (2007) Acute postnatal ablation of Hif-2alpha results in anemia. Proc Natl Acad Sci U S A 104, 2301-2306CrossRef Google Scholar PubMed

36Zelzer, E. et al. (1998) Insulin induces transcription of target genes through the hypoxia-inducible factor HIF-1alpha/ARNT. EMBO J 17, 5085-5094CrossRef Google Scholar PubMed

37Percy, M.J. et al. (2008) A gain-of-function mutation in the HIF2A gene in familial erythrocytosis. N Engl J Med 358, 162-168CrossRef Google Scholar PubMed

38Blanchard, K.L. et al. (1992) Hypoxic induction of the human erythropoietin gene: cooperation between the promoter and enhancer, each of which contains steroid receptor response elements. Mol Cell Biol 12, 5373-5385Google Scholar PubMed

39Ebert, B.L. and Bunn, H.F. (1998) Regulation of transcription by hypoxia requires a multiprotein complex that includes hypoxia-inducible factor 1, an adjacent transcription factor, and 300/CREB binding protein. Mol Cell Biol 18, 4089–4096Google Scholar

40Makita, T., Duncan, S.A. and Sucov, H.M. (2005) Retinoic acid, hypoxia, and GATA factors cooperatively control the onset of fetal liver erythropoietin expression and erythropoietic differentiation. Dev Biol 280, 59-72CrossRef Google Scholar PubMed

41Makita, T. et al. (2001) A developmental transition in definitive erythropoiesis: erythropoietin expression is sequentially regulated by retinoic acid receptors and HNF4. Genes Dev 15, 889-901CrossRef Google Scholar PubMed

42Alberta, J.A. et al. (2003) Role of the WT1 tumor suppressor in murine hematopoiesis. Blood 101, 2570-2574CrossRef Google Scholar PubMed

43Dame, C. et al. (2006) Wilms tumor suppressor, Wt1, is a transcriptional activator of the erythropoietin gene. Blood 107, 4282-4290CrossRef Google Scholar PubMed

44Sanchez-Elsner, T. et al. (2004) A cross-talk between hypoxia and TGF-beta orchestrates erythropoietin gene regulation through SP1 and Smads. J Mol Biol 336, 9-24CrossRef Google Scholar PubMed

45Ma, G.T. et al. (1997) GATA-2 and GATA-3 regulate trophoblast-specific gene expression in vivo. Development 124, 907-914CrossRef Google Scholar PubMed

46Zhou, Y., Yamamoto, M. and Engel, J.D. (2000) GATA2 is required for the generation of V2 interneurons. Development 127, 3829-3838CrossRef Google Scholar PubMed

47Pandolfi, P.P. et al. (1995) Targeted disruption of the GATA3 gene causes severe abnormalities in the nervous system and in fetal liver haematopoiesis. Nat Genet 11, 40-44CrossRef Google Scholar PubMed

48Hoshino, T. et al. (2008) Reduced BMP4 abundance in Gata2 hypomorphic mutant mice result in uropathies resembling human CAKUT. Genes Cells 13, 159-170CrossRef Google Scholar PubMed

49Gao, X. et al. (1998) Distinct functions are implicated for the GATA-4, -5, and -6 transcription factors in the regulation of intestine epithelial cell differentiation. Mol Cell Biol 18, 2901-2911CrossRef Google Scholar PubMed

50Peterkin, T., Gibson, A. and Patient, R. (2007) Redundancy and evolution of GATA factor requirements in development of the myocardium. Dev Biol 311, 623-635CrossRef Google Scholar PubMed

51Capo-Chichi, C.D. et al. (2005) Perception of differentiation cues by GATA factors in primitive endoderm lineage determination of mouse embryonic stem cells. Dev Biol 286, 574-586CrossRef Google Scholar PubMed

52Dame, C. et al. (2004) Hepatic erythropoietin gene regulation by GATA-4. J Biol Chem 279, 2955-2961CrossRef Google Scholar PubMed

53Imagawa, S., Yamamoto, M. and Miura, Y. (1997) Negative regulation of the erythropoietin gene expression by the GATA transcription factors. Blood 89, 1430-1439CrossRef Google Scholar PubMed

54La Ferla, K. et al. (2002) Inhibition of erythropoietin gene expression signaling involves the transcription factors GATA-2 and NF-kappaB. FASEB J 16, 1811-1813CrossRef Google Scholar PubMed

55Rogers, H.M. et al. (2008) Hypoxia alters progression of the erythroid program. Exp Hematol 36, 17-27CrossRef Google Scholar PubMed

56Yu, X. et al. (2002) Erythropoietin receptor signalling is required for normal brain development. Development 129, 505-516CrossRef Google Scholar PubMed

57Ogilvie, M. et al. (2000) Erythropoietin stimulates proliferation and interferes with differentiation of myoblasts. J Biol Chem 275, 39754-39761CrossRef Google Scholar PubMed

58Wu, H. et al. (1995) Generation of committed erythroid BFU-E and CFU-E progenitors does not require erythropoietin or the erythropoietin receptor. Cell 83, 59-67CrossRef Google Scholar PubMed

59Lin, C.S. et al. (1996) Differential effects of an erythropoietin receptor gene disruption on primitive and definitive erythropoiesis. Genes Dev 10, 154-164CrossRef Google Scholar PubMed

60Broudy, V.C. et al. (1991) Erythropoietin receptor characteristics on primary human erythroid cells. Blood 77, 2583-2590CrossRef Google Scholar PubMed

61Chiba, T., Ikawa, Y. and Todokoro, K. (1991) GATA-1 transactivates erythropoietin receptor gene, and erythropoietin receptor-mediated signals enhance GATA-1 gene expression. Nucleic Acids Res 19, 3843-3848CrossRef Google Scholar PubMed

62Anagnostou, A. et al. (1994) Erythropoietin receptor mRNA expression in human endothelial cells. Proc Natl Acad Sci U S A 91, 3974-3978CrossRef Google Scholar PubMed

63Morishita, E. et al. (1997) Erythropoietin receptor is expressed in rat hippocampal and cerebral cortical neurons, and erythropoietin prevents in vitro glutamate-induced neuronal death. Neuroscience 76, 105-116CrossRef Google Scholar PubMed

64Wu, H. et al. (1999) Inactivation of erythropoietin leads to defects in cardiac morphogenesis. Development 126, 3597-3605CrossRef Google Scholar PubMed

65Juul, S.E. et al. (1998) Erythropoietin and erythropoietin receptor in the developing human central nervous system. Pediatr Res 43, 40-49CrossRef Google Scholar PubMed

66Arcasoy, M.O. (2008) The non-haematopoietic biological effects of erythropoietin. Br J Haematol 141, 14-31CrossRef Google Scholar PubMed

67Youssoufian, H. et al. (1993) Structure, function, and activation of the erythropoietin receptor. Blood 81, 2223-2236CrossRef Google Scholar PubMed

68Noguchi, C.T. et al. (1991) Cloning of the human erythropoietin receptor gene. Blood 78, 2548-2556CrossRef Google Scholar PubMed

69Syed, R.S. et al. (1998) Efficiency of signalling through cytokine receptors depends critically on receptor orientation. Nature 395, 511-516CrossRef Google Scholar PubMed

70D'Andrea, A.D. and Zhu, Y. (1996) Cloning and functional analysis of erythropoietin-, interleukin-3- and thrombopoietin-inducible genes. Stem Cells 14 Suppl 1, 82-87CrossRef Google Scholar PubMed

71Hilton, D.J. et al. (1995) Increased cell surface expression and enhanced folding in the endoplasmic reticulum of a mutant erythropoietin receptor. Proc Natl Acad Sci U S A 92, 190-194CrossRef Google Scholar PubMed

72Yoshimura, A. et al. (1992) Mutations in the Trp-Ser-X-Trp-Ser motif of the erythropoietin receptor abolish processing, ligand binding, and activation of the receptor. J Biol Chem 267, 11619-11625CrossRef Google Scholar PubMed

73Parganas, E. et al. (1998) Jak2 is essential for signaling through a variety of cytokine receptors. Cell 93, 385-395CrossRef Google Scholar PubMed

74Funakoshi-Tago, M. et al. (2008) Jak2 FERM domain interaction with the erythropoietin receptor regulates Jak2 kinase activity. Mol Cell Biol 28, 1792-1801CrossRef Google Scholar PubMed

75Livnah, O. et al. (1999) Crystallographic evidence for preformed dimers of erythropoietin receptor before ligand activation. Science 283, 987-990CrossRef Google Scholar PubMed

76Neubauer, H. et al. (1998) Jak2 deficiency defines an essential developmental checkpoint in definitive hematopoiesis. Cell 93, 397-409CrossRef Google Scholar PubMed

77Baxter, E.J. et al. (2005) Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 365, 1054-1061CrossRef Google Scholar PubMed

78Levine, R.L. et al. (2005) Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell 7, 387-397CrossRef Google Scholar PubMed

79Horn, T. et al. (2006) Detection of the activating JAK2 V617F mutation in paraffin-embedded trephine bone marrow biopsies of patients with chronic myeloproliferative diseases. J Mol Diagn 8, 299-304CrossRef Google Scholar PubMed

80Scott, L.M. et al. (2007) JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis. N Engl J Med 356, 459-468CrossRef Google Scholar PubMed

81Kerenyi, M.A. et al. (2008) Stat 5 regulates cellular iron uptake of erythroid cells via IRP-2 and TfR-1. Blood 112, 3878-3888CrossRef Google Scholar PubMed

82Grebien, F. et al. (2008) Stat5 activation enables erythropoiesis in the absence of EpoR and Jak2. Blood 111, 4511-4522CrossRef Google Scholar PubMed

83Miura, Y. et al. (1994) Activation of the mitogen-activated protein kinase pathway by the erythropoietin receptor. J Biol Chem 269, 29962-29969CrossRef Google Scholar PubMed

84D'Andrea, A.D. et al. (1991) The cytoplasmic region of the erythropoietin receptor contains nonoverlapping positive and negative growth-regulatory domains. Mol Cell Biol 11, 1980-1987CrossRef Google Scholar PubMed

85Supino-Rosin, L. et al. (1999) A cytosolic domain of the erythropoietin receptor contributes to endoplasmic reticulum-associated degradation. Eur J Biochem 263, 410-419CrossRef Google Scholar PubMed

86Nahari, T. et al. (2008) A transplanted NPVY sequence in the cytosolic domain of the erythropoietin receptor enhances maturation. Biochem J 410, 409-416CrossRef Google Scholar PubMed

87Gross, A.W. and Lodish, H.F. (2006) Cellular trafficking and degradation of erythropoietin and novel erythropoiesis stimulating protein (NESP). J Biol Chem 281, 2024-2032CrossRef Google Scholar PubMed

88Sawyer, S.T., Krantz, S.B. and Goldwasser, E. (1987) Binding and receptor-mediated endocytosis of erythropoietin in Friend virus-infected erythroid cells. J Biol Chem 262, 5554-5562CrossRef Google Scholar PubMed

89Meyer, L. et al. (2007) beta-Trcp mediates ubiquitination and degradation of the erythropoietin receptor and controls cell proliferation. Blood 109, 5215-5222CrossRef Google Scholar PubMed

90Arcasoy, M.O., Harris, K.W. and Forget, B.G. (1999) A human erythropoietin receptor gene mutant causing familial erythrocytosis is associated with deregulation of the rates of Jak2 and Stat5 inactivation. Exp Hematol 27, 63-74CrossRef Google Scholar PubMed

91Kralovics, R. and Prchal, J.T. (2001) Genetic heterogeneity of primary familial and congenital polycythemia. Am J Hematol 68, 115-121CrossRef Google Scholar PubMed

92Kralovics, R. et al. (1997) Two new EPO receptor mutations: truncated EPO receptors are most frequently associated with primary familial and congenital polycythemias. Blood 90, 2057-2061CrossRef Google Scholar PubMed

93Chin, K. et al. (1995) Regulation of transcription of the human erythropoietin receptor gene by proteins binding to GATA-1 and Sp1 motifs. Nucleic Acids Res 23, 3041-3049CrossRef Google Scholar PubMed

94Sato, T. et al. (1998) Induction of the erythropoietin receptor gene and acquisition of responsiveness to erythropoietin by stem cell factor in HML/SE, a human leukemic cell line. J Biol Chem 273, 16921-16926CrossRef Google Scholar PubMed

95Zon, L.I. et al. (1991) Activation of the erythropoietin receptor promoter by transcription factor GATA-1. Proc Natl Acad Sci U S A 88, 10638-10641CrossRef Google Scholar PubMed

96Weiss, M.J., Keller, G. and Orkin, S.H. (1994) Novel insights into erythroid development revealed through in vitro differentiation of GATA-1 embryonic stem cells. Genes Dev 8, 1184-1197CrossRef Google Scholar PubMed

97Zhang, Q. et al. (2008) Synergistic upregulation of erythropoietin receptor (EPO-R) expression by sense and antisense EPO-R transcripts in the canine lung. Proc Natl Acad Sci U S A 105, 7612-7617CrossRef Google Scholar PubMed

98Maouche, L. et al. (1995) A CCACC motif mediates negative transcriptional regulation of the human erythropoietin receptor. Eur J Biochem 233, 793-799CrossRef Google Scholar PubMed

99Liu, Z.Y., Chin, K. and Noguchi, C.T. (1994) Tissue specific expression of human erythropoietin receptor in transgenic mice. Dev Biol 166, 159-169CrossRef Google Scholar PubMed

100Lee, R. et al. (2001) Erythropoietin (Epo) and EpoR expression and 2 waves of erythropoiesis. Blood 98, 1408-1415CrossRef Google Scholar PubMed

101Yu, X. et al. (2001) The human erythropoietin receptor gene rescues erythropoiesis and developmental defects in the erythropoietin receptor null mouse. Blood 98, 475-477CrossRef Google Scholar PubMed

102Chen, Z.Y., Warin, R. and Noguchi, C.T. (2006) Erythropoietin and normal brain development: receptor expression determines multi-tissue response. Neurodegener Dis 3, 68-75CrossRef Google Scholar PubMed

103Noguchi, C.T. et al. (2007) Role of erythropoietin in the brain. Crit Rev Oncol Hematol 64, 159-171CrossRef Google Scholar PubMed

104Anagnostou, A. et al. (1990) Erythropoietin has a mitogenic and positive chemotactic effect on endothelial cells. Proc Natl Acad Sci U S A 87, 5978-5982CrossRef Google Scholar

105Ribatti, D. et al. (1999) Human erythropoietin induces a pro-angiogenic phenotype in cultured endothelial cells and stimulates neovascularization in vivo. Blood 93, 2627-2636CrossRef Google Scholar PubMed

106Chong, Z.Z., Kang, J.Q. and Maiese, K. (2002) Erythropoietin is a novel vascular protectant through activation of Akt1 and mitochondrial modulation of cysteine proteases. Circulation 106, 2973-2979CrossRef Google Scholar PubMed

107Beleslin-Cokic, B.B. et al. (2004) Erythropoietin and hypoxia stimulate erythropoietin receptor and nitric oxide production by endothelial cells. Blood 104, 2073-2080CrossRef Google Scholar PubMed

108Kanagy, N.L. et al. (2003) Erythropoietin administration in vivo increases vascular nitric oxide synthase expression. J Cardiovasc Pharmacol 42, 527-533CrossRef Google Scholar PubMed

109Quaschning, T. et al. (2003) Erythropoietin-induced excessive erythrocytosis activates the tissue endothelin system in mice. FASEB J 17, 259-261CrossRef Google Scholar PubMed

110Defouilloy, C. et al. (1998) Polycythemia impairs vasodilator response to acetylcholine in patients with chronic hypoxemic lung disease. Am J Respir Crit Care Med 157, 1452-1460CrossRef Google Scholar PubMed

111Sasaki, R. (2003) Pleiotropic functions of erythropoietin. Intern Med 42, 142-149CrossRef Google Scholar PubMed

112Yasuda, Y. et al. (1998) Estrogen-dependent production of erythropoietin in uterus and its implication in uterine angiogenesis. J Biol Chem 273, 25381-25387CrossRef Google Scholar PubMed

113Kertesz, N. et al. (2004) The role of erythropoietin in regulating angiogenesis. Dev Biol 276, 101-110CrossRef Google Scholar PubMed

114Heeschen, C. et al. (2003) Erythropoietin is a potent physiologic stimulus for endothelial progenitor cell mobilization. Blood 102, 1340-1346CrossRef Google Scholar PubMed

115Bahlmann, F.H. et al. (2004) Erythropoietin regulates endothelial progenitor cells. Blood 103, 921-926CrossRef Google Scholar PubMed

116Urao, N. et al. (2006) Erythropoietin-mobilized endothelial progenitors enhance reendothelialization via Akt-endothelial nitric oxide synthase activation and prevent neointimal hyperplasia. Circ Res 98, 1405-1413CrossRef Google Scholar PubMed

117Satoh, K. et al. (2006) Important role of endogenous erythropoietin system in recruitment of endothelial progenitor cells in hypoxia-induced pulmonary hypertension in mice. Circulation 113, 1442-1450CrossRef Google Scholar PubMed

118Nakano, M. et al. (2007) Important role of erythropoietin receptor to promote VEGF expression and angiogenesis in peripheral ischemia in mice. Circ Res 100, 662-669CrossRef Google Scholar PubMed

119Saito, T. et al. (1983) Serum erythropoietin titres in the anaemia of premature infants. Br J Haematol 54, 53-58CrossRef Google Scholar PubMed

120Stockman, J.A., 3rd et al. (1984) Anemia of prematurity: determinants of the erythropoietin response. J Pediatr 105, 786-792CrossRef Google Scholar PubMed

121Ohls, R.K. et al. (1997) The effect of erythropoietin on the transfusion requirements of preterm infants weighing 750 grams or less: a randomized, double-blind, placebo-controlled study. J Pediatr 131, 661-665CrossRef Google Scholar PubMed

122Turker, G. et al. (2005) The effect of early recombinant erythropoietin and enteral iron supplementation on blood transfusion in preterm infants. Am J Perinatol 22, 449-455CrossRef Google Scholar PubMed

123Fortes Filho, J.B. et al. (2007) Incidence and risk factors for retinopathy of prematurity in very low and in extremely low birth weight infants in a unit-based approach in southern Brazil. Eye Jul 6; [Epub ahead of print]Google Scholar

124Aiello, L.P. et al. (1995) Suppression of retinal neovascularization in vivo by inhibition of vascular endothelial growth factor (VEGF) using soluble VEGF-receptor chimeric proteins. Proc Natl Acad Sci U S A 92, 10457-10461CrossRef Google Scholar PubMed

125Morita, M. et al. (2003) HLF/HIF-2alpha is a key factor in retinopathy of prematurity in association with erythropoietin. EMBO J 22, 1134-1146CrossRef Google Scholar PubMed

126Chen, J. et al. (2008) Erythropoietin deficiency decreases vascular stability in mice. J Clin Invest 118, 526-533Google Scholar PubMed

127Friedman, E.A., Brown, C.D. and Berman, D.H. (1995) Erythropoietin in diabetic macular edema and renal insufficiency. Am J Kidney Dis 26, 202-208CrossRef Google Scholar PubMed

128Tong, Z. et al. (2008) Promoter polymorphism of the erythropoietin gene in severe diabetic eye and kidney complications. Proc Natl Acad Sci U S A 105, 6998-7003CrossRef Google Scholar PubMed

129Watanabe, D. et al. (2005) Erythropoietin as a retinal angiogenic factor in proliferative diabetic retinopathy. N Engl J Med 353, 782-792CrossRef Google Scholar PubMed

130Lee, I.G., Chae, S.L. and Kim, J.C. (2006) Involvement of circulating endothelial progenitor cells and vasculogenic factors in the pathogenesis of diabetic retinopathy. Eye 20, 546-552CrossRef Google Scholar PubMed

131Liu, C. et al. (1997) Regulated human erythropoietin receptor expression in mouse brain. J Biol Chem 272, 32395-32400CrossRef Google Scholar PubMed

132Patapoutian, A. et al. (1993) Isolated sequences from the linked Myf-5 and MRF4 genes drive distinct patterns of muscle-specific expression in transgenic mice. Development 118, 61-69CrossRef Google Scholar PubMed

133Calvillo, L. et al. (2003) Recombinant human erythropoietin protects the myocardium from ischemia-reperfusion injury and promotes beneficial remodeling. Proc Natl Acad Sci U S A 100, 4802-4806CrossRef Google Scholar PubMed

134Wright, G.L. et al. (2004) Erythropoietin receptor expression in adult rat cardiomyocytes is associated with an acute cardioprotective effect for recombinant erythropoietin during ischemia-reperfusion injury. FASEB J 18, 1031-1033CrossRef Google Scholar PubMed

135Suzuki, N. et al. (2002) Erythroid-specific expression of the erythropoietin receptor rescued its null mutant mice from lethality. Blood 100, 2279-2288CrossRef Google Scholar PubMed

136Tada, H. et al. (2006) Endogenous erythropoietin system in non-hematopoietic lineage cells plays a protective role in myocardial ischemia/reperfusion. Cardiovasc Res 71, 466-477CrossRef Google Scholar

137Parsa, C.J. et al. (2003) A novel protective effect of erythropoietin in the infarcted heart. J Clin Invest 112, 999-1007CrossRef Google Scholar PubMed

138Moon, C. et al. (2003) Erythropoietin reduces myocardial infarction and left ventricular functional decline after coronary artery ligation in rats. Proc Natl Acad Sci U S A 100, 11612-11617CrossRef Google Scholar PubMed

139Rui, T. et al. (2005) Erythropoietin prevents the acute myocardial inflammatory response induced by ischemia/reperfusion via induction of AP-1. Cardiovasc Res 65, 719-727CrossRef Google Scholar PubMed

140Burger, D. et al. (2006) Erythropoietin protects cardiomyocytes from apoptosis via up-regulation of endothelial nitric oxide synthase. Cardiovasc Res 72, 51-59CrossRef Google Scholar PubMed

141Narmoneva, D.A. et al. (2004) Endothelial cells promote cardiac myocyte survival and spatial reorganization: implications for cardiac regeneration. Circulation 110, 962-968CrossRef Google Scholar PubMed

142Westenbrink, B.D. et al. (2007) Erythropoietin improves cardiac function through endothelial progenitor cell and vascular endothelial growth factor mediated neovascularization. Eur Heart J 28, 2018-2027CrossRef Google Scholar PubMed

143van der Meer, P. et al. (2005) Erythropoietin induces neovascularization and improves cardiac function in rats with heart failure after myocardial infarction. J Am Coll Cardiol 46, 125-133CrossRef Google Scholar PubMed

144Masuda, S. et al. (1994) A novel site of erythropoietin production. Oxygen-dependent production in cultured rat astrocytes. J Biol Chem 269, 19488-19493Google Scholar PubMed

145Marti, H.H. et al. (1997) Detection of erythropoietin in human liquor: intrinsic erythropoietin production in the brain. Kidney Int 51, 416-418CrossRef Google Scholar PubMed

146Marti, H.H. et al. (1996) Erythropoietin gene expression in human, monkey and murine brain. Eur J Neurosci 8, 666-676CrossRef Google Scholar PubMed

147Tsai, P.T. et al. (2006) A critical role of erythropoietin receptor in neurogenesis and post-stroke recovery. J Neurosci 26, 1269-1274CrossRef Google Scholar PubMed

148Chen, Z.Y. et al. (2007) Endogenous erythropoietin signaling is required for normal neural progenitor cell proliferation. J Biol Chem 282, 25875-25883CrossRef Google Scholar PubMed

149Chin, K. et al. (2000) Production and processing of erythropoietin receptor transcripts in brain. Brain Res Mol Brain Res 81, 29-42CrossRef Google Scholar PubMed

150Shingo, T. et al. (2001) Erythropoietin regulates the in vitro and in vivo production of neuronal progenitors by mammalian forebrain neural stem cells. J Neurosci 21, 9733-9743CrossRef Google Scholar PubMed

151Studer, L. et al. (2000) Enhanced proliferation, survival, and dopaminergic differentiation of CNS precursors in lowered oxygen. J Neurosci 20, 7377-7383CrossRef Google Scholar PubMed

152Sakanaka, M. et al. (1998) In vivo evidence that erythropoietin protects neurons from ischemic damage. Proc Natl Acad Sci U S A 95, 4635-4640CrossRef Google Scholar PubMed

153Sadamoto, Y. et al. (1998) Erythropoietin prevents place navigation disability and cortical infarction in rats with permanent occlusion of the middle cerebral artery. Biochem Biophys Res Commun 253, 26-32CrossRef Google Scholar PubMed

154Bernaudin, M. et al. (2002) Normobaric hypoxia induces tolerance to focal permanent cerebral ischemia in association with an increased expression of hypoxia-inducible factor-1 and its target genes, erythropoietin and VEGF, in the adult mouse brain. J Cereb Blood Flow Metab 22, 393-403CrossRef Google Scholar PubMed

155Bernaudin, M. et al. (1999) A potential role for erythropoietin in focal permanent cerebral ischemia in mice. J Cereb Blood Flow Metab 19, 643-651CrossRef Google Scholar PubMed

156Prass, K. et al. (2003) Hypoxia-induced stroke tolerance in the mouse is mediated by erythropoietin. Stroke 34, 1981-1986CrossRef Google Scholar PubMed

157Malhotra, S. et al. (2006) Ischemic preconditioning is mediated by erythropoietin through PI-3 kinase signaling in an animal model of transient ischemic attack. J Neurosci Res 83, 19-27CrossRef Google Scholar

158Ruscher, K. et al. (2002) Erythropoietin is a paracrine mediator of ischemic tolerance in the brain: evidence from an in vitro model. J Neurosci 22, 10291-10301CrossRef Google Scholar PubMed

159Grimm, C. et al. (2002) HIF-1-induced erythropoietin in the hypoxic retina protects against light-induced retinal degeneration. Nat Med 8, 718-724CrossRef Google Scholar PubMed

160Grimm, C. et al. (2004) Constitutive overexpression of human erythropoietin protects the mouse retina against induced but not inherited retinal degeneration. J Neurosci 24, 5651-5658CrossRef Google Scholar

161Xenocostas, A. et al. (2005) The pharmacokinetics of erythropoietin in the cerebrospinal fluid after intravenous administration of recombinant human erythropoietin. Eur J Clin Pharmacol 61, 189-195CrossRef Google Scholar PubMed

162Banks, W.A. et al. (2004) Passage of erythropoietic agents across the blood-brain barrier: a comparison of human and murine erythropoietin and the analog darbepoetin alfa. Eur J Pharmacol 505, 93-101CrossRef Google Scholar PubMed

163Brines, M.L. et al. (2000) Erythropoietin crosses the blood-brain barrier to protect against experimental brain injury. Proc Natl Acad Sci U S A 97, 10526-10531CrossRef Google Scholar PubMed

164Sun, Y. et al. (2004) Mechanisms of erythropoietin-induced brain protection in neonatal hypoxia-ischemia rat model. J Cereb Blood Flow Metab 24, 259-270CrossRef Google Scholar PubMed

165Yatsiv, I. et al. (2005) Erythropoietin is neuroprotective, improves functional recovery, and reduces neuronal apoptosis and inflammation in a rodent model of experimental closed head injury. FASEB J 19, 1701-1703CrossRef Google Scholar

166Kilic, E. et al. (2005) Brain-derived erythropoietin protects from focal cerebral ischemia by dual activation of ERK-1/-2 and Akt pathways. FASEB J 19, 2026-2028CrossRef Google Scholar PubMed

167Chong, Z.Z., Kang, J.Q. and Maiese, K. (2003) Erythropoietin fosters both intrinsic and extrinsic neuronal protection through modulation of microglia, Akt1, Bad, and caspase-mediated pathways. Br J Pharmacol 138, 1107-1118CrossRef Google Scholar PubMed

168Byts, N. et al. (2008) Essential role for Stat5 in the neurotrophic but not in the neuroprotective effect of erythropoietin. Cell Death Differ 15, 783-792CrossRef Google Scholar

169Zhang, F. et al. (2006) Erythropoietin protects CA1 neurons against global cerebral ischemia in rat: potential signaling mechanisms. J Neurosci Res 83, 1241-1251CrossRef Google Scholar PubMed

170Digicaylioglu, M. and Lipton, S.A. (2001) Erythropoietin-mediated neuroprotection involves cross-talk between Jak2 and NF-kappaB signalling cascades. Nature 412, 641-647CrossRef Google Scholar PubMed

171Liu, J. et al. (2005) Neuroprotection by hypoxic preconditioning involves oxidative stress-mediated expression of hypoxia-inducible factor and erythropoietin. Stroke 36, 1264-1269CrossRef Google Scholar PubMed

172Wang, L. et al. (2004) Treatment of stroke with erythropoietin enhances neurogenesis and angiogenesis and improves neurological function in rats. Stroke 35, 1732-1737CrossRef Google Scholar PubMed

173Wang, L. et al. (2006) Matrix metalloproteinase 2 (MMP2) and MMP9 secreted by erythropoietin-activated endothelial cells promote neural progenitor cell migration. J Neurosci 26, 5996-6003CrossRef Google Scholar PubMed

174Wang, L. et al. (2008) Neural progenitor cells treated with EPO induce angiogenesis through the production of VEGF. J Cereb Blood Flow Metab 28, 1361-1368CrossRef Google Scholar PubMed

175Gonzalez, F.F. et al. (2007) Erythropoietin enhances long-term neuroprotection and neurogenesis in neonatal stroke. Dev Neurosci 29, 321-330CrossRef Google Scholar PubMed

176Siren, A.L. et al. (2006) Global brain atrophy after unilateral parietal lesion and its prevention by erythropoietin. Brain 129, 480-489CrossRef Google Scholar PubMed

177Ehrenreich, H. et al. (2002) Erythropoietin therapy for acute stroke is both safe and beneficial. Mol Med 8, 495-505CrossRef Google Scholar PubMed

178Ehrenreich, H. et al. (2007) Exploring recombinant human erythropoietin in chronic progressive multiple sclerosis. Brain 130, 2577-2588CrossRef Google Scholar PubMed

179Ehrenreich, H. et al. (2007) Improvement of cognitive functions in chronic schizophrenic patients by recombinant human erythropoietin. Mol Psychiatry 12, 206-220CrossRef Google Scholar PubMed

180Skibeli, V., Nissen-Lie, G. and Torjesen, P. (2001) Sugar profiling proves that human serum erythropoietin differs from recombinant human erythropoietin. Blood 98, 3626-3634CrossRef Google Scholar PubMed

181Elliott, S. et al. (2003) Enhancement of therapeutic protein in vivo activities through glycoengineering. Nat Biotechnol 21, 414-421CrossRef Google Scholar PubMed

182Ling, B. et al. (2005) Darbepoetin alfa administered once monthly maintains hemoglobin concentrations in patients with chronic kidney disease. Clin Nephrol 63, 327-334CrossRef Google Scholar PubMed

183Warwood, T.L. et al. (2005) Single-dose darbepoetin administration to anemic preterm neonates. J Perinatol 25, 725-730CrossRef Google Scholar PubMed

184Sytkowski, A.J. et al. (1999) An erythropoietin fusion protein comprised of identical repeating domains exhibits enhanced biological properties. J Biol Chem 274, 24773-24778CrossRef Google Scholar PubMed

185Sytkowski, A.J. et al. (1998) Human erythropoietin dimers with markedly enhanced in vivo activity. Proc Natl Acad Sci U S A 95, 1184-1188CrossRef Google Scholar PubMed

186Kochendoerfer, G.G. et al. (2003) Design and chemical synthesis of a homogeneous polymer-modified erythropoiesis protein. Science 299, 884-887CrossRef Google Scholar PubMed

187Topf, J.M. (2008) CERA: third-generation erythropoiesis-stimulating agent. Expert Opin Pharmacother 9, 839-849CrossRef Google Scholar PubMed

188Macdougall, I.C. (2005) CERA (Continuous Erythropoietin Receptor Activator): a new erythropoiesis-stimulating agent for the treatment of anemia. Curr Hematol Rep 4, 436-440Google Scholar PubMed

189Wrighton, N.C. et al. (1996) Small peptides as potent mimetics of the protein hormone erythropoietin. Science 273, 458-464CrossRef Google Scholar PubMed

190Liu, Z. et al. (2007) A potent erythropoietin-mimicking human antibody interacts through a novel binding site. Blood 110, 2408-2413CrossRef Google Scholar PubMed

191Bernhardt, W.M. et al. (2006) Preconditional activation of hypoxia-inducible factors ameliorates ischemic acute renal failure. J Am Soc Nephrol 17, 1970-1978CrossRef Google Scholar PubMed

192Hsieh, M.M. et al. (2007) HIF prolyl hydroxylase inhibition results in endogenous erythropoietin induction, erythrocytosis, and modest fetal hemoglobin expression in rhesus macaques. Blood 110, 2140-2147CrossRef Google Scholar PubMed

193Heinicke, K. et al. (2006) Excessive erythrocytosis in adult mice overexpressing erythropoietin leads to hepatic, renal, neuronal, and muscular degeneration. Am J Physiol Regul Integr Comp Physiol 291, R947-956CrossRef Google Scholar PubMed

194Erbayraktar, S. et al. (2003) Asialoerythropoietin is a nonerythropoietic cytokine with broad neuroprotective activity in vivo. Proc Natl Acad Sci U S A 100, 6741-6746CrossRef Google Scholar PubMed

195Fiordaliso, F. et al. (2005) A nonerythropoietic derivative of erythropoietin protects the myocardium from ischemia-reperfusion injury. Proc Natl Acad Sci U S A 102, 2046-2051CrossRef Google Scholar PubMed

196Leist, M. et al. (2004) Derivatives of erythropoietin that are tissue protective but not erythropoietic. Science 305, 239-242CrossRef Google Scholar

197Wang, L. et al. (2007) The Sonic hedgehog pathway mediates carbamylated erythropoietin-enhanced proliferation and differentiation of adult neural progenitor cells. J Biol Chem 282, 32462-32470CrossRef Google Scholar PubMed

198Brines, M. et al. (2004) Erythropoietin mediates tissue protection through an erythropoietin and common beta-subunit heteroreceptor. Proc Natl Acad Sci U S A 101, 14907-14912CrossRef Google Scholar PubMed

199Um, M., Gross, A.W. and Lodish, H.F. (2007) A “classical” homodimeric erythropoietin receptor is essential for the antiapoptotic effects of erythropoietin on differentiated neuroblastoma SH-SY5Y and pheochromocytoma PC-12 cells. Cell Signal 19, 634-645CrossRef Google Scholar

200Nadam, J. et al. (2007) Neuroprotective effects of erythropoietin in the rat hippocampus after pilocarpine-induced status epilepticus. Neurobiol Dis 25, 412-426CrossRef Google Scholar PubMed

201Drueke, T.B. et al. (2006) Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med 355, 2071-2084CrossRef Google Scholar PubMed

202Singh, A.K. et al. (2006) Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med 355, 2085-2098CrossRef Google Scholar PubMed

203Jelkmann, W. et al. (2008) The erythropoietin receptor in normal and cancer tissues. Crit Rev Oncol Hematol 67, 39-61CrossRef Google Scholar PubMed

204Littlewood, T.J. et al. (2001) Effects of epoetin alfa on hematologic parameters and quality of life in cancer patients receiving nonplatinum chemotherapy: results of a randomized, double-blind, placebo-controlled trial. J Clin Oncol 19, 2865-2874CrossRef Google Scholar PubMed

205Glaser, C.M. et al. (2001) Impact of hemoglobin level and use of recombinant erythropoietin on efficacy of preoperative chemoradiation therapy for squamous cell carcinoma of the oral cavity and oropharynx. Int J Radiat Oncol Biol Phys 50, 705-715CrossRef Google Scholar PubMed

206Leyland-Jones, B. (2003) Breast cancer trial with erythropoietin terminated unexpectedly. Lancet Oncol 4, 459-460CrossRef Google Scholar PubMed

207Henke, M. et al. (2003) Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: randomised, double-blind, placebo-controlled trial. Lancet 362, 1255-1260CrossRef Google Scholar PubMed

208Bennett, C.L. et al. (2008) Venous thromboembolism and mortality associated with recombinant erythropoietin and darbepoetin administration for the treatment of cancer-associated anemia. JAMA 299, 914-924CrossRef Google Scholar PubMed

209Rizzo, J.D. et al. (2008) Use of epoetin and darbepoetin in patients with cancer: 2007 American Society of Clinical Oncology/American Society of Hematology clinical practice guideline update. J Clin Oncol 26, 132-149CrossRef Google Scholar

210Bunn, H.F. et al. (1998) Erythropoietin: a model system for studying oxygen-dependent gene regulation. J Exp Biol 201, 1197-1201CrossRef Google Scholar

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Survival and proliferative roles of erythropoietin beyond the erythroid lineage

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Survival and proliferative roles of erythropoietin beyond the erythroid lineage

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