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1998 Fiscal Year Final Research Report Summary

サイトカインによるシグナル伝達機構の解析

Research Project

Project/Area Number 07409001
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section一般
Research Field 広領域
Research InstitutionInstitute of Molecular and Cellular Biosciencesa, The University of Tokyo

Principal Investigator

MIYAJIMA Atsushi  Institute of Molecular and Cellular Biosciences, The University of Tokyo, PROFESSOR, 分子細胞生物学研究所, 教授 (50135232)

Co-Investigator(Kenkyū-buntansha) KINOSHITA Taisei  Institute of Molecular and Cellular Biosciences, The University of Tokyo, ASSIST, 分子細胞生物学研究所, 助手 (40301113)
HARA Takahiko  Institute of Molecular and Cellular Biosciences, The University of Tokyo, ASSOCI, 分子細胞生物学研究所, 助教授 (80280949)
Project Period (FY) 1995 – 1998
Keywordscytokine / cytokine receptors / signal transduction / hematopoiesis / differentiation / apoptosis / RAS / STAT
Research Abstract

As studies on signaling by using the mutant IL-3/GM-CSF/IL-5 receptors revealed two major signaling pathways, RAS and STAT5, we have focused our efforts to elucidate the role of these pathways in cytokine functions. Hematopoietic cells require cytokines for their growth and also for their survival. We found that activation of RAS is important for suppression of cell death. RAS activates both RAF/MAP kinase and P13 kinase and both pathways were found to be involved in suppression of cell death. We also showed that caspase-3 is involved in cell death induced by cytokine depletion in hematopoietic cells. To find the role of STAT5 in cytokine functions, we isolated STAT5 target genes. Among them, ClS encodes a novel SH2 protein that negatively regulates cytokine signaling. Expression of a dominant negative form of STAT5 blocked proliferation induced by IL-3 and erythroid differentiation induced by EPO, indicating that STAT5 plays a distinct role depending on the cell tynes. Cross talk between STAT5 and RAS was also demonstrated. In addition, we studied the function of Oncostatin M(OSM), another STAT5 target gene, and found that OSM plays an important role in development of hematopoietic cells and germ cells. The OSM receptor cDNA was cloned and the molecular structure of the functional receptor was elucidated.

  • Research Products

    (28 results)

All Other

All Publications (28 results)

  • [Publications] Mui,A.L-F.et.al: "Interleukin-3,granulocyte-macrophage colony stimulating factor,and interleukin-5 transduce signals through two STAT5 homologues" EMBO J.14. 1166-1175 (1995)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Wakao,H.et.al: "Interleukin-2 and erythropoietin activate STAT5 via distinct pathways" EMBO J.14. 2527-2535 (1995)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kinoshita,T.et.al: "Suppression of apoptotic death in hematopoietic cells by signaling through the IL-3 and GM-CSF receptors" EMBO J.14. 266-75 (1995)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Yoshimura,A.et.al: "A novel cytokine-inducible gene encodes an SH2-containing protein that binds to the tvrosine phosphorvlated interleukin-3 and ervthropoietin receptors" EMBO J.14. 2816-2826 (1995)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Mui,A.L-F.et.al: "Suppression of interleukin-3-induced gene expression by C-terminal truncated Stat5 : role of Stat5 in proliferation" EMBO J.15. 2425-2433 (1996)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Yoshimura,A.et.al: "Mouse Oncostatin M : an immediate early gene induced by multiple cytokines through the JAK-STAT5 pathway" EMBO J.15. 1055-1063 (1996)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kinoshita,T.et al: "Raf/MAPK-and rapamycin-sensitive pathways mediate the anti-apoptotic function of p21 Ras in IL-3 dependent hematopoietic cells" Oncogene. 15. 619-627 (1997)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Ohta,T.et al.: "Requirement of the caspase-3/CPP32 protease cascade for apoptotic death following cytokine deprivation in hematopoietic cells" J..iol.Chem.272. 23111-23116 (1997)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Ichihara,M.et al.: "Oncostatin M and leukemia inhibitory factor do not utilize the same functional receptor in mice" Blood. 90. 165-173 (1997)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Chida,D.et al.: "Transcriptional regulation of the b-casein gene by cytokines : cross-talk between STAT5 and other signaling molecules" Mol.Endocrinol.12. 1792-1805 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Hara,T.et al.: "Distinct roles of oncostatin M and leukemia inhibitory factor for the development of germ cells and testis" Develop.Biol.201. 144-153 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Mukouyama,Y.et al.: "In vitro expansion of murine hematopoietic progenitors derived from the embryonic aorta gonad mesonephros region." immunity. 8. 105-114 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Chida,D.et al.: "Role of cytokine signaling molecules in erythroid differentiation of mouse fetal liver hematopoietic cells : functional analysis of signaling molecules by retrovirus-mediated gene expression." Blood. (in press). (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Tanaka,M.et al.: "Reconstitution of the functional mouse oncostatin M (OSM) receptor : molecular cloning of the mouse OSM receptor b subunit." Blood. 93. 804-815 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Mui, A.L-F., Wakao, H., Harada, N., O'Farrell, A-M., and Miyajima, A.: "Interleukin-3, granulocyte-macrophage colony stimulating factor.and interleukin-5 transduce signals through two STAT5 homologues." EMBO J.14. 1166-1175 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Wakao, H., Harada, N., Kitamura, T., Mui, A.L., and Miyajima, A.: "Interleukin-2 and erythropoietin activate STAT5 via distinct pathways." EMBO J.14. 2527-2535 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kinoshita, T., Yokota, T., Arai, K., and Miyasjima, A.: "Suppression of apoptotic death in hematopoietic cells by signaling through the IL-3 and GM-CSF receptors." EMBO J.14. 266-275 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Yoshimura, A., Ohkubo, T., Jenkins, N.A., Gilbert, D.J., Copeland, N.G., Hara, T., and Miyajima, A.: "A novel cytokine-inducible gene encodes an SH2-containing protein that binds to the tyrosine phosphorylated interleukin-3 and erythropoietin receptors." EMBO J.14. 2816-2828 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Mui, A.L-F., Wakao H., Kinoshita T., Kitamura T., and Miyajima A.: "Suppression of interleukin-3-induced gene expression by a C-terminal truncated Stat5 : role of Stat5 in proliferation." EMBO J.15. 2425-2433 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Yoshimura A., Ichihara, M., Kinjyo I., Moriyama M., Copeland N.G., Gilbert D.J., Jenkins N.A., Hara T., and Miyajima A.: "Mouse Oncostatin M : an immediate early gene induced by multiple cytokines through the JAK-STAT5 pathway." EMBO J.15. 1055-1063 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kinoshita, T., M.Shirouzu, A.Kamiya, K.Hashimoto, S.Yokoyama and A.Miyajima: "Raf/MAPK-and rapamycin-sensitive pathways mediate the anti-apoptotic function of p21 Ras in IL-3 dependent hematopoietic cells." Oncogene. 15. 619-627 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Ohta, T., T.Kinoshita, M.Naito, M.Masutani, T.Tsuruo and A.Miyajima: "Requirement of the caspase-3/CPP32 protease cascade for apoptotic death following cytokine deprivation in hematopoietic cells." J.Biol.Chem.272. 23111-23116 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Ichihara, M., T.Hara, H.J.Kim, T.Murata, and A.Miyajima: "Oncostatin M and leukemia inhibitory factor do not utilize the same functional receptor in mice." Blood. 90. 165-173 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Chida D., H.Wakao, and A.Miyajima: "Transcriptional regulation of the b-casein gene by cytokines : cross-talk between STAT5 and other signaling molecules." Mol.Endocrinol.12. 1792-1805 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Hara, T., K.Tamura, Y.Mukouyama, H.J.Kim, H.Kogo, P.J.Donovan and A.Miyajima: "Distinct roles of oncostatin M and leukemia inhibitory factor for the development of germ cells and testis." Develop.Biol.201. 144-153 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Mukouyama, Y., T.Hara, M.J.Xu, K.Tamura, P.J.Donovan, H.Kogo, K.Tsuji, T,Nakahata, and A.Miyajima: "In vitro expansion of murine hematopoietic progenitors derived from the embryonic aorta gonad mesonephros region." Immunity. 8. 105-114 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Chida D,O.Miura, A.Yoshimura, and A.Miyaji, A: "Role of cytokine signaling molecules in erythroid differentiation of mouse fetal liver hematopoietic cells : functional analysis of signaling molecules by retrovirus-mediated gene expression." Blood. (in press). (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Tanaka M., T.Hara, N.G.Copeland, D.J.Gilbert, N.A.Jenkins, and A.Miyajima: "Reconstitution of the functional mouse oncostatin M (OSM) receptor : molecular cloning of the mouse OSM receptor b subunit." Blood. 93. 804-815 (1999)

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 1999-12-08  

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