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MOLECULAR MECHANISM OF ERYTHROID DIFFERENTIATION

Research Project

Project/Area Number 06454173
Research Category

Grant-in-Aid for General Scientific Research (B)

Allocation TypeSingle-year Grants
Research Field General medical chemistry
Research InstitutionTHE INSTITUTE OF PYSICAL AND CHEMICAL RESEARCH (RIKEN)

Principal Investigator

TODOKORO Kazuo  THE INSTITUTE OF PHYSICAL AND CHEMICAL RESEARCH (RIKEN), TSUKUBA LIFE SCIENCE CENTER,SUB-CHIEF, 安全評価研究室, 副主任研究員 (80172170)

Co-Investigator(Kenkyū-buntansha) KOJIMA Souichi  THE INSTITUTE OF PHYSICAL AND CHEMICAL RESEARCH (RIKEN), TSUKUBA LIFE SCIENCE CE, 安全評価研究室, 研究員 (10202061)
Project Period (FY) 1994 – 1995
Project Status Completed (Fiscal Year 1995)
Budget Amount *help
¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 1995: ¥1,800,000 (Direct Cost: ¥1,800,000)
KeywordsERYTHROID / CELL DIFFERENTIATION / ERYTHROPOIETIN / SIGNAL TRANSDUCTION / エリスロポエチンレセプター
Research Abstract

We have studied the molecular mechanism of erythropoietin receptor-mediated erythroid cell differentiation. We found that the binding of erythropoietin to the receptor induces the tyrosine-phosphorylation of the receptor, which in turen induces the binding of SH2 adaptor molecules Shc and Grb2 to the receptor, activation of Ras through Sos, phosphorylation and activation of Raf-1, MAPKK and MAPK.Furthermore, we found that Vav and Tec kinase can be phosphorylated by Epo stimulation and that Vav binds to Tec through Tec homology domain. It was also found that the activation of JAK2 induces activation of not only STAT5 but also STAT1 and STAT3, which in turn induces the specific binding of the STAT molecules in the specific target genes. After Epo stimulation, erythroid-specific transcription factors NF-E2 and GATA-1 were found to be activated, while these factors can be also activated by thrombopoietin, which is a specific cytokine regulating megakaryocyte-platelet formation. The GATA-1 and NF-E2 induces globin gene expression in erythroid cells, while they stimulate CD61 and other platelet-specific antigens. We also found that without tyrosine-phosphorylation of the receptor, JAK-STAT pathway can be activated, and both cell growth and crythroid differentiation can be induced.

Report

(3 results)
  • 1995 Annual Research Report   Final Research Report Summary
  • 1994 Annual Research Report
  • Research Products

    (47 results)

All Other

All Publications (47 results)

  • [Publications] K. Todokoro: "Activation of MAP Kinose cascade through erythropoietin receptor" BBRC. 203. 1912 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Y. Nagata: "Activation of helix loop helix proteins Hl. H2eH3" BBRC. 199. 1355 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] K. Todokoro: "A second subunit of enythropoietin receptor" Noture. 372. 138 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] M. Machide: "Inherleukin3 and erythropoietin induceassociation of Vav with Tes kinase through Tec honulogy dumain" Oncogene. 11. 619-625 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Y. Nagata: "Phosphorylation of helix loop helix pwteius Hl. H2eH3" BBRC. 207. 916-926 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Y. Nagata: "Thrown bopuretin induces megakaryo ayte differeutiatin in hermatopurefic progenitorgDCP2 cells" J. Biol. Chem.270. 19673-19675 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] T. Wada: "Charactenization of the treuecoted thumbopuietin vasiants" BBRC. 213. 1091-1098 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] T. Tauge: "Eestablinhment and charactrization of a new human mesothelralna cell line from malignant perifoneal mesothelioma with remorkable thurnbosis" Path. Intl.45. 791-800 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] H. Kojima: "Modnlation of platelet activation in vitro by thumbrpiots." Thromb. Hemast.74. 1541-1545 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Y. Nagata: "Thumbsquietsm inchuees activation of at leat fow chatinct synaling pathuqus" FEBS Lett.377. 497-501 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] H. Nagahisa: "Bone manos stronal ullb anodure thorbapishn and Stormlates mejalroyongles gruoh and maturation but suppruess eroplatets formation" Blood. 78. 1309-1316 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Y. Nagata: "Regulation of mega kauya ugfopurests by rhumboguretor and stronal cells" Lenkemia. (in press). (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] 戸所一雄: "サイトカインのすべて" 科学評論社, (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] 戸所一雄: "癌細胞の分化活等とアポトーシス" 共立出版, (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] 戸所一雄: "免疫系のシグナル伝達" 羊土社, (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] K.Todokoro, M.sugiyama, E.Nishida & K.Nakaya: "Activattion of mitogenactivated protein kinase cascades through erythropoietin receptor." Biochem.Biophys.Res.Commun.203. 1912 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Y.Nagata & K.Todokoro: "Activation of Helix-Loop-Helix proteins Id1, Id2 and Id3 during neural differentiation." Biochem.Biophys.Res.Commun.199. 1355 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] K.Todokoro: "A second subunit of erythropoietin receptor." Nature. 372. 138 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Y.Nagata, W.Shoji, M.Obinata & K.Todokoro: "Phosphorylation of Helix-Loop-Helix proteins Id1, Id2 and Id3." Biochem.Biophys.Res.Commun.207. 916 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] M.Machide, H.Mano & K.Todokoro: "Interleukin 3 and erythropoietin induce association of Vav with Tec kinase through Tec homology domain." Oncogene. 11. 619 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Y.Nagata, H.Nagahisa, Y.Aida, K.Okutomi, Nagasawa, T,& K.Todokoro: "Thrombopoietin induces megakaryocyte differentiation in hematopoietic progenitor FDC-P2 cells." J.Biol.Chem.270. 19673 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] T.Wada, Y.Nagata, H.Nagahisa, K.Okutomi, S.H.Ha, T.Ohnuki, T.Kanaya, M.Matsumura & K.Todokoro: "Characterization of the truncated thrombopoietin variants." Biochem.Biophys.Res.Commun.213. 1091 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] T.Tange, Y.Hasegawa, T.Oka, S.Sunaga, M.Higashihara, K.Matsul, H.Miyazaki, A.Shimosaka, A.Okano, K.Todokoro, T.Ishikawa & R.Machinami: "Establishment and characterization of a new human mesothelioma cell line (T-85) from malignant peritoneal mesothelioma with remarkable thrombocytosis." Pathol.Int.45. 791-800 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] H.Kojima, Y.Hamazaki, Y.Nagata, K.Todokoro, T.Nagasawa & T.Abe: "Modulation of platelet activation in vitro by thrombopoietin" Thromb.Haemost.74. 1541-1545 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Y.Nagata & K.Todokoro: "Thrombopoietin induces activation of at least two distinct signaling pathways." FEBS Lett.377. 497-501 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] H.Nagahisa, Y.Nagata, T.Ohnuki, M.Osada, T.Nagasawa, T.Abe & K.Todokoro: "Bone marrow stromal cells produce thrombopoietin and stimulate megakaryocyte growth and maturation but suppress proplatelet formation." Blood. 78. 1309-1316 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Y.Nagata, H.Nagahisa, T.Nagasawa & K.Todokoro: "Thrombopoietin level is regulated not only by platelet counts but also by megakaryocyte mass." (submitted). (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] S.Kotami, S.Tugendreich, Y.Nagata, P.Hieter, Y.Shiratori & K.Todokoro: "Control of late mitosis events by phosphorylation of Cdc27 with Plk in centrosomes before anaphase." (submitted). (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] H.Y.Mukai, H.Kojima, K.Todokoro, T.Tahara, T.Kato, Y.Hasegawa, T.Kobayashi, H.Ninomiya, T.Nagasawa & T.Abe: "Serum thrombopoietin (Tpo) levels in patients with amegakaryocytic thrombocytopenia is much higher thatn those with immune thrombocytopenic purpura-The evidence that serum Tpo levels are regulated by megakaryocyte mass." (submitted).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Y.Nagata & K.Todokoro: "Interleukin 3 activates not only JAK2 and STAT5, but also Tyk2, STAT1 and STAT3" (submitted). (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Y.Nagata, H.Nagahisa, T.Nagasawa & K.Todokoro: "Regulation of megakaryocytopoiesis by thrombopoietin and stromal cells. Leukemia." (in press). (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] K.Todokoro, K.Okutomi, T.Kitamura, Y.Nagata, M.Nagao & R.Sasaki: "A second subunit of erythropoietin receptor." (submitted). (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Y.Nagata & K.Todokoro: "Erythroid-specific Hox2 gene expression is regulated by GATA-1." (submitted). (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Y.Nagata & K.Todokoro: "Erythropoietin, thrombopoietin and interleukin 3 activates SEK-JNK pathway." (submitted). (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Machide, M: "Interleukin-3 and eythropoietin induce association of vav with Tec kinase through tec homology domain" Oncogene. 11. 619-625 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Nasata, Y: "Phosphory lation of Helix-Loop-Helix proteins Id 1,Id 2 and Id 3" Blochem. Bioplup. Res. Commuu.207. 916-926 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Nagata, Y: "Thrombopoietin induces megakaryocyte differentiation in hematopoietic progenitor FDC P2 cells" J.Biol. Chem.270. 19673-19675 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Wada, T: "Characterization of the truncated thrombopoietin variants" Biochem. Biophys. Res. Commuu.213. 1091-1098 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Tange, T: "Establishment and characterization of a new human mesothelioma cell line from malignant peritoneal mesothelioma with remarkable thrombocytosis." Path. lnt.45. 791-800 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Kojima, H: "Modulation of platelet activation in vitro by thrombopoietin" Thromb. Haemost.74. 1541-1545 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Nasata, Y: "Thrombopoietin induces actiration of at least two distinct signaling pathways" FEBS Lett.377. 497-501 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Nagahisa, H: "Bone marrow stromal cells produce thrombopoietin and stimulate megakaryocyte growth and maturation but suppress proplatelet formation" BLOOD. 78. 1309-1316 (1996)

    • Related Report
      1995 Annual Research Report
  • [Publications] K.TODOKORO et.al.: "Activation of MAP kinsse-caoiade thrush eulhtropietr recoptcr" Biochem.Bioplup Res.Commun.203. 1912-1919 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Y.NAGATA et al: "Activation of Helix-Looplkly pcleius H1,H2,H3" Biochem.Bioplup.Res.Commun.199. 1355-1362 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] K.TODOKORO: "A second cubunit of eiythropaietn reccptor" Naturo. 372. 138-138 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Y.NAGATA et al: "Phosphonylation of Helix-Loop-Helix puxleius H1,H2 & H3" Biochem.Biophup.Res.Commun.(1995)

    • Related Report
      1994 Annual Research Report
  • [Publications] M.MACHIDE et al: "IL3 and Euyrhupietn induce associeition of Vav with Tec Kimee" Onwzane. (1995)

    • Related Report
      1994 Annual Research Report

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Published: 1995-04-01   Modified: 2016-04-21  

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