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Regulation of Cell proliferation by GM-CSF

Research Project

Project/Area Number 08680678
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Functional biochemistry
Research InstitutionThe University of Tokyo

Principal Investigator

WATANABE Sumiko  The University of Tokyo, Institute of Medical Science, Research Associate, 医科学研究所, 助手 (60240735)

Project Period (FY) 1996 – 1997
Project Status Completed (Fiscal Year 1997)
Budget Amount *help
¥2,100,000 (Direct Cost: ¥2,100,000)
Fiscal Year 1997: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 1996: ¥1,100,000 (Direct Cost: ¥1,100,000)
KeywordsGM-CSF / receptor / signal trancduction / proliferation / STAT5 / STAT5
Research Abstract

Granulocyte-macrophage colony-stimulating factor (GM-CSF) induces various functions including the proliferation and differentiation of a broad rango of hematopoietic cells. We reported that at least two distinct pathways are involved in human GM-CSF receptor signaling both of which require the box 1 region of the common beta (betac) subunit. This region is essential for the activation of JAK2, which is necessary for all the biological functions of GM-CSF.Activation of JAK2 by GM-CSF leads to rapid tyrosine phosphorylation of cellular proteins, including the betac. However, the siguificance of the betac phosphorylation in regards to the regulation of signaling molecules and the expression of GM-CSF function is less well understood. Here we investigated the role of cytoplasmic tyrosine residues of the betac by using a series of betac mutants expressed in murine BA/F3 cells. A mutant betac with all eight cytoplasmic tyrosines converted to phenylalanine (Fall) activated JAK2, but not SHP-2, MAPK cascades, STAT5 or c-fos promoter in BA/F3 cells, nor did it effectively induce proliferation. Adding back each tyrosine to Fall revealed that Tyr577, Tyr612 and Tyr695 are involved in the activation of SHP-2, MAPK cascades and c-fos transcription, while every tyrosine, particularly Tyr612, Tyr695, Tyr750 and Tyr806, facilitated STAT5 activation. Impaired growth was also reatored, at least partly, by any of the tyrosines. These results provide evidence that betac tyrosines possess distinct yet overlapping functions to activate multiple signaling pathways induced by GM-CSF.

Report

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

    (24 results)

All Other

All Publications (24 results)

  • [Publications] Itoh, T.et al.: "Definition of the pole of tyrosine residues of the common β subunit regulating multiple signaling pathwors of GM-CSF" Mol.Cell.Biol.18・2. 742-752 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Watanabe, S.et al.: "Characterigation of eis-acting signals regulating early growth response 1 and c-tos promotes thioyh GM-CSFR in BA/F3 cells." Blood. 89. 1197-1206 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Yasuda, Y.et al.: "human nulocyto-macrophage cdony-stimulating factor (hGM-CSF)induces inhibition of intrathymic I-cell development in hGM-CSF receptor transgenic mice." Blood. 89. 1349-1356 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Muto, A.et al.: "The β subunit of hGM-CSF R foms a homodimer and is aetivated ky association with the α subuint." J.Exp.Med.183. 1911-1916 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Itoh, T. et al.: "GM-CSF provokes RAS activation and transcuption of c-fos throngh different modes of signaling." J.Biol.Chem.271. 7587-7592 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Watanabe, S.: "JAKα is essential fr activation of c-fos and c-myc promoters and cell proliferahl thcongh the hGM-CSFR in BA/F3 cells." J.Biol.Chem.271. 12681-12686 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Itoh, T., Liu, R., Yokota, T., Arai, K.and Watanabe, S: "Definition of the role of tyrosine residues of the common beta subunit regulating multiple signaling pathways of Granulocyto Macrophage Colony Stimulating Factor recepter" Mol.Cell.Biol. 18,2. 742-752 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Watanabe, S., Kubota, H., Sakamoto, M.K.and Arai, K: "Characterization of cis-acting sequences and trans-acting signals regulating early growth response 1 (egr-1) and c-fos promoters through the granulocyte-macrophage colony-stimulating factor recepter in BA/F3 cells" Blood. 89. 1197-1206 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Yasuda, Y., Nishijima, I., Watanabe, S., Arai, K., Zlotonik, A.and Moore, T.A: "Human granulocyto-macrophage colony-stimulating factor (hGM-CSF) induces inhibition of intrathymic T-cell development in hGM-CSF receptor transgenic mice" Blood. 89. 1349-1356 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Muto, A., Watanabe, S., Miyajima, A., Yokota, T.and Arai, K: "The beta subunit of human GM-CSF receptor forms a homodimer and is activated by association with the alpha subunit" J.Exp.Med. 183. 1911-1916 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Itoh, T., Muto, A., Watanabe, S.and Arai, K: "Granulocyte-macrophage colony-stimulating factor provokes RAS activation and transcription of c-fos through different modes of signaling" J.Biol.Chem. 271. 7587-7592 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Watanabe, S., Itoh, T.and Arai, K: "JAK2 is essential for activation of c-fos and c-myc promoters and cell proliferation through the human granulocyte-macrophage colony stimulating factor (GM-CSF) receptor in BA/F3 cells" J.Biol.Chem. 271. 12681-12686 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] ITOH,T.et al: "Definition of the role of tyrosine residues of the commonB subunit regulating multiple signaling pathwags of GM-CSF" Mol.Cell.Biol.18(印刷中). (1998)

    • Related Report
      1997 Annual Research Report
  • [Publications] Watanabe,S.et al.: "Characterigation of eis-acting signals regulating early growth rectance I and c-fos promoter throngh GM-CSFR in BA/F3 cells." Blood. 89. 1197-1206 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Yasuda,Y.et al: "Intrathymic T cell development in hGM-CSF receptor transgenic mice is inhibited by hGM-CSF" Blood. 89. 1349-1356 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Muto A et al: "The β subunit of hGM-CSF R foms a homodimen and is activated by association with the α subuimt" J.Exp.Med.183. 1911-1916 (1996)

    • Related Report
      1997 Annual Research Report
  • [Publications] ITOH T et al.: "GM-CSF provokes RAS activation and transcription of c-fos through dfflerent modes of signaling" J.Biol.Chem.271. 7587-7592 (1996)

    • Related Report
      1997 Annual Research Report
  • [Publications] Watanabe S.: "JAK2 is essential for activation of c-fos and c-myc promotes and cell proliferad through the hGM-CSFR in BAF3 cers" J.Biol.Chem.271. 12681-12686 (1996)

    • Related Report
      1997 Annual Research Report
  • [Publications] Muto.A.et al.: "The β subunit of human GM-CSF receptor forms a homodimer and is activated by association with the α subunit" J.Exp.Med.183. 1911-1916 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Ito.T et al.: "Granulocyte-macrophage colony-stimulating factor provokes RAS activation and transcription of c-fos through different modes of signaling" J.Biol.Chem. 271. 7587-7592 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Watanabe S.et al.: "JAK2 is essential for activation of c-fos and c-myc promoters and cell proliferation through the human granulocyte-macrophage colony-stimilating factor(GM-CSF)receptor in BA/F3 cells" J.Biol Chem. 271. 12681-12686 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Watanabe.S.Arai K.: "Roles of the JAK-STAT systems in signal transduction via cytokine receptors" Current Opinion Biotech. 6. 587-596 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Yasuda Y.et al.: "Intrathynic T cell development in human granulocyte-macrophage colony stimulating factor(hGM-CSF)receptor transgenic mice is inhibited by hGM-CSF" Blood. (in press).

    • Related Report
      1996 Annual Research Report
  • [Publications] Watanabe.S et al: "characterization of cis-acting signals regulating early growth response 1(egr-1)and c-fos promoters through the granulocyte-macrophage colony-stimulating factor recepter in BA/F3 cells" Blood. (in press).

    • Related Report
      1996 Annual Research Report

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

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