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Functional analysis of intracellular factors involved in the growth, differentiation, and transformation of lymphocytes

Research Project

Project/Area Number 04404034
Research Category

Grant-in-Aid for General Scientific Research (A)

Allocation TypeSingle-year Grants
Research Field Immunology
Research InstitutionOsaka University

Principal Investigator

TANIGUCHI Tadatsugu  Institute for Molecular and Cellular Biology Osaka University, Professor, 細胞生体工学センター, 教授 (50133616)

Co-Investigator(Kenkyū-buntansha) HARADA Hisashi  Institute for Molecular and Cellular Biology Osaka University, Research Associat, 細胞生体工学センター, 助手 (10222233)
TANAKA Nobuyuki  Institute for Molecular and Cellular Biology Osaka University, Assistant Profess, 細胞生体工学センター, 講師 (80222115)
Project Period (FY) 1992 – 1994
Project Status Completed (Fiscal Year 1994)
Budget Amount *help
¥31,000,000 (Direct Cost: ¥31,000,000)
Fiscal Year 1994: ¥4,000,000 (Direct Cost: ¥4,000,000)
Fiscal Year 1993: ¥4,000,000 (Direct Cost: ¥4,000,000)
Fiscal Year 1992: ¥23,000,000 (Direct Cost: ¥23,000,000)
KeywordsIRF-1 / anti-oncogene / apoptosis / leukemia / MDS / IL-2 signaling / IL-2 receptor / Syk tyrosine kinase / Jak family kinase / IRE-1 / Sykチロシンキナーゼ / Jak-ファミリーケロシンキナーゼ / チロシンキナーゼ / インターフェロン / IRF-2 / 遺伝子ノックアウトマウス / 誘導型NO合成酵素 / 転写因子 / IRF / 細胞増殖 / 癌化 / 5q欠損
Research Abstract

IRF-1 is a transcription factor that functions in the interferon system. We observed that expression of an activated Ha-ras gene in embryo fibroblasts from IRF-1-deficient mice resulted in their oncogenic transformation, indicating that IRF-1 can function as an anti-oncogene. We also observed that Ha-ras-induced apoptosis did not occur in embryo fibroblasts lacking IRF-1. These results strongly suggest that IRF-1 can determine oncogene-induced cell transformation and death. IRF-1 maps to the chromosomal 5q regon, a region frequently deleted in patients afflicted with leukemia or preleukemic myelodysplastic syndrome (MDS). We have shown previously that IRF-1 is a critically-deleted gene in these "5q syndrome" patients. Recently we discovered the existence of an alternatively-spliced form of the IRF-1 mRNA that encodes a protein lacking DNA-binding and anti-oncogenic activities. We found this abnormally-spliced product, but not the normal IRF-1 mRNA,in approximately 20% of patients affli … More cted with leukemia or MDS.Abnormal splicing may thus represent a new mechanism by which IRF-1 is inactivated, thereby promoting the development of leukemia.
We have also found that Syk, a non-receptor-type protein kinase (PTK), associates with the intracellular "serine-rich" region of the interleukin-2 receptor beta chain (IL-2Rbeta) and is activated upon IL-2 stimulation. This "serine-rich" region is essential for induction of the c-myc gene and cell proliferation following IL-2 stimulation. Furthermore, we have found that two recently-identified members of the Jak PTK family, Jak-1 and Jak-3, specifically associate with regions of the IL-2Rbeta and -g chains, respoctively, which are critical for transmission of the IL-2 signal, and are rapidly activated upon IL-2 stimulation. Ectopic expression of Jak-3 in NIH 3T3 fibroblasts, which express functional endogenous IL-2R and Jak-1, conferred upon these cells the ability to respond to IL-2 and thereby progress from the G1 to S phase of the cell cycle. Less

Report

(4 results)
  • 1994 Annual Research Report   Final Research Report Summary
  • 1993 Annual Research Report
  • 1992 Annual Research Report
  • Research Products

    (27 results)

All Other

All Publications (27 results)

  • [Publications] Ryutaro Kamijo: "Essential role for the transcription factor IRE-1 in the induction of nitric oxide synthase in macrophages" Science. 263. 1612-1615 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Nobuyuki Tanaka: "Cellular commitment to oncogene-induced transformation or apoptosis is dependent on the transcription of facotr IRF-1." Cell. 77. 829-839 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Toru Kimura: "Involvement of the IRF-1 transcription factor in antiviral responses to interferons." Science. 264. 1921-1924 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Yasuhiro Minami: "Signal transduction mediated by the reconstituted IL-2 receptor." J. Immunol.152. 5680-5690 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Tadaaki Miyazaki: "Functional activation of Jak1 and Jak3 by selective association with IL-2 receptor subunits." Science. 266. 1045-1047 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Yasuhiro Minami: "Protein tyrosine kinase syk is associated with and activated by the IL-2 receptor possible link with the c-myc inducton pathway" Immunity. 2. 89-100 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Kamijo, R., Harada, H., Matsuyama, T., Bosland, M., Gerecitano, J., Shapiro, D., Koh, S.I., Kimura, T., Green, J.S., Mak, T.W., Taniguchi, T., Vilcek, J.: "Essential role for the transcription factor IRF-1 in the induction of nitric oxide synthase in macrophages." Science. 263. 1612-1615 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Tanaka, N., Ishihara, M., Kitagawa, M., Harada, H., Kimura, T., Matsuyama, T., Lamphier, M.S., Aizawa, S., Mak, T.W.and Taniguchi, T.: "Cellular commitment to oncogene-induced transformation or apoptosis is dependent on the transcription factor IRF-1." Cell. 77. 829-839 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Kimura, T., Nakayama, K., Penninger, J,Kitagawa, M., Harada, H., Matsuyama, T., Tanaka, N., Kamijo, R., Vilcek, J., Mak, T.W., Taniguchi, T: "Involvement of the IRF-1 transcription factor in antiviral responses to interferons" Science. 264. 1921-1924 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Minami, Y., Oishi, I., Liu, Z-J., Nakagawa, S., Miyazaki, T.and Taniguchi, T.: "Signal transduction mediated by the reconstituted IL-2 receptor." J.Immunol.152. 5680-5690 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Miyazaki, T., Kawahara, A,Fujii, H., Nakagawa, Y., Nminami, Y., Liu, Z-J., Oishi, I., Silvennoinen, O., Witthuhn, B.A., Ihle, J.N., Taniguchi, T.: "Functional activation of Jak 1 and Jak3 by selective association with IL-2 receptor subunits." Science. 266. 1045-1047 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Minami, Y., Nakagawa, Y., Kawahara, A., Miyazaki T., Sada, K., Yamamura, H.and Taniguchi, T.: "Protein tyrosine kinase Syk is associated with and activated by the IL-2 receptor, possible link with the c-myc induction pathway." Immunity. 2. 89-100 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Ryutaro Kamijo: "Essential role for the transcription factor IRF-1 in the induction of nitric oxide synthase in macrophages" Science. 263. 1612-1615 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Nobuyuki Tanaka: "Cellular commitment to oncogene-induced transformatin or apoptosis is dependent on the transcription factor IRF-1." Cell. 77. 829-839 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Toru Kimura: "Involvemento of the IRF-1 transcription factor in antiviral responses to interferoms" Science. 264. 1921-1924 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Yasuhiro Minami: "Signal transduction mediated by the reconstituted IL-2 receptor." J.Immunol.152. 5680-5690 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Tadaaki Miyazaki: "Functional activation of Jakl and Jak3 by selective association with IL-2 receptor subunits." Science. 266. 1045-1047 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Yasuhiro Minami: "Protein tyrosine kinase Syk is associated with and activated by the IL-2 receptor possiblelink with the c-myciodertoo patha" Immunity. 2. 89-100 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Naoki Kobayashi: "Functional coupling of the src-family protein tyrosine kinases,p59^<fyn> and p53/56^<lyn> with the interleukin-2 receptor" Proc.Natl.Acad.Sci.USA.90. 4201-4205 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Tadatsugu Taniguchi: "The IL-2/IL-2 receptor system:A current overview" Cell. 73. 5-8 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Nobuyuki Tanaka: "Recognition DNA sequences of interferon regulatory factor 1(IRF-1)and IRF-2,regulators of cell growth and the interferon system" Mol.Cell.Biol.13. 4531-4538 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Toshifumi Matsuyama: "Targeted disruption of IRF-1 or IRF-2 results in abnormal type I IFN gene induction and aberrant lymphocyte development" Cell. 75. 83-97 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Hisashi Harada: "Structure and regulation of the human interferon regulatory factor 1(IRF-1)and(IRF-2)genes" Mol.Cell.Biol.14. 1500-1509 (1994)

    • Related Report
      1993 Annual Research Report
  • [Publications] Ryutaro Kamijo: "Essential Role for the Transcription Factor IRF-1 in the Induction of Nitric Oxide Synthase in Macrophages" Science. (in press).

    • Related Report
      1993 Annual Research Report
  • [Publications] Nobuyuki Tanaka: "Cytokine Gene Regulation:Regulatory cis-Elements and DNA Binding Factors Involved in the Interferon System." Adv.Lmmunol.52. 263-281 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] Hisashi Harada: "Anti-Oncogenic and Oncogenic Potentials of Interferon Regulatory Factors-1 and-2." Science. 259. 971-974 (1993)

    • Related Report
      1992 Annual Research Report
  • [Publications] Cheryl L Willman: "Deletion of IFR-1,Mapping to Chromosome 5q31.1,in Human Leukemia and Preleukemic Myelodysplasia." Science. 259. 968-971 (1993)

    • Related Report
      1992 Annual Research Report

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Published: 1992-04-01   Modified: 2016-04-21  

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