1994 Fiscal Year Final Research Report Summary
Functional analysis of intracellular factors involved in the growth, differentiation, and transformation of lymphocytes
| Project/Area Number |
04404034
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| Research Category |
Grant-in-Aid for General Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Research Field |
Immunology
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| Research Institution | Osaka University |
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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)
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| 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)
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| Project Period (FY) |
1992 – 1994
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| Keywords | IRF-1 / anti-oncogene / apoptosis / leukemia / MDS / IL-2 signaling / IL-2 receptor / Syk tyrosine kinase / Jak family kinase |
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| 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
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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
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[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
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[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
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[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
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[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
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[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
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[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
