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Generation of disease model mice by the alteration of transcription factors regulating immune responses

Research Project

Project/Area Number 07557024
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section展開研究
Research Field Experimental pathology
Research InstitutionThe University of Tokyo

Principal Investigator

ARAI Ken-ichi  The University of Tokyo Inst.of Medical Science, , Professor, 医科学研究所, 教授 (00012782)

Co-Investigator(Kenkyū-buntansha) INOUE Toru  Dept.of Toxicology, National Inst.of Health Science, Chief Scientist, 毒性部, 部長 (50100110)
NAKAHATA Tatsutoshi  The University of Tokyo Inst.of Medical Science, , Professor, 医科学研究所, 教授 (20110744)
MASAI Hisao  The University of Tokyo Inst.of Medical Science, Associate Professor, 医科学研究所, 助教授 (40229349)
WATANABE Sumiko  The University of Tokyo Inst.of Medical Science, , Research Associate, 医科学研究所, 助手 (60240735)
YOKOTA Takashi  The University of Tokyo Inst.of Medical Science, , Professor, 医科学研究所, 客員教授 (50134622)
村松 正明  東京大学, 医科学研究所, 助手 (50230008)
Project Period (FY) 1995 – 1997
Project Status Completed (Fiscal Year 1997)
Budget Amount *help
¥9,500,000 (Direct Cost: ¥9,500,000)
Fiscal Year 1997: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 1996: ¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 1995: ¥5,000,000 (Direct Cost: ¥5,000,000)
KeywordsTranscription factor / NF-AT / STAT / Immune response / JAK2 / JAK / シグナル伝達 / GM-CSF受容体 / T細胞サブセット / 免疫応答 / GM-CSF / レセプター
Research Abstract

The purpose of this study is to regulate the immune responses in vitro and in vivo by the alteration of the function of the transcription factors NF-AT and STAT,which are involved in the regulation of immune responses.
We have isolated human NF-AT (NF-ATp/c/x) genes at the beginning of this research program, and during this study we isolated murine counterparts. Among the NF-AT family members, we focused on human and mouse NF-ATx for the analysis and alteration of its function. First, we performed domain mapping of human NF-ATx, and identified several distinct functional domains including the DNA binding domain, AP-1 interaction domain, transactivation domain CN-regulated inhibitory domain (CRI). For CRI sequence, specially deletion of this domain, resulted in nuclear translocation independent of calcium signaling. Next, we identified the calcineurin binding domain (CNBR) of mouse NF-ATx, and found that the over-expression of CNBR protein fragment inhibited NF-AT site calcineurin binding domain acted as a dominant negative mutant that prevents mNF-ATx-mediated gene activation.
STAT6 has been shown to be required for mejor IL-4 responses. We constructed a conditionally active form of STAT6 by fusing STAT6 to a modified form of the hormone binding domain of the mouse estrogen receptor. This protein activates a specific receptor construct in response to the bestradiol analog 4-Hydroxy-tamoxifen. We also succeeded in the regulation of GM-CSF-induced response of BAF/3 cells by using a dominant negative mutant of JAK2, which is known to act upstream of STAT proteins.
Mutant forms of NF-ATx and STAT6 derived from the above study will be useful fox the regulation of immune responses. We are now planning to generate transgenic mice expressing these mutants for the analysis of the effects of these mutants in vivo.

Report

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

    (38 results)

All Other

All Publications (38 results)

  • [Publications] Liu J.et al: "Calcineurin dependent nuclear translocation of a murine transcription factor NFATc:molecular clonning and functional characterization." Mol.Biol.Cell.8. 157-170 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Masuda, E.S.et al: "Control of NFATxl nuclear translocation by a calcineurin-regulated inhibitory domain." Mol.Cell.Biol.17・4. 2066-2075 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Pan S.et al: "Molecular cloning and functionalcharacterization of murine cDNA encloning transcription factor NFATc." Biochem.Biophys.Res.Communi. 240・2. 314-323 (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: "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(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Nishijima, I.et al: "Hematopoietic and lymphopoietic responses in hGM-CSF receptor transgenicmice injected with hGM-CSF." Blood. 90. 1031-1038 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Arai K.et al: "Cytokine signal networks and a new Era in biomedical research." Mol.Cells. 7. 1-12 (1997)

    • 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: "Characterization of cis-acting sequences and trans-acting signals regulating egr-l and c-fos promoters through the GM-CSF recepter 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] Itoh, T.et al: "Definition of the role of tyrosin residues of the common β subunit regulating multiple signaling pathways of GM-CSF recepter." Mol.Cell.Biol.18,3. 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] Lee, H.J.et al: "Characterization of cis-regulatory elements and nuclear factors conferring Th2-specific expression of the IL-5 gene:a role for a GATA-binding protein." J.Immunology. (in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Amasaki, Y.et al: "Distinict NFAT-family proteins are involved in the stimulation-dependentNFAT complexes from thymocyte subsets." J.Immunology. (in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Liu, J., Koyano-Nakagawa, N., Amasaki, Y., Saito-Ohara, F., Ikeuchi, T., Imai, S., Takano, T., Arai, N., Yokata, T., Arai, K.: "Calcineurin dependent nuclear translocation of a murine transcription factor NFATc : molecular clonning and functional characterization." Mol.Biol.Cell.8. 157-170 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Masuda, E.S., Liu, J., Imamura, R., Imai, S., Arai, K.and Arai, N.: "Control of NFATx1 nuclear translocation by a calcineurin-regulated inhibitory domain." Mol.Cell.Biol.17.4. 2066-2075 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Pan S., Koyano-Nakagawa N., Yokota T., Mori S., Arai, N.and Arai K.: "Molecular cloning and functional characterization of murine cDNA encloning transcription factor NFATc." Biochem.Biophys.Res.Communi.240,2. 314-323 (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., Aral, K., Zlotonik, A., 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] Nishijima, I., Nakahata.T., Watanabe.S., Tsuji, I., Tanaka.I., Hirabayashi.Y., Inoue.T., Arai.K.: "Hematopoietic and lymphopoietic responses in hGM-CSF receptor transgenic mice injected with hGM-CSF." Blood. 90. 1031-1038 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Arai, K., Tsuruta, L., Watanabe, S and Arai, N.: "Cytokine signal networks and a new Era in biomedical research." Mol.Cells.7. 1-12 (1997)

    • 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., Arai, K.: "Characterization ofcis-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] Itoh, T., Liu, R., Yokota, T., Arai, K.and Watanabe, S.: "Definition of the role of tyrosin residues of the common b subunit regulating multiple signaling pathways of GM-CSF recepter." Mol.Cell.Biol.18,3. 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] Lee, H.J., O'Garra, A., Arai, K.and Arai, N.: "Characterization of cis-regulatory elements and nuclear factors conferring Th2-specific expression of the IL-5 gene : a role for a GATA-binding protein." J.Immunology. (in press.).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Amasaki, Y., Masuda, ES., Imamura, R., Arai, K.and Arai, N.: "Distinict NFAT-family proteins are involved in the stimulation-dependent NFAT complexes from thymocyte subsets." J.Immunology. (in press.).

    • 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 tyrosin residues of the common β subunit regulating multiple signaling pathways of GM-CSF recepter." Mol.Cell.Biol.18・3. 742-752 (1998)

    • Related Report
      1997 Annual Research Report
  • [Publications] Masuda,E.S.et al: "Control of NFATxl nuclear translocation by a calcineurin-regulated inhibitory comain." Mol.Cell.Biol.17・4. 2066-2075 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Pan,S.et al: "Molecular cloning and functional characterization of murine cDNA encloning transcription factor NFATc." Biochem.Biophys.Res.Communi.240・2. 314-323 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Yasuda,Y.et al: "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)

    • Related Report
      1997 Annual Research Report
  • [Publications] Nishijima,I.et al: "Hematopoietic and lymphopoietic responses in hGM-CSF receptor transgenic mice injected with hGM-CSF." Blood.90. 1031-1038 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Watanabe,S.et al: "Characterization of cis-acting sequences and trans-acting signals regulating early growth response 1 (egr-1) and c-fos promoters through GM-CSF in BA/F3 cells." Blood. 89. 1197-1206 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Naito,Y: "Signal transduction in Th clones:Target of differential modulation by PGE2 may reside downstream of the PKC dependent pathway." Cytokine Research. 8. 346-356 (1996)

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

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

    • Related Report
      1996 Annual Research Report
  • [Publications] Koyano-Nakagawa,N: "Specific versus cooperative regulatory mechanism of the cytokine genes that are clustered on the same chromosome." J.Allergy Clinic.Immunol.98. 1-9 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Harada,Y: "Factors affecting the cytokine production of human T cells stimulated via different modes of activation." J.Allergy Clinic.(in press).

    • Related Report
      1996 Annual Research Report
  • [Publications] Liu,J: "Calcineurin dependent nuclear translocation of a murine transcription factor NFATc:molecular clonning and functional characterization." Mol.Biol.Cell. (in press).

    • Related Report
      1996 Annual Research Report
  • [Publications] Watanabe,S., et al: "Characterization of cis-regulatory elementsof the c-myc promoter responding to human GM-CSF or mouse IL-3 in mouse proB cell line BA/F3 cells expressing the human GM-CSF" Mol. Biol. Cell. 6. 627-636 (1995)

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

    • Related Report
      1995 Annual Research Report
  • [Publications] Watanabe, S., et al: "Granulocyte-macrophage colony stimulation factor dependent replication of polyoma virusreplicon in hematopoietic cells: Analyses of receptor signals for replication and transcription" J. Biol. Chem. 270. 9615-9621 (1995)

    • Related Report
      1995 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-sumulating factor(GM-CSF)reccptor in BA/F3 cells" J. Biol. Chem.(in press).

    • Related Report
      1995 Annual Research Report
  • [Publications] A. Muto, 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.(in press).

    • Related Report
      1995 Annual Research Report
  • [Publications] Ito, T., et al: "Granulocyte-macrophage colony-sumulating factor provokes different modes of signalling leading to ras activation and transcription of c-fos through tyrosine residues of the receptor B subunit" J. Biol. Chem.(in press).

    • Related Report
      1995 Annual Research Report

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

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