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1998 Fiscal Year Final Research Report Summary

Analyses of cytokine gene expression by helper T cell subsets : role of NFAT-mediated gene activation and subset-specific regulatory mechanism.

Research Project

Project/Area Number 08457103
Research Category

Grant-in-Aid for Scientific Research (B)

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

Principal Investigator

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

Co-Investigator(Kenkyū-buntansha) SATO Noriko  Inst.of Medical Science, The University of Tokyo, Assistant Professor, 医科学研究所, 助手 (70280956)
WATANABE Sumiko  Inst.of Medical Science, The University of Tokyo, Assistant Professor, 医科学研究所, 助手 (60240735)
MASAI Hisao  Inst.of Medical Science, The University of Tokyo, Associate Professor, 医科学研究所, 助教授 (40229349)
YOKOTA Takashi  Inst.of Medical Science, The University of Tokyo, Professor, 医科学研究所, 客員教授 (50134622)
Project Period (FY) 1996 – 1998
KeywordsT lymphocytes / Cytokines / Helper T cell subsets / Transcription factors / Nuclear translocation / NFAT / GATA-3 / Chromatin structure
Research Abstract

The aim of this study is to elucidate the regulatory mechanism of cytokine gene expression in helper T cells and their subsets.
(1) NFAT : regulation and function in T-cell activation. We have isolated human and murine genes of NFAT, a transcription factor that plays a critical role in transcriptional induction of cytokine genes. Throughout the mapping study on NFATx, a member of the NFAT family, we have defined a series of functional domains ; Rd domain critical for specific DNA-binding and association with AP-1 proteins, N-terminal domain for calcineurin-regulated activation of NFAT via nuclear translocation, and C-terminal domain for transactivation. in N-terminal domain, one of the critical segment for control of subcellular localization was narrowed down to 60-residue motif in N-terminal domain, as designated CRI.By modification of NFATx molecule (e.g., by deleting CRI or modifying calcineurin-interacting domains), we generated constitutively active of dominant negative mutants of … More NFATx with calcineurin-independent subcellular localization, that should be a useful tools for further understanding of NFAT-mediated gene regulation. We further analyzed expression and function of the NFAT family in thymocytes in which NFATx is predominantly expressed. We found that NFAT family mRNAs are developmentally regulated during the differentiation of T cells in the thymus, and that NFATx protein selectively contributes to the calcineurin-dependent NFAT-DNA binding activity in the DP stage, suggesting that NFAT is also involved in the signals required for generation of T cells in the thymus.
(2) Mechanism of Th2-specific cytokine gene regulation. We have previously described the regulatory motives in the promoters of cytokine genes including GM-CSF, IL-2, IL-3, IL-4, and IL-5, leading to discovery of conserved lymphokine elements (CLE). In current study was analyzed factors that facilitate the Th-subset specific expression of cytokines. In the analyzes of IL-5 promoter, 1.2 Kb-long promoter region was shown to define transactivation of IL-5 gene only in Th2 clones. Extensive studies of this region lead to discovery of NFIL-5CLEO and NFIL-5C, and GATA-3 or related transcription factor was indicated to involved in Th2-specific IL-5 gene induction via IL-5C-driven transactivation. Furthermore, in case of IL-4, the proximal promoter gives considerably less activity than intact IL-4 gene locus in Th2 cells. We performed DNaseI hypersensitive site (HSS) analysis using Th clones and in vitro differentiated Th1/Th2 cells, and identified that two out of three HSS located in IL-4 - IL-13 intergenic region were Th2-specific and appeared only after differentiation. These results provide novel and multiple regulatory mechanism in differential expression of Th2 cytokine gees. Less

  • Research Products

    (12 results)

All Other

All Publications (12 results)

  • [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
  • [Publications] Masuda E.S.,et al.: "Control of NFATxl nuclear translocation by a calcineurin-regulated inhibitory domain." Mol.Cell Biol.17. 2066-75 (1997)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Liu J.,et al.: "Calcineurin-dependent nuclear translocation of a murine transcription factor NFATx : molecular cloning and functional characterization." Mol.Biol.Cell. 8. 157-70 (1997)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Amasaki Y.,et al.: "Distinct NFAT family proteins are involved in the nuclear NFAT-DNA binding complexes from human thymocyte subsets." J.Immunol.160. 2324-33 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Lee HJ.,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.Immunol.160. 2343-52 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Takemoto N.,et al.: "Th2-specific DNase I-hypersensitive sites in the murine IL-13 and IL-4 intergenic region." Int.Immunol.10. 1981-5 (1998)

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

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Masuda ES,Liu J,Imamura R,Imai S,Arai K,Arai N.: "Control of NFAx1 nuclear translocation by a calcineurin-regulated inhibitory domain." Mol.Cell Biol. 17. 2066-75 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Liu J,Koyano-Nakagawa N,Amasaki Y,Saito-Ohara F,Ikeuchi T,Imai S,Takano T,Arai N,Yokota T,Arai K.: "Calcineurin-dependent nuclear translocation of a murine transcription factor NFATx : molecular cloning and functional characterization." Mol.Biol Cell. 8. 157-70 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Amasaki Y,Masuda ES,Imamura R,Arai K,Arai N: "Distinct NFAT family proteins are involved in the nuclear NFAT-DNA binding complexes from human thymocyte subsets." J Immunol. 160. 2324-33 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Lee HJ,O'Garra A,Arai K,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 Immunol. 160. 2343-52 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Takemoto N,Koyano NN,Arai N,Arai K,Yokota T: "Four P-like elements are required for optima transcription of the mouse IL-4 gene : involvement of a distinct set of nuclear factor of activated T cells and activator protein-1 family proteins." Int Immunol. 9. 1329-38 (1997)

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      「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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