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Gene Review

Epo  -  erythropoietin

Mus musculus

Synonyms: Erythropoietin
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Disease relevance of Epo


Psychiatry related information on Epo


High impact information on Epo

  • The p38alpha MAP kinase plays a critical role linking developmental and stress-induced erythropoiesis through regulation of Epo expression [9].
  • Inhibition of p38 activity also interferes with stabilization of Epo mRNA in human hepatoma cells undergoing hypoxic stress [9].
  • Whereas some p38alpha(-/-) embryos die between embryonic days 11.5 and 12.5, those that develop past this stage have normal morphology but are anemic owing to failed definitive erythropoiesis, caused by diminished erythropoietin (Epo) gene expression [9].
  • Stat5a-/-5b-/- embryos are severely anemic; erythroid progenitors are present in low numbers, show higher levels of apoptosis, and are less responsive to Epo [10].
  • During embryonic development, SOCS3 is highly expressed in erythroid lineage cells and is Epo independent [11].

Chemical compound and disease context of Epo


Biological context of Epo

  • Studies using hepatocyte-specific deletion of the Vegfa gene and hepatocyte-endothelial cell cocultures indicated that blockade of VEGF induced hepatic Epo by interfering with homeostatic VEGFR2-dependent paracrine signaling involving interactions between hepatocytes and endothelial cells [1].
  • Cell survival by Epo did not require activation of other known signaling pathways including PI-3 kinase, PLC-gamma, Ras or Stats [17].
  • Our results are consistent with the conclusion that SLF, Epo, IL-4, and IL-6 are important during the early stages of ES cell differentiation and hematopoietic development [18].
  • Expression levels of various angiogenic factors revealed that only erythropoietin (Epo) gene expression was significantly affected, in parallel with HLF expression [19].
  • Moreover, Y425 in the EpoR reduces the Epo requirement for Syp tyrosine phosphorylation and promotes proliferation [20].

Anatomical context of Epo

  • The morphology of the Epo-dependent cell lines (32D Epo1, -2, and -3) was heterogeneous and evolved with passage [21].
  • EpoR(R129C) completely abrogated the Epo requirement of erythroid colony-forming units to form erythrocytes after 2-5 days in culture and did not interfere with the differentiation program of these cells [22].
  • Further, antibodies against EpoR coimmunoprecipitated betacR from membranes prepared from neuronal-like P-19 cells that respond to Epo-induced tissue protection [23].
  • Finally, as predicted by the hypothesis, neither Epo nor CEpo was active in cardiomyocyte or spinal cord injury models performed in the betacR knockout mouse [23].
  • At the same concentration, Ro 25-6603 and Ro 25-7386 had little or no effect on G-CSF-induced colony formation, whereas they inhibited 75% and 53%, respectively, of SCF + Epo-stimulated BFU-E colony growth [24].

Associations of Epo with chemical compounds


Physical interactions of Epo

  • Activation of the erythropoietin receptor is not required for internalization of bound erythropoietin [29].
  • Epo stimulation of BMMCs led to the activation of a DNA-binding activity that comigrated with the SCF-induced band, but peaked and was maintained at later time points than SCF-induced activation [30].
  • Binding of IL-3 to the IL-3 receptor (IL-3R) and binding of EPO to the EPOR both induce changes in intracellular tyrosine and serine/threonine phosphorylation; the phosphorylation of a number of polypeptides appears to be a shared response upon cytokine stimulation [31].
  • Sf-Stk kinase activity and the Grb2 binding site are required for Epo-independent growth of primary erythroblasts infected with Friend virus [32].
  • Our novel results are consistent with the notion that specific receptors for epo exist on the cell surface of PEM and that binding of epo sets in motion a series of cellular events resulting in the internalization of CSF-1 receptors [33].

Enzymatic interactions of Epo

  • Both the receptor and Janus kinase 2 were phosphorylated after erythropoietin stimulation of J2E-NR cells [34].
  • Studies are in progress to identify the mechanism by which Stat proteins are phosphorylated in SFFV-infected cells in the absence of Epo [35].

Regulatory relationships of Epo


Other interactions of Epo

  • A novel cytokine-inducible gene CIS encodes an SH2-containing protein that binds to tyrosine-phosphorylated interleukin 3 and erythropoietin receptors [40].
  • We have recently characterized Epo derivatives that do not bind to the Epo receptor (EpoR) yet are tissue-protective [23].
  • TPO is most prominent in postnatal brain, whereas EPO is abundant in embryonic brain and decreases postnatally [41].
  • Immune complex kinase assays of anti-EpoR immunoprecipitates also revealed that activated JAK2 associates with the EpoR in Epo-stimulated cells [36].
  • In the presence of EPO, p53 activation leads only to prolonged but viable G(1) arrest [42].

Analytical, diagnostic and therapeutic context of Epo


  1. VEGF modulates erythropoiesis through regulation of adult hepatic erythropoietin synthesis. Tam, B.Y., Wei, K., Rudge, J.S., Hoffman, J., Holash, J., Park, S.K., Yuan, J., Hefner, C., Chartier, C., Lee, J.S., Jiang, S., Niyak, N.R., Kuypers, F.A., Ma, L., Sundram, U., Wu, G., Garcia, J.A., Schrier, S.L., Maher, J.J., Johnson, R.S., Yancopoulos, G.D., Mulligan, R.C., Kuo, C.J. Nat. Med. (2006) [Pubmed]
  2. Activation of the Jun N-terminal kinase pathway by friend spleen focus-forming virus and its role in the growth and survival of friend virus-induced erythroleukemia cells. Nishigaki, K., Hanson, C., Thompson, D., Yugawa, T., Ruscetti, S. J. Virol. (2005) [Pubmed]
  3. Zidovudine (AZT) treatment suppresses granulocyte-monocyte colony stimulating factor receptor type alpha (GM-CSFR alpha) gene expression in murine bone marrow cells. Chitnis, S., Mondal, D., Agrawal, K.C. Life Sci. (2002) [Pubmed]
  4. Brain-derived erythropoietin protects from focal cerebral ischemia by dual activation of ERK-1/-2 and Akt pathways. Kilic, E., Kilic, U., Soliz, J., Bassetti, C.L., Gassmann, M., Hermann, D.M. FASEB J. (2005) [Pubmed]
  5. Erythropoietin-mobilized endothelial progenitors enhance reendothelialization via Akt-endothelial nitric oxide synthase activation and prevent neointimal hyperplasia. Urao, N., Okigaki, M., Yamada, H., Aadachi, Y., Matsuno, K., Matsui, A., Matsunaga, S., Tateishi, K., Nomura, T., Takahashi, T., Tatsumi, T., Matsubara, H. Circ. Res. (2006) [Pubmed]
  6. Erythropoietin deficiency decreases vascular stability in mice. Chen, J., Connor, K.M., Aderman, C.M., Smith, L.E. J. Clin. Invest. (2008) [Pubmed]
  7. Cytokine gene expression in cerebral hemispheres and behavioral reactions of (CBAxC57Bl)F1 mice. Poveshchenko, A.F., Markova, E.V., Korotkova, N.A., Yakushenko, E.V., Abramov, V.V., Kozlov, V.A. Bull. Exp. Biol. Med. (2002) [Pubmed]
  8. Effects of epoetin alfa on cognitive function, mood, asthenia, and quality of life in women with breast cancer undergoing adjuvant chemotherapy. O'Shaughnessy, J.A. Clin. Breast Cancer (2002) [Pubmed]
  9. Requirement for p38alpha in erythropoietin expression: a role for stress kinases in erythropoiesis. Tamura, K., Sudo, T., Senftleben, U., Dadak, A.M., Johnson, R., Karin, M. Cell (2000) [Pubmed]
  10. Fetal anemia and apoptosis of red cell progenitors in Stat5a-/-5b-/- mice: a direct role for Stat5 in Bcl-X(L) induction. Socolovsky, M., Fallon, A.E., Wang, S., Brugnara, C., Lodish, H.F. Cell (1999) [Pubmed]
  11. SOCS3 is essential in the regulation of fetal liver erythropoiesis. Marine, J.C., McKay, C., Wang, D., Topham, D.J., Parganas, E., Nakajima, H., Pendeville, H., Yasukawa, H., Sasaki, A., Yoshimura, A., Ihle, J.N. Cell (1999) [Pubmed]
  12. Localization of specific erythropoietin binding sites in defined areas of the mouse brain. Digicaylioglu, M., Bichet, S., Marti, H.H., Wenger, R.H., Rivas, L.A., Bauer, C., Gassmann, M. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  13. Mutations in the Trp-Ser-X-Trp-Ser motif of the erythropoietin receptor abolish processing, ligand binding, and activation of the receptor. Yoshimura, A., Zimmers, T., Neumann, D., Longmore, G., Yoshimura, Y., Lodish, H.F. J. Biol. Chem. (1992) [Pubmed]
  14. Interferon-gamma mediates suppression of erythropoiesis but not reduced red cell survival following CpG-ODN administration in vivo. Thawani, N., Tam, M., Chang, K.H., Stevenson, M.M. Exp. Hematol. (2006) [Pubmed]
  15. Erythropoietin hypersensitivity in primary familial and congenital polycythemia: role of tyrosines Y285 and Y344 in erythropoietin receptor cytoplasmic domain. Arcasoy, M.O., Karayal, A.F. Biochim. Biophys. Acta (2005) [Pubmed]
  16. Curcumin inhibits hypoxia-inducible factor-1 by degrading aryl hydrocarbon receptor nuclear translocator: a mechanism of tumor growth inhibition. Choi, H., Chun, Y.S., Kim, S.W., Kim, M.S., Park, J.W. Mol. Pharmacol. (2006) [Pubmed]
  17. Cytokine rescue of p53-dependent apoptosis and cell cycle arrest is mediated by distinct Jak kinase signaling pathways. Quelle, F.W., Wang, J., Feng, J., Wang, D., Cleveland, J.L., Ihle, J.N., Zambetti, G.P. Genes Dev. (1998) [Pubmed]
  18. Hematopoietic development of embryonic stem cells in vitro: cytokine and receptor gene expression. Schmitt, R.M., Bruyns, E., Snodgrass, H.R. Genes Dev. (1991) [Pubmed]
  19. HLF/HIF-2alpha is a key factor in retinopathy of prematurity in association with erythropoietin. Morita, M., Ohneda, O., Yamashita, T., Takahashi, S., Suzuki, N., Nakajima, O., Kawauchi, S., Ema, M., Shibahara, S., Udono, T., Tomita, K., Tamai, M., Sogawa, K., Yamamoto, M., Fujii-Kuriyama, Y. EMBO J. (2003) [Pubmed]
  20. Tyrosine 425 within the activated erythropoietin receptor binds Syp, reduces the erythropoietin required for Syp tyrosine phosphorylation, and promotes mitogenesis. Tauchi, T., Damen, J.E., Toyama, K., Feng, G.S., Broxmeyer, H.E., Krystal, G. Blood (1996) [Pubmed]
  21. Selection of lineage-restricted cell lines immortalized at different stages of hematopoietic differentiation from the murine cell line 32D. Migliaccio, G., Migliaccio, A.R., Kreider, B.L., Rovera, G., Adamson, J.W. J. Cell Biol. (1989) [Pubmed]
  22. Expression of a constitutively active erythropoietin receptor in primary hematopoietic progenitors abrogates erythropoietin dependence and enhances erythroid colony-forming unit, erythroid burst-forming unit, and granulocyte/macrophage progenitor growth. Pharr, P.N., Hankins, D., Hofbauer, A., Lodish, H.F., Longmore, G.D. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  23. Erythropoietin mediates tissue protection through an erythropoietin and common beta-subunit heteroreceptor. Brines, M., Grasso, G., Fiordaliso, F., Sfacteria, A., Ghezzi, P., Fratelli, M., Latini, R., Xie, Q.W., Smart, J., Su-Rick, C.J., Pobre, E., Diaz, D., Gomez, D., Hand, C., Coleman, T., Cerami, A. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  24. The RAR-RXR as well as the RXR-RXR pathway is involved in signaling growth inhibition of human CD34+ erythroid progenitor cells. Rusten, L.S., Dybedal, I., Blomhoff, H.K., Blomhoff, R., Smeland, E.B., Jacobsen, S.E. Blood (1996) [Pubmed]
  25. Erythropoietin receptor signal transduction requires protein geranylgeranylation. Hamadmad, S.N., Henry, M.K., Hohl, R.J. J. Pharmacol. Exp. Ther. (2006) [Pubmed]
  26. Erythropoietin increases the radioresistance of a clonal hematopoietic progenitor cell line expressing a transgene for the erythropoietin receptor. Santucci, M.A., Pierce, J.H., Zannini, S., Fortuna, A., Frezza, G., Babini, L., Rosenstein, M.M., Greenberger, J.S. Stem Cells (1994) [Pubmed]
  27. Erythropoietin protects against 6-hydroxydopamine-induced dopaminergic cell death. Signore, A.P., Weng, Z., Hastings, T., Van Laar, A.D., Liang, Q., Lee, Y.J., Chen, J. J. Neurochem. (2006) [Pubmed]
  28. In vivo effects of the immunosuppressant 15-deoxyspergualin on hematopoiesis in murine allogeneic bone marrow chimeras. Its thrombopoietic activity and reversal of adverse effects with granulocyte colony-stimulating factor and/or erythropoietin. Imamura, M., Han, M., Hashino, S., Kobayashi, H., Imai, K., Kobayashi, S., Tanaka, J., Zhu, X., Kobayashi, M., Fujii, Y. Transplantation (1994) [Pubmed]
  29. Activation of the erythropoietin receptor is not required for internalization of bound erythropoietin. Beckman, D.L., Lin, L.L., Quinones, M.E., Longmore, G.D. Blood (1999) [Pubmed]
  30. Stem cell factor activates STAT-5 DNA binding in IL-3-derived bone marrow mast cells. Ryan, J.J., Huang, H., McReynolds, L.J., Shelburne, C., Hu-Li, J., Huff, T.F., Paul, W.E. Exp. Hematol. (1997) [Pubmed]
  31. Activation of 70-kDa S6 kinase, induced by the cytokines interleukin-3 and erythropoietin and inhibited by rapamycin, is not an absolute requirement for cell proliferation. Calvo, V., Wood, M., Gjertson, C., Vik, T., Bierer, B.E. Eur. J. Immunol. (1994) [Pubmed]
  32. Sf-Stk kinase activity and the Grb2 binding site are required for Epo-independent growth of primary erythroblasts infected with Friend virus. Finkelstein, L.D., Ney, P.A., Liu, Q.P., Paulson, R.F., Correll, P.H. Oncogene (2002) [Pubmed]
  33. Erythropoietin causes down regulation of colony-stimulating factor (CSF-1) receptors on peritoneal exudate macrophages of the mouse. Van Zant, G., Chen, B.D. J. Cell Biol. (1983) [Pubmed]
  34. Disrupted signaling in a mutant J2E cell line that shows enhanced viability, but does not proliferate or differentiate, with erythropoietin. Tilbrook, P.A., Bittorf, T., Busfield, S.J., Chappell, D., Klinken, S.P. J. Biol. Chem. (1996) [Pubmed]
  35. Constitutive activation of Stat-related DNA-binding proteins in erythroid cells by the Friend spleen focus-forming virus. Ohashi, T., Masuda, M., Ruscetti, S.K. Leukemia (1997) [Pubmed]
  36. Erythropoietin induces association of the JAK2 protein tyrosine kinase with the erythropoietin receptor in vivo. Miura, O., Nakamura, N., Quelle, F.W., Witthuhn, B.A., Ihle, J.N., Aoki, N. Blood (1994) [Pubmed]
  37. Lnk inhibits erythropoiesis and Epo-dependent JAK2 activation and downstream signaling pathways. Tong, W., Zhang, J., Lodish, H.F. Blood (2005) [Pubmed]
  38. Erythropoietin can induce the expression of bcl-x(L) through Stat5 in erythropoietin-dependent progenitor cell lines. Silva, M., Benito, A., Sanz, C., Prosper, F., Ekhterae, D., Nuñez, G., Fernandez-Luna, J.L. J. Biol. Chem. (1999) [Pubmed]
  39. CrkL mediates Ras-dependent activation of the Raf/ERK pathway through the guanine nucleotide exchange factor C3G in hematopoietic cells stimulated with erythropoietin or interleukin-3. Nosaka, Y., Arai, A., Miyasaka, N., Miura, O. J. Biol. Chem. (1999) [Pubmed]
  40. A novel cytokine-inducible gene CIS encodes an SH2-containing protein that binds to tyrosine-phosphorylated interleukin 3 and erythropoietin receptors. Yoshimura, A., Ohkubo, T., Kiguchi, T., Jenkins, N.A., Gilbert, D.J., Copeland, N.G., Hara, T., Miyajima, A. EMBO J. (1995) [Pubmed]
  41. A hematopoietic growth factor, thrombopoietin, has a proapoptotic role in the brain. Ehrenreich, H., Hasselblatt, M., Knerlich, F., von Ahsen, N., Jacob, S., Sperling, S., Woldt, H., Vehmeyer, K., Nave, K.A., Sirén, A.L. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  42. The death-promoting activity of p53 can be inhibited by distinct signaling pathways. Lin, Y., Brown, L., Hedley, D.W., Barber, D.L., Benchimol, S. Blood (2002) [Pubmed]
  43. Effect of anemia and renal cytokine production on erythropoietin production during blood-stage malaria. Chang, K.H., Stevenson, M.M. Kidney Int. (2004) [Pubmed]
  44. Erythropoietin protects from axotomy-induced degeneration of retinal ganglion cells by activating ERK-1/-2. Kilic, U., Kilic, E., Soliz, J., Bassetti, C.I., Gassmann, M., Hermann, D.M. FASEB J. (2005) [Pubmed]
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