Erythropoietin: Multiple physiological functions and regulation of biosynthesis

Bioscience, Biotechnology and Biochemistry

Volumn 64, Issue 9, 2000, Pages 1775-1793

  Sasaki, Ryuzo ^a   Masuda, Seiji ^a   Nagao, Masaya ^a  

^a KYOTO UNIVERSITY   (Japan)

Author keywords

Brain; Erythropoietin; Hypoxia; Kidney; Uterus

Indexed keywords

ERYTHROPOIETIN; ERYTHROPOIETIN RECEPTOR;

ADULT; ANGIOGENESIS; ANIMAL; CHEMISTRY; CYTOLOGY; DRUG EFFECT; ERYTHROID PRECURSOR CELL; GENETIC TRANSCRIPTION; GENETICS; HUMAN; PHYSIOLOGY; REVIEW;

ADULT; ANIMALS; ERYTHROID PROGENITOR CELLS; ERYTHROPOIETIN; HUMANS; NEOVASCULARIZATION, PHYSIOLOGIC; RECEPTORS, ERYTHROPOIETIN; TRANSCRIPTION, GENETIC;

EID: 0034279419     PISSN: 09168451     EISSN: 13476947     Source Type: Journal    
DOI: 10.1271/bbb.64.1775     Document Type: Article

References (209)

1. Krantz, S. B., Erythropoietin. Blood, 77, 419-434 (1991).
2. Jelkmann, W., Erythropoietin: structure, control of production, and function. Physiol. Rev., 72, 449-489 (1992).
3. Wu, H., Liu, X., Jaenisch, R., and Lodish, H. F., Generation of committed erythroid BFU-E and CFU-E progenitors does not require erythropoietin or the erythropoietin receptor. Cell, 83, 59-67 (1995).
4. Lin, C. S., Lim, S. K., D’Agati, V., and Costantini, F., Differential effects of an erythropoietin receptor gene disruption on primitive and definitive erythropoiesis. Genes Dev., 10, 154-164 (1996).
5. Fisher, J. W., Erythropoietin: physiologic and pharmacologic aspects. Proc. Soc. Exp. Biol. Med., 216, 358-369 (1997).
6. Jacobs, K., Shoemaker, C., Rudersdorf, R., Neill, S. D., Kaufman, R. J., Mufson, A., Seehra, J., Jones, S. S., Hewick, R., Fritsch, E. F., Kawakita, M., Shimizu, T., and Miyake, T., Isolation and characterization of genomic and cDNA clones of human erythropoietin. Nature, 313, 806-810 (1985).
7. Lin, F. K., Suggs, S., Lin, C. H., Browne, J. K., Smalling, R., Egrie, J. C., Chen, K. K., Fox, G. M., Martin, F., Stabinsky, Z., Badrawi, S. M., Lai, P. FL, and Goldwasser, E., Cloning and expression of the human erythropoietin gene. Proc. Natl. Acad. Sci. USA, 82, 7580-7584 (1985).
8. D’Andrea, A. D., Lodish, H. F., and Wong, G. G., Expression cloning of the murine erythropoietin receptor. Cell, 57, 277-285 (1989).
9. McDonald, J. D., Lin, F. K., and Goldwasser, E., Cloning, sequencing, and evolutionary analysis of the mouse erythropoietin gene. Mol. Cell. Biol., 6, 842-848 (1986).
10. Shoemaker, C. B. and Mitsock, L. D., Murine erythropoietin gene: cloning, expression, and human gene homology. Mol. Cell. Biol., 6, 849-858 (1986).
11. Kuramochi, S., Ikawa, Y., and Todokoro, K., Characterization of murine erythropoietin receptor genes. J. Mol. Biol., 216, 567-575 (1990).
12. Youssoufian, FL, Zon, L. I., Orkin, S. H., D’Andrea, A. D., and Lodish, H. F., Structure and transcription of the mouse erythropoietin receptor gene. Mol. Cell. Biol., 10, 3675-3682 (1990).
13. Winkelmann, J. C., Penny, L. A., Deaven, L. L., Forget, B. G., and Jenkins, R. B., The gene for the human erythropoietin receptor: analysis of the coding sequence and assignment to chromosome 19p. Blood, 76, 24-30 (1990).
14. Jones, S. S., D’Andrea, A. D., Haines, L. L., and Wong, G. G., Human erythropoietin receptor: cloning, expression, and biologic characterization. Blood, 76, 31-35 (1990).
15. Sakanaka, M., Wen, T. C., Matsuda, S., Masuda, S., Morishita, E., Nagao, M., and Sasaki, R., In vivo evidence that erythropoietin protects neurons from ischemic damage. Proc. Natl. Acad. Sci. USA, 95, 4635-4640 (1998).
16. Sadamoto, Y., Igase, K., Sakanaka, M., Sato, K., Otsuka, H., Sakaki, S., Masuda, S., and Sasaki, R., Erythropoietin prevents place navigation disability and cortical infarction in rats with permanent occlusion of the middle cerebral artery. Biochem. Biophys. Res. Commun., 253, 26-32 (1998).
17. Yasuda, Y., Masuda, S., Chikuma, M., Inoue, K., Nagao, M., and Sasaki, R., Estrogen-dependent production of erythropoietin in uterus and its implication in uterine angiogenesis. J. Biol. Chem., 273, 25381-25387, (1998).
18. Masuda, S., Nagao, M., and Sasaki, R., Erythropoietic, neurotrophic, and angiogenic functions of erythropoietin and regulation of erythropoietin production. Int. J. Hematol., 70, 1-6 (1999).
19. D’Andrea, A. D. and Jones, S. S., Activation of the erythropoietin receptor in stable lymphoid and myeloid transfectants. Semin. Hematol., 28, 152-157 (1991).
20. Bazan, J. F., Neuropoietic cytokines in the hematopoietic fold. Neuron, 1, 197-208 (1991).
21. Sytkowski, A. J., Control of erythropoietin production. Blood Rev., 5, 15-18 (1991).
22. Youssoufian, H., Longmore, G., Neumann, D., Yoshimura, A., and Lodish, H. F., Structure, function, and activation of the erythropoietin receptor. Blood, 81, 2223-2236 (1993).
23. Porter, D. L. and Goldberg, M. A., Regulation of erythropoietin production. Exp. Hematol., 21, 399-404 (1993).
24. Ihle, J. N., Cytokine receptor signalling. Nature, 377, 591-594 (1995).
25. Bauer, C., The oxygen sensor that controls EPO production: facts and fancies. J. Perinat. Med., 23, 7-12 (1995).
26. Bunn, H. F. and Poyton, R. O., Oxygen sensing and molecular adaptation to hypoxia. Physiol. Rev., 76, 839-885 (1996).
27. Guillemin, K. and Krasnow, M. A., The hypoxic response: huffing and HIFing. Cell, 89, 9-12 (1997).
28. and the hypoxia-inducible factor-1. Biol. Chem., 378, 609-616 (1997).
29. Moritz, K. M., Lim, G. B., and Wintour, E. M., Developmental regulation of erythropoietin and erythropoiesis. Am. J. Physiol., 273, R1829-R1844 (1997).
30. Semenza, G. L., Hypxia-inducible factor-1 and the molecular physiology of oxygen homeostasis. J. Lab. Clin. Med., 131, 207-214 (1998).
31. Ratcliffe, P. J., O’Rourke, J. F., Maxwell, P. EE, and Pugh, C. W., Oxygen sensing, hypoxia-inducible factor-1 and the regulation of mammalian gene expression. J. Exp. Biol., 201, 1153-1162 (1998).
32. Recny, M. A., Scoble, H. A., and Kim, Y., Structural characterization of natural human urinary and recombinant DNA-derived erythropoietin. J. Biol. Chem., 262, 17156-17163 (1987).
33. Sasaki, El., Bothner, B., Dell, A., and Fukuda, M., Carbohydrate Structure of erythropoietin expressed in Chinese hamster ovary cells by a human erythropoietin cDNA. J. Biol. Chem., 262, 12059-12076 (1987).
34. Tsuda, E., Goto, M., Murakami, A., Akai, K., Ueda, M., Kawanishi, G., Takahashi, N., Sasaki, R., Chiba, El., Ishihara, El., Mori, M., Tejima, S., Endo, S., and Arata, Y., Comparative structural study of iV-linked oligosaccharides of urinary and recombinant erythropoietins. Biochemistry, 27, 5646-5654 (1988).
35. Takeuchi, M., Takasaki, S., Miyazaki, H., Kato, T., Hoshi, S., Kochibe, N., and Kobata, A., Comparative study of the asparagine-linked sugar chains of human erythropoietins purified from urine and the culture medium of recombinant Chinese hamster ovary cells. /. Biol. Chem., 263, 3657-3663 (1988).
36. Davis, J. M., Arakawa, T., Strickland, T. W., and Yphantis, D. A., Characterization of recombinant human erythropoietin produced in Chinese hamster ovary cells. Biochemistry, 26, 2633-2638 (1987).
37. Goto, M., Akai, K., Murakami, A., Hashimoto, C., Tsuda, E., Ueda, M., Kawanishi, G., Takahashi, N., Ishimoto, A., Chiba, EE, and Sasaki, R., Production of recombinant human erythropoietin in mammalian cells: Host-cell dependency of the biological activity of the cloned glycoprotein. Biol Technology, 6, 67-71 (1988).
38. Spivak, J. L. and Hogans, B. B., The in vivo metabolism of recombinant human erythropoietin in the rat. Blood, 73, 90-99 (1989).
39. Fukuda, M. N., Sasaki, H., Lopez, L., and Fukuda, M., Survival of recombinant erythropoietin in the circulation: The role of carbohydrates. Blood, 73, 84-89 (1989).
40. Tsuda, E., Kawanishi, G., Ueda, M., Masuda, S., and Sasaki, R., The role of carbohydrate in recombinant human erythropoietin. Eur. J. Biochem., 188, 405-411 (1990).
41. Yamaguchi, K., Akai, K., Kawanishi, G., Ueda, M., Masuda, S., and Sasaki, R., Effects of site-directed removal of N-glycosylation sites in human erythropoietin on its production and biological properties. J. Biol. Chem., 266, 20434-20439(1991).
42. Wasley, L. C., Timony, G., Murtha, P., Stoudemire, J., Dorner, A. J., Caro, J., Krieger, M., and Kaufman, R. J., The importance of N- and O-linked oligosaccharides for the biosynthesis and in vitro and in vivo biological activities of erythropoietin. Blood, 77, 2624-2632 (1991).
43. Higuchi, M., Oh-eda, M., Kuboniwa, H., Tomonoh, K., Shimonaka, Y., and Ochi, N., Role of sugar chains in the expression of the biological activity of human erythropoietin. J. Biol. Chem., 261, 7703-7709 (1992).
44. Nagao, M., Suga, H., Okano, M., Masuda, S., Narita, H., Ikura, K., and Sasaki, R., Nucleotide sequence of rat erythropoietin. Biochim. Biophys. Acta, 1171, 99-102 (1992).
45. Takeuchi, M., Inoue, N., Strickland, T. W., Kubota, M., Wada, M., Shimizu, R., Hoshi, S., Kozutsumi, H., Takasaki, S., and Kobata, A., Relationship between sugar chain structure and biological activity of recombinant human erythropoietin produced in Chinese hamster ovary cells. Proc. Natl. Acad. Sci. USA, 86, 7819-7822 (1989).
46. Kitgawa, Y., Sano, Y., Ueda, M., Higashio, K., Narita, H., Okano, M., Matsumoto, S., and Sasaki, R., N-glycosylation of erythropoietin is critical for apical secretion by Madin-Darby canine kidney cells. Exp. Cell Res., 213, 449-457 (1994).
47. Wrighton, N. C., Farrell, F. X., Chang, R., Kashyap, A. K., Barbone, F. P., Mulcahy, L. S., Johonson, D. L., Barrett, R. W., Jolliffe, L. K., and Dower, W. J., Small peptides as potent mimetics of the protein hormone erythropoietin. Science, 273, 458-464 (1996).
48. Livnah, O., Stura, E. A., Johnson, D. L., Middleton, S. A., Mulcahy, L. S., Wrighton, N. C., Dower, W. J., Jollife, L. K., and Wilson, I. A., Functional mimicry of a protein hormone by a peptide agonist: The EPO receptor complex at 2.8 A. Science, 273, 464-471 (1996).
49. Yoshimura, A., Longmore, G., and Lodish, H. F., Point mutation in the exoplasmic domain of the erythropoietin receptor resulting in hormone-independent activation and tumorigenicty. Nature, 348, 647-649 (1990).
50. Qiu, H., Belanger, A., Yoon, H. W., and Bunn, H. F., Homodomerization restores biological activity to an inactive erythropoietin mutant. J. Biol. Chem., 273, 11173-11176 (1998).
51. Sytkowski, A. J., Lunn, E. D., Davis, K. L., Feldman, L., and Siekman, S., Human erythropoietin dimers with markedly enhenced in vivo activity. Proc. Natl. Acad. Sci. USA, 95, 1184-1188 (1998).
52. Syed, R. S., Reid, S. W., Li, C., Cheetham, J. C., Aoki, K. H., Liu, B., Zhan, H., Osslund, T. D., Chirino, A. J., Zhang, J., Finer-Moore, J., Elliot, S., Sitney, K., Katz, B. A., Mattews, D. J., Wendoloski, J. J., Egrie, J., and Stroud, R. M., Efficiency of signaling through cytokine receptors depends critically on receptor orientation. Nature, 395, 511-516 (1998).
53. Livnah, O., Stura, E. A., Middleton, S. A., Johnson, D. L., Jolliffe, L. K., and Wilson, I. A., Crystallographic evidence for performed dimers of erythropoietin receptor before ligand activation. Science, 283, 987-990 (1999).
54. Remy, I., Wilson, I. A., and Michnick, S. W., Erythropoietin receptor activation by a ligand-induced conformation change. Science, 283, 990-993 (1999).
55. Wrighton, N. C., Balasubramanian, P., Barbone, F. P., Kashyap, A. K., Farrell, F. X., Jolliffe, L. K., Barrett, R. W., and Dower, W. J., Increased potency of an erythropoietin peptide mimetic through covalent dimerization. Nat. Biotechnol., 15, 1261-1265 (1997).
56. Miyajima, A., Hara, T., and Kitamura, T., Common subunits of cytokine receptors and the functional redundancy of cytokines. Trends Biochem. Sci., 17, 378-382 (1992).
57. Sato, N. and Miyajima, A., Multimeric cytokine receptors: common versus specific functions. Curr. Opin. Cell Biol., 6, 174-179 (1994).
58. Joneja, B. and Wojchowski, D. M., Mitogenic signaling and inhibition of apoptosis via the erythropoietin receptor Box-1 domain. J. Biol. Chem., 272, 11176-11184 (1997).
59. Neubauer, H., Cumano, A., Muller, M., Wu, FL, Huffstadt, U., and Pfeffer, K., Jak2 deficiency defines an essential development checkpoint in definitive hematopoiesis. Cell, 93, 397-409 (1998).
60. Parganas, E., Wang, D., Stravopodis, D., Topham, D. J., Marine, J. C., Teglund, S., Vanin, E. F., Bodner, S., Colamonici, O. R., van Deursen, J. M., Grosveld, G., and Ihle, J. N., Jak2 is essential for signalling through a variety of cytokine receptors. Cell, 93, 385-395 (1998).
61. Damen, J. E., Wakao, FL, Miyajima, A., Krosl, J., Humphries, R. K., Cutler, R. L., and Krystal, G., Tyrosine 343 in the erythropoietin receptor positively regulates erythropoietin-induced cell proliferation and Stat5 activation. EMBO J., 14, 5557-5568 (1995).
62. Gobert, S., Chretien, S., Gouilleux, F., Muller, O., Pallard, C., Dusanter, F. I., Groner, B., Lacombe, C., Gisselbrecht, S., and Mayeux, P., Identification of tyrosine residues within the intracellular domain of the erythropoietin receptor crucial for STAT5 activation. EMBO J., 15, 2434-2441 (1996).
63. Quelle, F. W., Wang, D., Nosaka, T., Thierfelder, W. E., Stravopodis, D., Weinstein, Y., and Ihle, J. N., Erythropoietin induces activation of Stat5 through association with specific tyrosines on the receptor that are not required for a mitogenic response. Mol. Cell. Biol., 16, 1622-1631 (1996).
64. Klingmuller, U., Bergelson, S., Hsiao, J. G., and Lodish, H. F., Multiple tyrosine residues in the cytosolic domain of the erythropoietin receptor promote activation of STAT5. Proc. Natl. Acad. Sci. USA, 93, 8324-8328 (1996).
65. Chin, H., Nakamura, N., Kamiyama, R., Miyasaka, N., Ihle, J. N., and Miura, O., Physical and functional interactions between Stat5 and the tyrosine-phosphorylated receptors for erythropoietin and interleukin-3. Blood, 88, 4415-4425 (1996).
66. Chretien, S., Varlet, P., Verdier, F., Gobert, S., Cartron, J. P., Gisselbrecht, S., Mayeux, P., and Lacombe, C., Erythropoietin-induced erythroid differentiation of the human erythroleukemia cell line TF-1 correlates with impaired STAT5 activation. EMBO J., 15, 4174-4181 (1996).
67. Iwatsuki, K., Endo, T., Misawa, H., Yokouchi, M., Matsumoto, A., Ohtsubo, M., Mori, K. J., and Yoshimura, A., STAT5 activation correlates with erythropoietin receptor-mediated erythroid differentiation of an erythroleukemia cell line. J. Biol. Chem., 272, 8149-8152 (1997).
68. Wakao, H., Chida, D., Damen, J. E., Krystal, G., and Miyajima, A., A possible involvement of Stat5 in erythropoietin-induced hemoglobin synthesis. Biochem. Biophys. Res. Commun., 234, 198-205 (1997).
69. Liu, X., Robinson, G. W., Wagner, K. U., Garrett, L., Wynshaw-Boris, A., and Henninghausen, L., Stat5 is mandatory for adult mammary gland development and lactogenesis. Genes Dev., 11, 179-186 (1997).
70. Udy, G. B., Towers, R. P., Snell, R. G., Wilkins, R. J., Park, S. H., Ram, P. A., Waxman, D. J., and Davey, H. W., Requirement of STAT5b for sexual dimorphism of body growth rates and liver gene expression. Proc. Natl. Acad. Sci. USA, 94, 7239-7244 (1997).
71. Teglund, S., McKay, C., Schuetz, E., van Deursen, J. M., Stravopodis, D., Wang, D., Brown, M., Bodner, S., Grosveld, G., and Ihle, J. N., Stat5a and Stat5b proteins have essential and nonessential, or redundant, roles in cytokine responses. Cell, 93, 841-850 (1998).
72. Koury, M. J. and Bondurant, M. C., Erythropoietin retards DNA breakdown and prevents programmed death in erythroid progenitor cell. Science, 248, 378-381 (1990).
73. Landschulz, K. T., Boyer, S. H., Noyes, A. N., Rogers, O. C., and Frelin, L. P., Onset of erythropoietin response in murine erythroid colony-forming units: assignment to early S-phase in an specific cells generation. Blood, 79, 2749-2758 (1992).
74. Kelley, L. L., Koury, M. J., Bondurant, M. C., Koury, S. T., Sawyer, S. T., and Wickrema, A., Survival or death of individual proerythroblasts results from differing erythropoietin sensitivities: a mechanism for controlled rates of erythrocyte production. Blood, 82, 2340-2352 (1993).
75. L and apopain in the control of erythropoiesis by erythropoietin. Blood, 90, 630-640 (1997).
76. L through STAT5 in erythropoietin-dependent progenitor cell lines. J. Biol. Chem., 274, 22165-22169 (1999).
77. L induction. Cell, 98, 181-191 (1999).
78. Miura, O., Miura, Y., Nakamura, N., Quelle, F. W., Witthuhn, B. A., Ihle, J. N., and Aoki, N., Induction of tyrosine phosphorylation of Vav and expression of Pim-1 correlates with Jak2-mediated growth signaling from the erythropoietin receptor. Blood, 84, 4135-4141 (1994).
79. Crespo, P., Schuebel, K. E., Ostrom, A. A., Gutkind, J. S., and Bustelo, X. R., Phos-photyrosine-dependent activation of Rac-1 GDP/ GTP exchange by the vav proto-oncogene product. Nature, 385, 169-172 (1997).
80. in erythropoietin-mediated cell proliferation and phosphoatidylinositol 3-kinase activity. /. Biol. Chem., 272, 14334-14340 (1997).
81. Torti, M., Marti, K. B., Altshuler, D., Yamamoto, K., and Lapetina, E., G. Erythropoietin induces p21 ras activation and pi20 GAP tyrosine phosphorylation in human erythroleukemia cells. J. Biol. Chem., 267, 8293-8298 (1992).
82. Hanazono, Y., Chiba, S., Sasaki, K., Mano, FI., Yazaki, Y., and Elirai, H., Erythropoietin induces tyrosine phosphorylation and kinase activity of the c-fps/fes proto-oncogene product in human erythropoietin-responsive cells. Blood, 81, 3193-3196 (1993).
83. Chin, H., Arai, A., Wakao, H., Kamiyama, R., Miyasaka, N., and Miura, O., Lyn physically associates with the erythropoietin receptor and may play a role in activation of the Stat5 pathway. Blood, 91, 3734-3745 (1998).
84. Odai, H., Sasaki, K., Iwamatsu, A., Hanazono, Y., Tanaka, T., Mitani, K., Yazaki, Y., and Hirai, H., The proto-oncogene product c-Cbl becomes tyrosine phosphorylated by stimulation with GM-CSF or Epo and constitutively binds to the SH3 domain of Grb2/Ash in human hematopoietic cells. J. Biol. Chem., 270, 10800-10805 (1995).
85. receptor after Epo-induced receptor tyrosine phosphorylation: identification of potential binding sites. Blood, 85, 87-95 (1995).
86. Klingmuller, U., lorenz, U., Cantley, L. C., Neel, B. G., and Lodish, H. F., Specific recruitment of SH-PTP1 to the erythropoietin receptor causes inactivation of JAK2 and termination of proliferative signals. Cell, 80, 729-738 (1995).
87. Tsui, H. W., Siminovitch, K. A., de Souza, L., and Tsui, F. W., Motheaten and viable motheaten mice have mutations in the hematopoietic cell phosphatase gene. Nat. Genet., 4, 124-129 (1993).
88. gene. Cell, 73, 1445-1454 (1993).
89. Endo, T. A., Masuhara, M., Yokouchi, M., Suzuki, R., Sakamoto, H., Mitsui, K., Matsumoto, A., Tanimura, S., Ohtsubo, M., Misawa, H., Miyazaki, T., Leonor, N., Taniguchi, T., Fujita, T., Kanakura, Y., Komiya, S., and Yoshimura, A., A new protein containing an SH2 domain that inhibits JAK kinases. Nature, 387, 921-924 (1997).
90. Naka, T., Narazaki, M., Hirata, M., Matsumoto, T., Minamoto, S., Aono, A., Nishimoto, N., Kajita, T., Taga, T., Yoshizaki, K., Akira, S., and Kishimoto, T., Structure and function of a new STAT-induced STAT inhibitor. Nature, 387, 924-929 (1997).
91. Starr, R., Willson, T. A., Viney, E. M., Murray, L. J., Rayner, J. R., Jenkins, B. J., Gonda, T. J., Alexander, W. S., Metcalf, D., Nicola, N. A., and Hilton, D. J., A family of cytokine-inducible inhibitors of signalling. Nature, 387, 917-921 (1997).
92. 2+ uptake in Friend virus-infected erythroid cells. J. Biol. Chem., 259, 2769-2774 (1984).
93. Mladenovic, J. and Kay, N. E., Erythropoietin induces rapid increases in intracellular free calcium in human bone marrow cells. J. Lab. Clin. Med., 112, 23-27 (1988).
94. Miller, B. A., Bell, L. L., Lynch, C. J., and Cheung, J. Y., Erythropoietin modulation of intracellular calcium: a role for tyrosine phosphorylation. Cell Calcium,16,481-490 (1994).
95. Miller, B. A., Bell, L., Hansen, C. A., Robishow, J. D., Linder, M. E., and Cheung, J. Y., G-protein a subunit Gia2 mediates erythropoietin signal transduction in human erythroid precursors. J. Clin. Invest., 98, 1728-1736 (1996).
96. Cheung, J. Y., Zhang, X. Q., Bokvist, K., Tillotson, D. L., and Miller, B. A. Modulation of calcium channels in human erythroblasts by erythropoietin. Blood, 89, 92-100 (1997).
97. Miller, B. A., Barber, D. L., Bell, L. L., Beattie, B. K., Zhang, M. Y., Neel, B. G., Yoakim, M., Rothblum, L. I., and Cheung, J. Y., Identification of the erythropoietin receptor domain required for calcium channel activation. J. Biol. Chem., 274, 20465-20472 (1999).
98. Imagawa, S., Smith, B. R., Palmer-Crocker, R., and Bunn, H. F., The effect of recombinant erythropoietin on intracellular free calcium in erythropoietin-responsive cells. Blood, 73, 1452-1457 (1989).
99. Masuda, S., Nagao, M., Takahata, K., Konishi, Y., Galiyas, F. Jr., Tabira, T., and Sasaki, R., Functional erythropoietin receptor of the cells with neural characteristics: Comparison with receptor properties of erythroid cells. J. Biol. Chem., 268, 11208-11216 (1993).
100. Koshimura, K., Murakami, Y., Sohmiya, M., Tanaka, J., and Kato, Y., Effects of erythropoietin on neuronal activity. J. Neurochem., 72, 2565-2572 (1999).
101. Assandri, R., Egger, M., Gassman, M., Niggli, E., Bauer, C., Forster, I., and Gorlach, A., Erythropoietin modulates intracellular calcium in a human neuroblastoma cell line. J. Physiol., 516, 343-352 (1999).
102. Goldberg, M. A., Dunning, S. P., and Bunn, H. F., Regulation of the erythropoietin gene: Evidence that the oxygen sensor is a heme protein. Science, 242, 1412-1415 (1988).
103. Bern, N., McDonald, J., Lacombe, C., and Goldwasser, E., Expression of the erythropoietin gene. Mol. Cell. Biol., 6, 2571-2575 (1986).
104. Bondurant, M. C. and Koury, M. J., Anemia induces accumulation of erythropoietin mRNA in the kidney and liver. Mol. Cell. Biol., 6, 2731-2733 (1986).
105. Schuster, S. J., Badiavas, E. V., Costa-Giomi, P., Weinmann, R., Erslev, A., and Caro, J., Stimulation of erythropoietin gene transcription during hypoxia and cobalt exposure. Blood, 73, 13-16 (1989).
106. Lacombe, C., Da Silva, J.-L., Bruneval, P., Fouurnier, J.-G., Wending, F., Casadevall, N., Camilleti, J.-P., Bariety, J., Varet, B., and Tam-bourin, P., Peritubular cells are the site of erythropoietin synthesis in the murine hypoxic kidney. J. Clin. Invest., 81, 620-623 (1988).
107. Koury, S. T., Bondurant, M. C., and Koury, M. J., Localization of erythropoietin synthesizing cells in murine kidneys by in situ hybridization. Blood, 71, 524-527 (1988).
108. Koury, S. T., Koury, M. J., Bondurant, M. C., Caro, J., and Graber, S. E., Quantification of erythropoietin-producing cells in kidneys of mice by in situ hybridization: Correlation with hematocrit, renal erythropoietin mRNA, and serum erythropoietin concentration. Blood, 74, 645-651 (1989).
109. Semenza, G. L., Koury, S. T., Neifelt, M. K., Gearhart, J. D., and Antonarakis, S. E., Cell-type-specific and hypoxia-inducible expression of the human erythropoietin gene in transgenic mice. Proc. Natl. Acad. Sci. USA, 88, 8725-8729 (1991).
110. Maxwell, P. FL, Osmond, M. K., Pugh, C. W., Heryet, A., Nicholls, L. G., Tan, C. C., Doe, B. G., Ferguson, D. J. P., Johnson, M. FL, and Ratcliffe, P. J., Identification of the renal erythropoietin-producing cells using transgenic mice. Kidney Int., 44, 1149-1162 (1993).
111. Bachmann, S., LeHir, M., andEckardt, K.-U., Colocalization of erythropoietin mRNA and ecto-5'-nucleotidase immunoreactivity in peritubular cells of rat renal cortex indicates that fibroblasts produce erythropoietin. J. Histochem. Cytochem., 41, 335-341 (1993).
112. Fisher, J. W., Koury, S., Ducey, T., and Mendel, S., Erythropoietin production by interstitial cells of hypoxic monkey kidneys. Br. J. Haematol., 95, 27-32 (1996).
113. Maxwell, A. P., Lappin, T. R. J., Johnston, C. F., Bridges, J. M., and McGeown, M. G., Erythropoietin production in kidney tubular cells. Br. J. Haematol., 74, 534-539 (1990).
114. Loya, F., Yang, Y., Lin, FL, Goldwasser, E., and Alsitar, M., Transgenic mice carrying the erythropoietin gene promoter linked to LacL express the reporter in proximal convoluted tubule cells after hypoxia. Blood, 84, 1831-1836 (1994).
115. Mujais, S. K., Beru, N., Pullman, T. N., and Goldwasser, E., Erythropoietin is produced by tubular cells of the rat kidney. Cell. Biochem. Biophys., 30, 153-166 (1999).
116. Koury, S. T., Bondurant, M. C., Koury, M. J., and Semenza, G. L., Localization of cells producing erythropoietin in murine liver by in situ hybridization. Blood, 11, 2497-2503 (1991).
117. Maxwell, P. FI., Ferguson, D. J. P., Osmond, M. K., Pugh, C. W., Heryet, B. A., Doe, B. G., Johnson, M. H., and Ratcliffe, P. J., 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 (1994).
118. Costa-Giomi, P., Caro, J., and Weinman, R., Enhancement by hypoxia of human erythropoietin gene transcription in vitro. J. Biol. Chem., 265, 10185-10188 (1990).
119. Goldberg, M. A., Gaut, C. C., and Bunn, H. F., Erythropoietin mRNA levels are governed by both the rate of gene transcription and posttranscription-al events. Blood, 11, 271-277 (1991).
120. Rondon, I. J., MacMillan, L. A., Beckman, B. S., Goldberg, M. A., Schneider, T., Bunn, H. F., and Malter, J. S., Hypoxia up-regulates the activity of a novel erythropoietin mRNA binding protein. J. Biol. Chem., 266, 16594-16598 (1991).
121. Rondon, I. J., Scandurro, A. B., Wilson, R. B., and Beckman, B. S., Changes in redox affect the activity of erythropoietin RNA binding protein. FEBSLett., 359, 267-270 (1995).
122. McGary, E. C., Rondon, I. J., and Beckman, B. S., Post-transcriptional regulation of erythropoietin mRNA stability by erythropoietin mRNA-binding protein. J. Biol. Chem., 272, 8628-8634 (1997).
123. Scandurro, A. B. and Beckman, B. S., Common proteins bind mRNAs encoding erythropoietin, tyrosine hydroxylase, and vascular endothelial growth factor. Biochem. Biophys. Res. Commun., 246, 436-440 (1998).
124. Semenza, G. L., Traystman, M. D., Gearhart, J. D., and Antonarakis, S. E., Polycythemia in transgenic mice expressing the human erythropoietin gene. Proc. Natl. Acad. Sci. USA, 86, 2301-2305 (1989).
125. Semenza, G. L., Dureza, R. C., Traystman, M. D., Gearhart, J. D., and Antonarakis, S. E., Human erythropoietin gene expression in transgenic mice: multiple transcription initiation sites and cA-acting regulatory elements. Mol. Cell. Biol., 10, 930-938 (1990).
126. Madan, A., Lin, C., Hatch, S. L., and Curtin, P. T., Regulated basal, inducible, and tissue-specific human erythropoietin gene expression in transgenic mice requires multiple cis DNA sequences. Blood, 85, 2735-2741 (1995).
127. Haidar, M. A., Loya, F., Yang, Y., Lin, H., Glassma, A., Keating, M. J., Goldwasser, E., and Albitar, M., Differential expression of LacL in the liver and kidney of transgenic mice carrying chimeric LacZ-erythropoietin gene constructs with or without its 1.2 kb 3'-flanking sequence. Nucleic Acids Res., 24, 3621-3628 (1996).
128. Goldberg, M. A., Glass, G. A., Cunningham, J. M., and Bunn, H. F., The regulated expression of erythropoietin by two human hepatoma cell lines. Proc. Natl. Acad. Sci. USA, 84, 7972-7976 (1987).
129. Beck, I., Ramirez, S., Weinmann, R., and Caro, J., Enhancer element at the 3'-flanking region controls transcriptional response to hypoxia in the human erythropoietin gene. J. Biol. Chem., 266, 15563-15566 (1991).
130. Semenza, G. L., Nejfelt, M. K., Chi, S. M., and Antonarakis, S. E., Hypoxia-inducible nuclear factors bind to an enhancer element located 3' to the human erythropoietin gene. Proc. Natl. Acad. Sci. USA, 88, 5680-5684 (1991).
131. Pugh, C. W., Tann, C. C., Jones, R. W., and Ratcliffe, P. J., Functional analysis of an oxygen-regulated transcriptional enhancer lying 3' to the mouse erythropoietin gene. Proc. Natl. Acad. Sci. USA, 88, 10553-10557 (1991).
132. Semenza, G. L. and Wang, G. L., 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 (1992).
133. Wang, G. L. and Semenza, G. L., Purification and characterization of hypoxia-inducible factor 1. J. Biol. Chem., 270, 1230-1237 (1995).
134. 2 tension. Proc. Natl. Acad. Sci. USA, 92, 5510-5514 (1995).
135. Huang, Z. J., Edery, I., and Rosbach, M., PAS is a dimerization domain common to Drosophila period and several transcription factors. Nature, 364, 259-262 (1993).
136. Gradin, K., McGuire, J., Wenger, R. H., Kvietikova, I., Whitelaw, M. L., Toftgard, R., Tora, L., Gassmann, M., and Poellinger, L., Functional interference between hypoxia and dioxin signal transduction pathway; competition for recruitment of the arnt transcription factor. Mol. Cell. Biol., 16, 5221-5231 (1996).
137. Huang, L. E., Arany, Z., Livingston, D. M., and Bunn, H. F., Activation of hypoxia-inducible transcription factor depends primarily upon redox-sensi-tive stabilization of its a subunit. /. Biol. Chem., 271, 32253-32259 (1996).
138. protein is rapidly degraded by the ubi-quitin-proteasome system under normoxic conditions. J. Biol. Chem., 272, 22642-22647 (1997).
139. 2-dependent degradation domain via the ubiquitin-proteasome pathway. Proc. Natl. Acad. Sci. USA, 95, 7987-7992 (1998).
140. Blanchard, K. L., Acquaviva, A. M., Galson, D. L., and Bunn, H. F., 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, 5373-5385 (1992).
141. Galson, D. L., Tsuchiya, T., Tendler, D. S., Huang, L. E., Ren, Y., Ogura, T., and Bunn, H. F., 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 (1995).
142. Arany, Z., Huang, L. E., Eckner, R., Bhattacharya, S., Jiang, C., Goldberg, M. A., Bunn, H. F., and Livingston, D. M., An essential role of p300/CBP in the cellular response to hypoxia. Proc. Natl. Acad. Sci. USA, 93, 12969-12973 (1996).
143. Ebert, B. L. and Bunn, H. F., Regulation of transcription by hypoxia requires a multiprotein complex that includes hypoxia-inducible factor 1, an adjacent transcription factor, and p300/CREB binding protein. Mol. Cell. Biol, 18, 4089-4096 (1998).
144. Bunn, H. F., Gu, J., Huang, L. E., Park, J. W., and Zhu, H., Erythropoietin: a model system for studying oxygen-dependent gene regulation. J. Exp. Biol., 201, 1197-1201 (1998).
145. Maxwell, P. H., Pugh, C. W., and Ratcliffe, P. J., Inducible operation of the erythropoietin 3' enhancer in multiple cell lines: Evidence for a widespread oxygen-sensing mechanism. Proc. Natl. Acad. Sci. USA, 90, 2423-2427 (1993).
146. Wang, G. L. and Semenza, G. L., General involvement of hypoxia-inducible factor 1 in transcriptional response to hypoxia. Proc. Natl. Acad. Sci. USA, 90, 4304-4308 (1993).
147. Wenger, R. H. and Gassman, M., HIF-1 and the molecular response to hypoxia in mammals. In “Environmental stress and gene regulation” (K. B. Storey ed.), BIOS Scientific Publishers Ltd., Oxford, pp. 25-45 (1999).
148. 2 homeostasis by hypoxia-inducible factor la. Genes Dev., 12, 149-162 (1998).
149. Lois, A. F., Ditta, G. S., and Helinski, D. R., The oxygen sensor FixL of Rizobium meliloti is a membrane protein containing four possible transmembrane segments. J. Bacteriol., 175, 1103-1109 (1993).
150. Maxwell, P. H., Wiesener, M. S., Chang, G. W., Clifford, S. C., Vaux, E. C., Cockman, M. E., Wykoff, C. C., Pugh, C. W., Maher, E. R., and Ratcliffe, P. J., The tumor suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature, 399, 271-275 (1999).
151. Fandrey, J., Pagel, H., Frede, S., Wolff, M., and Jelkmann, W., Thyroid hormones enhance hypoxia-induced erythropoietin in vitro. Exp. Hematol., 22, 272-277 (1994).
152. Yoshioka, K. and Fisher, J. W., Nitric oxide enhancement of erythropoietin production in the isolated perfused rat kidney. Am. J. Physiol., 269, C917-C922 (1995).
153. Todorov, V., Gess, B., Godecke, A., Wagner, C., Schrader, J., and Kurtz, A., Endogenous nitric oxide attenuates erythropoietin gene expression in vivo. Pflugers Arch., 439, 445-448 (2000).
154. Kambe, T., Tada, J., Chikuma, M., Masuda, S., Nagao, M., Tsuchiya, T., Ratcliffe, P. J., and Sasaki, R., Embryonal carcinoma P19 cells produce eryhtropoietin constitutively but express lactate dehydrogenase in an oxygen-dependent manner. Blood, 91, 1185-1195 (1998).
155. Kambe, T., Tada-Kambe, J., Kuge, Y., Yamaguchi-Iwai, Y., Nagao, M., and Sasaki, R., Retinoic acid stimulates erythropoietin gene transcription in embryonal carcinoma cells through the direct repeat of a steroid /thyroid hormone receptor response element half-site in the hypoxia-response enhancer. Blood, in press (2000).
156. Okano, M., Masuda, S., Narita, H., Masushige, S., Kato, S., Imagawa, S., and Sasaki, R., Retinoic acid up-regulates erythropoietin production in hepatoma cells and in vitamin A-depletded rats. FEBS Letters, 349, 229-233 (1994).
157. Yasuda, Y., Okano, M., Nagao, M., Masuda, S., Konishi, H., Ueda, K., Matsuo, T., Tsujiguchi, S., Tajima, S., Sasaki, R., Tanimura, T., Erythropoietin in mouse avascular yolk sacs is increased by retinoic acid. Dev. Dynam., 207, 184-194 (1996).
158. Digicaylioglu, M., Bichet, S., Marti, H. EL, Wenger, R. H., Rivas, L. A., Bauer, C., and Gass-mann, M., Localization of specific erythropoietin binding sites in defined areas of the mouse brain. Proc. Natl. Acad. Sci. USA, 92, 3717-3720 (1995).
159. Morishita, E., Narita, H., Nishida, M., Kawashima, N., Yamagishi, K., Masuda, S., Nagao, M., Hatta, EL, and Sasaki, R., Anti-erythropoietin receptor monoclonal antibody: Epitope mapping, quantification of the soluble receptor, and detection of the solubilized transmembrane receptor and the receptor-expressing cells. Blood, 88, 465-471 (1996).
160. Morishita, E., Masuda, S., Nagao, M., Yasuda, Y., and Sasaki, R., Erythropoietin receptor is expressed in rat hippocampal and cerebral cortical neurons, and erythropoietin prevents in vitro glutamate-induced neuronal death. Neuroscience, 76, 105-116 (1997).
161. Liu, C., Shen, K., Liu, Z., and Noguchi, C. T., Regulated human erythropoietin receptor expression in mouse brain. J. Biol. Chem., 272, 32395-32400 (1997).
162. Konishi, Y., Chui, D. H., Hirose, El., Kunishita, T., and Tabira, T., Trophic effect of erythropoietin and other hematopoietic factors on central cholinergic neurons in vitro and in vivo. Brain Res., 609, 29-35 (1993).
163. Masuda, S., Okano, M., Yamagishi, K., Nagao, M., Ueda, M., and Sasaki, R., A novel site of erythropoietin production: Oxygen-dependent production in cultured rat astrocytes. J. Biol. Chem., 269, 19488-19493 (1994).
164. Marti, H. El., Wenger, R. H., Rivas, L. A., Straumann, U., Digicaylioglu, M., Henn, V., Yonekawa, Y., Bauer, C., and Gassmann, M., Erythropoietin gene expression in human, monkey and murine brain. Eur. J. Neurosci., 8, 666-676 (1996).
165. Tan, C. C., Eckardt, K. U., Firth, J. D., and Ratcliffe, P. J., Feedback modulation of renal and hepatic erythropoietin mRNA in response to graded anemia and hypoxia. Am. J. Physiol., 263, F474-F481 (1992).
166. Marti, H. El., Gassmann, M., Wenger, R. EL, Kvietikova, I., Morganti-Kossmann, M. C., Koss-mann, T., Trentz, O., and Bauer, C., Detection of erythropoietin in human liquor, intrinsic erythropoietin production in the brain. Kidney Int., 51, 416-418 (1997).
167. Yasuda, Y., Nagao, M., Okano, M., Masuda, S., Sasaki, R., Konishi, EL, and Tanimura, T., Localization of erythropoietin and erythropoietin-receptor in postimplantation mouse embryos. Develop. Growth &Differ., 35, 711-722 (1993).
168. Juul, S. E., Li, Y., Anderson, D. K., and Christensen, R. D., Erythropoietin and erythropoietin receptor in the developing human central nervous system. Pediatr. Res., 43, 40-9 (1998).
169. Nagao, M., Masuda, S., Abe, S., Ueda, M., and Sasaki, R., Production and ligand-binding characteristics of the soluble form of murine erythropoietin receptor. Biochem. Biophys. Res. Commun., 188, 888-897 (1992).
170. Kirino, T., Delayed neuronal death in the gerbil hippocampus following ischemia. Brain Res., 239, 57-69 (1982).
171. Choi, D. W., Glutamate neurotoxicity and diseases of the nervous system. Neuron, 1, 623-634 (1988).
172. Choi, D. W. and Rothman, S. M., The role of glutamate neurotoxicity in hypoxic-ischemic neuronal death. Ann. Rev. Neurosci., 13, 171-182 (1990).
173. Michaelis, E. K., Molecular biology of glutamate receptors in the central nervous system and their role in excitotoxicity, oxidative stress and aging. Prog. Neurobiol., 54, 369-415 (1998).
174. Choi, D. W., Glutamate neurotoxicity in cortical cell culture is calcium dependent. Neurosci. Lett., 58, 293-297 (1985).
175. Choi, D. W., Ionic dependence of glutamate neurotoxicity. J. Neurosci., 1, 369-379 (1987).
176. Siesjo, B. K., Historical overview: Calcium, ischemia and death of brain cells. Ann. N. Y. Acad. Sci., 522, 638-661 (1988).
177. Pulsinelli, W. A., Brierly, J. B., and Plum, F., Temporal profile of neuronal damage in a model of transient forebrain ischemia. Ann. Neurol., 11, 491-498 (1982).
178. Bredt, D. S. and Snyder, S. H., Isolation of nitric oxide synthetase, a calmodulin-requiring enzyme. Proc. Natl. Acad. Sci. USA, 87, 682-685 (1990).
179. Dawson, V. L., Dawson, T. M., London, E. D., Bredt, D. S., and Snyder, S. H., Nitric oxide mediates glutamate neurotoxicity in primary cortical cultures. Proc. Natl. Acad. Sci. USA, 88, 6368-6371 (1991).
180. Masuda, S., Chikuma, M., and Sasaki, R., Insulinlike growth factors and insulin stimulate erythropoietin production in primary cultured astrocytes. Brain Res., 746, 63-70 (1997).
181. Baskin, D. G., Wilcox, B. J., Figlewicz, D. P., and Dorsa, D. M., Insulin and insulin-like growth factors in the CNS. Trends Neurosci., 11, 107-111 (1988).
182. Anagnostou, A., Liu, Z., Steiner, M., Chin, K., Lee, E. S., Kessimian, N., and Noguchi, C. T., Erythropoietin receptor mRNA expression in human endothelial cells. Proc. Natl. Acad. Sci. USA, 91, 3974-3978 (1994).
183. Yamaji, R., Okada, T., Moriya, M., Naito, M., Tsuruo, T., Miyatake, K., and Nakano, Y., Brain capillary endothelial cells express two forms of erythropoietin receptor mRNA. Eur. J. Biochem., 239, 494-500 (1996).
184. Anagnostou, A., Lee, E. S., Kessimian, N., Levinson, R., and Steiner, M., Erythropoietin has a mitogenic and positive chemotactic effect on endothelial cells. Proc. Natl. Acad. Sci. USA, 87, 5978-5982 (1990).
185. Carlini, R. G., Reyes, A. A., and Rothstein, M., Recombinant human erythropoietin stimulates an-giogenesis in vitro. Kidney Int., 47, 740-745 (1995).
186. Wang, X. Q. and Vaziri, N. D., Erythropoietin depresses nitric oxide synthase expression by human endothelial cells. Hypertension, 33, 894-899 (1999).
187. Ribatti, D., Presta, M., Vacca, A., Ria, R., Giuliani, R., Dell’Era, P., Nico, B., Roncali, L., and Dammacco, F., Human erythropoietin induces a pro-angiogenic phenotype in cultured endothelial cells and stimulates neovascularization in vivo. Blood, 93, 2627-2636 (1999).
188. Haller, H., Christel, C., Dannenberg, L., Thiele, P., Lindschau, C., and Luft, F. C., Signal transduction of erythropoietin in endothelial cells. Kidney Int., 50, 481-488 (1996).
189. Bikfalvi, A. and Han, Z. C., Angiogenic factors are hematopoietic growth factors and vice versa. Leukemia, 8, 523-529 (1994).
190. Hanahan, D. and Folkman, J., Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell, 86, 353-364 (1996).
191. Clark, J. H. and Markaverich, B. B., Actions of ovarian steroids. In The Physiology of Reproduction (Knobil, E. and Neil, J. eds.), New York, Raven Press, pp. 675-724 (1988).
192. Ham, K. N., Hurley, J. V., Lopata, A., and Ryan, G. B., A combined isotopic and electron microscopic study of the response of the rat uterus to exogenous oestradiol. J. Endocrinol., 46, 71-81 (1970).
193. Stack, G. and Gorski, J., Direct mitogenic effect of estrogen on the prepuberal rat uterus: studies on isolated nuclei. Endocrinology, 115, 1141-1150 (1984).
194. Kirkland, J. L., LaPointe, L., Justin, E., and Stancel, G. M., Effects of estrogen on mitosis in individual cell types of the immature rat uterus. Biol. Reprod., 21, 269-272 (1979).
195. Folkman, J. and Klagsburn, M., Angiogenic factors. Science, 235, 442-447 (1987).
196. Schott, R. J. and Morrow, L. A., Growth factors and angiogenesis. Cardiovas. Res., 27, 1155-1161 (1993).
197. Hechter, O., Krohn, L., and Harris, J., The effect of estrogen on the permeability of the uterine capillaries. Endocrinol., 23, 25-31 (1941).
198. Cullinan-Bove, K. and Koos, R. D., Vascular endothelial growth factor/vascular permeability factor expression in the rat uterus: rapid stimulation by estrogen correlates with estrogen-induced increases in uterine capillary permeability and growth. Endocrinology, 133, 829-837 (1993).
199. Connolly, D. T., Heuvelman, D. M., Nelson, R., Olander, J. V., Eppley, B. L., Delfino, J. J., Siegel, N. R., Leimgruber, R. M., and Feder, J., Tumor vascular permeability factor stimulates endothelial cell growth and angiogenesis. J. Clin. Invest., 84, 1470-1478 (1989).
200. Ferrara, N., Houck, K., Jakeman, L., and Leung, D. W., Molecular and biological properties of the vascular endothelial growth factor family of proteins. Endocrinol. Rev., 13, 18-32 (1992).
201. Leung, D. W., Cachianes, G., Kuang, W. J., Goeddel, D. V., and Ferrara, N., Vascular endothelial growth factor is a secreted angiogenic mitogen. Science, 246, 1306-1309 (1989).
202. and VEGF receptors in mice suggest a role in hormonally regulated angiogenesis. J. Clin. Invest., 91, 2235-2243 (1993).
203. Masuda, S., Kobayashi, T., Chikuma, M., Nagao, M., and Sasaki, R., The oviduct produces erythropoietin in an estrogen- and oxygen-dependent manner. Am. J. Physiol., 278, E1038-E1044 (2000).
204. Mioni, R., Gottardello, F., Bordon, P., Montini, G., and Foresta, C., Evidence for specific binding and stimulatory effects of recombinant human erythropoietin on isolated adult rat Leydig cells. Acta Endocrinol., 127, 459-465 (1992).
205. Yamamoto, Y., Sofikitis, N., and Miyagawa, I., Effects of erythropoietin, bromocryptine and hydralazine on testicular function in rats with chronic renal failure. Andrologia, 29, 141-144 (1997).
206. Foresta, C., Mioni, R., Bordon, P., Miotto, D., Montini, G., and Varotto, A., Erythropoietin stimulates testosterone production in man. J. Clin. Endocrinol. Metab., 78, 753-756 (1994).
207. Chikuma, M., Masuda, S., Kobayashi, T., Nagao, M., and Sasaki, R., Tissue-specific regulation of erythropoietin production in mouse kidney, brain and uterus. Am. J. Physiol., in press (2000).
208. Eckardt, K.-U., Dittmer, J., Neumann, R., Bauer, C., and Kurtz, A., Decline of erythropoietin formation at continuous hypoxia is not due to feedback inhibition. Am. J. Physiol., 258, F1432-F1437 (1990).
209. Le Hir, M., Eckardt, K.-U., Kaissling, B., Koury, S. T., and Kurtz, A., Structure-function correlations in erythropoietin formation and oxygen sensing in the kidney. Klin. Wochenschr., 69, 567-575 (1991).