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Control of cytokine function by modified signaling molecules

Research Project

Project/Area Number 07559018
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section展開研究
Research Field 広領域
Research InstitutionInstitute of Molecular and Cellular Biosciences, 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
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)
若尾 宏  東京大学, 分子細胞生物学研究所, 助手 (10280950)
Project Period (FY) 1995 – 1997
Project Status Completed (Fiscal Year 1997)
Budget Amount *help
¥7,600,000 (Direct Cost: ¥7,600,000)
Fiscal Year 1997: ¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 1996: ¥4,100,000 (Direct Cost: ¥4,100,000)
Keywordscytokines / signal transduction / hematopoietic growth factors / RAS / STAT / cell proliferation / cell differentiation / cell death / 造血 / JAK / レトロウイルス / アポトーシス / サイトカイン受容体 / JAKキナーゼ / 転写因子 / 分化
Research Abstract

We investigated the signaling mechanisms of RAS and STAT5, which are major signaling molecules activated by hematopoietic cytokines such as IL-3/GM-CSF.We also attempted to develop means to regulate these pathways by modification of signaling molecules.
RAS is required for prevention of apoptosis by cytokines in hematopoietic cells. By using partially active RAS mutants, we found that RAS prevents apoptosis through both activation of the RAF/MAP kinase cascade as well as the P13 kinase pathway. As'the mechanism of apoptosis induced by cytokine depletion has remained uncovered, we tested if Caspases are involved in the apoptotic process. We found that Caspase-3 is activated in the absence of a cytokine in hematopoietic cells and the activation of Caspase-3 is required for the apoptosis.
While STAT5 is activated by various cytokines including IL-3/GM-CSF,the role of STAT5 in cytokine functions was unknown. To uncover the role of STAT5, we attempted to isolate STAT5 target genes. Among such genes we obtained a novel SH-2 protein CIS Oncostatin M,a member of IL-6 family cytokines. CIS is induced by cytokines through STAT5 and inhibits signaling by binding to a tyrosine phosphorylated signaling moleculea. OSM is expressed in the aorta/gonad/mesonephros (AGM) region where the definitive hematopoiesis is believed to emerge. OSM stimulates the development of hematopoietic cells as well as endothelial cells in the in vitro culture of AGM cells. This raised a possibility that the putative common precursor of hematopoietic cells and endothelial cells may be a target of OSM.
We generated a dominant negative (dn) form of STAT5 and demonstrated that expression of dnSTAT5 blocks IL-3-induced proliferation of BaF3, suggesting that STAT5 may be involved in proliferation. We also showed that STAT5 is involved in erythropoietininduced maturation of the erythroid cell line, SKT6.

Report

(4 results)
  • 1997 Annual Research Report   Final Research Report Summary
  • 1996 Annual Research Report
  • 1995 Annual Research Report
  • Research Products

    (36 results)

All Other

All Publications (36 results)

  • [Publications] Mukouyama, Y.et al.: "In vitro expansion of murine multipotential 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
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Kinoshita, T.et al.: "Raf/MAPK-and rapamycin-sensitivepathways 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
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Wakao H.et al.: "A possible involvement of STAT5 in erythropoietin-induced hemoglobin synthesis." Biochem.Biophys.Ras.Commun.234. 198-205 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Mui, A.L-F.et al.: "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(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Yoshimura A.et al.: "Mouse oncostatinM: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
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Yoshimura A.et al.: "A novel cytokine-inducible gene encodes an SH2-containing protein that binds to the tyrosine phosphorylated interleukin-3 and erythropoietin receptors." EMBO.J.14. 2816-2826 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Y.Mukouyama, T.Hara, M.-j.Xu, K.Tamura, P.J.Donovan, H.-j.Kim, H.Kogo, K.Tsuji, T.Nakahata, and A.Miyajima: "In vitro expansion of murine multipotential 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
    • Related Report
      1997 Final Research Report Summary
  • [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 p21Ras 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
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Wakao H., D.Chida, J.E.Damen, G.Krystal and A.Miyajima: "A possible involvement of STAT5 in erythropoietin-induced hemoglobin synthesis." Biochem.Biophys.Res.Commun.234. 198-205 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [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
    • Related Report
      1997 Final Research Report Summary
  • [Publications] A.Yoshimura, M.Ichihara, I.Kinjyo, M.Moriyama, N.G.Copeland, D.J.Gilbert, N.A.Jenkins, T.Hara and A.Miyajima.: "Mouse oncostatinM : 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
    • Related Report
      1997 Final Research Report Summary
  • [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. 2816-2826 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Kinoshita,T.et al.: "Raf/MAPK-and rapamycin-sensitive pathways mediate the anti-apototic function of p21Ras in IL-3 dependent hematopoietic cells." Oncogene. 15. 619-627 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Ohta,T.et al: "Requirement of the caspase-3/CPP32 protease cascade for apoptotic death following cytokine deprivation in hematopoietic cells." J.Biol.Chem.272. 23111-23116 (1997)

    • Related Report
      1997 Annual Research Report
  • [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)

    • Related Report
      1997 Annual Research Report
  • [Publications] Wakao H.et al.: "A possible involvement of STAT5 in erythropoietin-induced hemoglobin synthesis." Biochem.Biophys.Res.Commun.234. 198-205 (1997)

    • Related Report
      1997 Annual Research Report
  • [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)

    • Related Report
      1997 Annual Research Report
  • [Publications] Furusawa,T.et al.: "Integrin-associated protein (IAP,also termed CD47) is involved in stroma-supported erythropoiesis." J.Biochem.123. 101-106 (1998)

    • Related Report
      1997 Annual Research Report
  • [Publications] Nishinakamura et al.: "Hematopoiesis in mice lacking the entire granuiocyte macrophage colony stimulating factor/interleukin 3/interleukin 5 function" Blood. 88. 2458-2464 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Mui et al.: "Suppression of interleukin-3-induced gene expression by a C-terminal truncated Stat5:role of Stat5 in proliferation" EMBO J.15. 2425-2433 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Onishi et al.: "Identification of an oncogenic form of the TPO receptor using retrovirus-mediated gene transfer" Blood. 88. 1399-1406 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] O'Farrell et al.: "Signaling pathways activated in a unique mast cell line where IL-3 supports survival and stem cell factor is required for a proliferative response" Blood. 87. 3655-3668 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Yoshimura et al.: "Mouse Oncostatin M:an immediate early gene induced by multiple cytokines through the JAK-STAT5 pathway" EMBO J.15. 1055-1063 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Muto et al.: "The β subunit of human GM-CSF receptor forms a homodimer and is activated via association with the α subunit" J.Exp.Med.183. 1911-1916 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Yoshimura, 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. 2816-2826 (1995)

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

    • Related Report
      1995 Annual Research Report
  • [Publications] Nishinakamura, R: "Mice deficient for the IL-3/GM-CSF/IL-5βc recepor exhibit lung pathology and impaired immune response, while βIL3 receptor-deficient mice are normal" Immunity. 2. 211-222 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Hara, T: "Interleukin-3(IL-3)nonresponder inbred mouse strains carry the identical deletion of a branch point in the the IL-3 receptor α subunit gene." Blood. 85. 2331-2336 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Wakao, H: "Interleukin-2 and erythropoietin activate STAT5 via distinct pathways." EMBO J.14. 2527-2535 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Ho, A. S. Y: "Functional regions of the mouse interleukin 10 receptor cytoplasmic domain." Mol. Cell. Biol.15. 5043-5053 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Mui, A. L-F: "Interleukin-3, granulocyte-macrophage colony stimulating factor, and interleukin 5 transduce signals through two forms of STAT5." J. Leukocyte Biology.57. 799-803 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Kinoshita, T: "Suppression of apoptotic death in hematopoietic cells by signaling through the IL-3 and GM-CSF receptors." EMBO. J.14. 266-275 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Ichihara, M: "mpaired interleukin 3(IL-3)response of the A/J mouse is caused by a branch point deletion in the IL-3 receptor α subunit gene" EMBO. J.14. 939-950 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Miyajima, I: "The murine interleukin-3 receptor α subunit gene: chromosomal localization, genomic structure and promoter function." Blood.85. 1246-1253 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Takagi, M: "Multi-colony stimulating activity of interleukin-5(IL-5)on hematopoietic progenitors from transgenic mouse that express IL-5 receptor α subunit consititutively" J. Exp. Med.181. 889-899 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Kinoshita T: "Regulation of Bcl-2 expression by oncogenic Ras protein in hematopoietic cells" Oncogene. 10. 2207-2212 (1995)

    • Related Report
      1995 Annual Research Report

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Published: 1996-04-01   Modified: 2016-04-21  

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