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Analysis of signal transduction of OX40/gp34 and its role in pathogenesis of hematologic diseases

Research Project

Project/Area Number 10307023
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section一般
Research Field Hematology
Research InstitutionKYOTO UNIVERSITY

Principal Investigator

UCHIYAMA Takashi  Kyoto, University, graduate School of Medicine, Professor, 医学研究科, 教授 (80151900)

Co-Investigator(Kenkyū-buntansha) HIRO Toshiyuki  Kyoto University, graduate School of Medicine, Lecturer, 医学研究科, 講師 (70243102)
Project Period (FY) 1998 – 1999
Project Status Completed (Fiscal Year 1999)
Budget Amount *help
¥38,200,000 (Direct Cost: ¥38,200,000)
Fiscal Year 1999: ¥13,100,000 (Direct Cost: ¥13,100,000)
Fiscal Year 1998: ¥25,100,000 (Direct Cost: ¥25,100,000)
KeywordsOX40 / gp34 / TRAF / ATL / endothelial cell / NF-κB / c-jun / 共刺激
Research Abstract

(1) Moleclar mechanism of OX40 signaling
We previously reported that OX40 signaling leads to NF-κB activation via TRAF2 and TRAF5. TRAF3 also binds to the cytoplasmic domain or OX40 but functions rather negatively to suppress NF-κB activation. In the present study we found that TRAF3 did not affect NIK-mediated NF-κB activation and that both N-terminus and C-terminus deletion mutants of TRAF3 have inhibitory effects. These results indicate that TRAF3 suppresses NF-κB activation at the pathway between TRAF2 and NIK, which is not necessarily due to competitive inhibition of binding between OX40 and TRAF2.
(2) Intracytoplasmic signaling of gp34
We exzmined expression induction of c-fos and c-jun mRNA in MMCE-gp34, a human gp34 stable transfectant line of a mouse epithelial cell line as well as human umbilical vein endothelial cells (HUVEC) when stimulated wth soluble OX40. Northern blot analysis showed that both c-fos and c-jun mRNA were induced in MMCE-gp34, and c-jun mRNA in HUVEC upon bin … More ding of soluble OX40. This indicates that signlaing of the OX40/gp34 system is bidirectional.
(3) Costimulation of T cells by endothelial cells via the OX40/gp34 system
Purified CD4^+ T cells responded with proliferation to immobilized anti-CD3 mAb in the presence of irradiated HUVEC.This proliferative response was shown to be mediated by IL-2 autocrine mechanism and inhibited by addition of anti-gp34 mAb. The inhibitory effect of anti-gp34 was stronger than that of anti-ICAM-1 or anti-LFA1, indicating that the OX40/gp34 system is one of the major pathways of costimulation by endothelial cells.
(4) Possible role of the OX40/gp34 in the leukemogenesis of ATL
We studied the relationship between OX40 signals and apoptosis of ATL cells. ATL constitutively express OX40 and became resistant to anti-Fas-induced apoptosis when cocultured MMCE-gp34 while coculture with MMCE-mock had no effects. This acquisition of resistance to apoptosis was accompanied by expression induction of XIAP, an anti-apoptotic protein. It is suggested that ATL cells receive favoraous sigals for survival through the OX40/gp34 system. Less

Report

(3 results)
  • 1999 Annual Research Report   Final Research Report Summary
  • 1998 Annual Research Report
  • Research Products

    (20 results)

All Other

All Publications (20 results)

  • [Publications] Shin Kawamata, Toshiyuki Hori, Akihiro Imura, Akifumi Takaori-Kondo and Takashi Uchiyama.: "Activation of OX40 signal transduction pathways leads to TRAF2- and TRAF5-mediated NF-κB activation."J Biol Chem. 273(10). 5808-5814 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Akifumi Takaori-Kondo, Kazunori Imada, Itsuo Yamamoto, Akane Kunitomi, Yasuharu Numata, Hitoshi Sawada and Takashi Uchiyama.: "Parathyroid hormone-related protein-induced hypercalcemia in SCID mouse engrafted with adult T-cell leukemia cells."Blood. 91(12). 4747-4751 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Yusei Ohshima, Liang-Peng Yang, Takashi Uchiyama, Yuetsu Tanaka, Peter Baum, Martin Sergerie, Patrice Hermann, and Guy Delespesse: "OX40 costimulation enhances interleukin-4 (IL-4) expression at priming and promotes the differentiation of naive human CD4+ T cells into IL-4-producing effectors."Blood. 92(9). 3338-3345 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Yumi Matsumura, Toshiyuki Hori, Shin Kawamata, Akihiro Imura and Takashi Uchiyama.: "Intracellular signaling of gp34, the OX40 ligand : Induction of c-jun and c-for mRNA expression through gp34 upon binding of its receptor, OX40."J Immunol. 163. 3007-3011 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Akifumi Takaori-Kondo, Toshiyuki Hori, Keiko Fukunaga, Rinpei Morita, Shin Kawamata and Takashi Uchiyama.: "Both amino- and carboxyl-terminal domains of TRAF3 negatively regulate NF-κB activation induced by OX40 signaling."Biochem and Bioph Res Co. 272. 856-863 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Akane Kunitomi, Toshiyuki Hori, Akihiro Imura and Takashi Uchiyama.: "Vascular endothelial cells provide T cells with costimulatory signals via the OX40/gp34 system."J Leuk Biol.. 67. 111-118 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Akane Kunitomi, Toshiyuki Hori, Michiyuki Maeda and Takashi Uchiyama.: "OX40 signaling renders adult T cell leukemia cells resistant to Fas-mediated apoptosis."(発表予定).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Shin Kawamata, Toshiyuki Hori, Akihiro Imura, Akifumi Takaori-Kondo and Takashi Uchiyama: "Activation of OX40 signal transduction pathways leads to TRAF2- and TRAF5-mediated NF-κB activation"J Biol Chem. 273(10). 5808-5814 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Akifumi Takaori-Kondo, Kazunori Imada, Itsuo Yamamoto, Akane Kunitomi, Yasuharu Numata, Hitoshi Sawada and Takashi Uchiyama: "Parathyroid hormone-related protein-induced hypercalcemia in SCID mouse engrafted with adult T-cell leukemia cells"Blood. 91(12). 4747-4751 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Yusei Ohshima, Liang-Peng Yang, Takashi Uchiyama, Yuetsu Tanaka, Peter Baum, Martin Sergerie, Patrice Hermann, and Guy Delespesse: "OX40 costimulation enhances interleukin-4 (IL-4) expression at priming and promotes the differentiation of naive human CD4+ T cells into IL-4-producing effectors"Blood. 92(9). 3338-3345 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Yumi Matsumura, Toshiyuki Hori, Shin Kawamata, Akihiro Imura and Takashi Uchiyama: "Intracellular signaling of gp34, the OX40 ligand : Induction of c-jun and c-fos mRNA expression through gp34 upon binding of its receptor, OX40"J Immunol. 163. 3007-3011 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Akifumi Takaori-Kondo, Toshiyuki Hori, Keiko Fukunaga, Rinpei Morita, Shin Kawamata and Takashi Uchiyama: "Both amino- and carboxyl-termainal domains of TRAF3 negatively regulate NF-κB activation induced by OX40 signaling"Biochem and Bioph Res Co. 272. 856-863 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Akane Kunitomi, Toshiyuki Hori, Akihiro Imura and Takashi Uchiyama: "Vascular endothelial cells provide T cells with costimulatory signals via the OX40/gp34 system."J Leuk Biol.. 67. 111-118 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Akane Kunitomi, Toshiyuki Hori, Michiyuki Maeda and Takashi Uchiyama: "OX40 signaling renders adult T cell leukemia cells resistant to Fas-mediated apoptosis."(in preparation).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Y.Matsumura et al.: "Intracellular signaling of gp34, the ox40"The Journal of Immunology. 163. 3007-3011 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] A.Kunitomi et al.: "vascular endothelial cells provide Tcells with costimulatory signal via the ox40/gp34 system"Journal of Leukocyte Biology. (発表予定).

    • Related Report
      1999 Annual Research Report
  • [Publications] Shin Kawamata: "Activation of Ox40 signal transduction pathways leads to TRAF2- and TRAF5-mediated NF-κB activation." J Biol Chem.273(10). 5808-5814 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Akifumi Takaori-Kondo: "Parathyroid hormone-related protein-induced hypercalcemia in SCID mouse engrafted with adult T-cell leukemia cells." Blood. 91(12). 4747-4751 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Y.Ohshima: "OX40 costimulation enhances interleukin-4(IL-4) expression at priming and promotes the differentiation of naive human CD4+ T cells into IL-4-producing effectors." Blood. 92(9). 3338-3345 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Shin Kawamata: "The upregulation of p27Kip1 by rapamycin results in G1 arrest in exponentially growing T cell lines." Blood. 91(2). 561-569 (1998)

    • Related Report
      1998 Annual Research Report

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Published: 1998-04-01   Modified: 2016-04-21  

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