| Project/Area Number |
10470037
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Pathological medical chemistry
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| Research Institution | Tohoku University |
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Principal Investigator |
TAMURA Shinri Tohoku University, Institute of Development, Aging & Cancer, Professor, 加齢医学研究所, 教授 (20124604)
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| Co-Investigator(Kenkyū-buntansha) |
KOBAYASHI Takayasu Tohoku University, Institute of Development, Aging & Cancer, Assistant, 加齢医学研究所, 助手 (10221970)
HIRAGA Akira Tohoku University, Institute of Development, Aging & Cancer, Assistant Professor, 加齢医学研究所, 助教授 (80134047)
TAKAI Toshiyuki Tohoku University, Institute of Development, Aging & Cancer, Professor, 加齢医学研究所, 教授 (20187917)
柳川 右千夫 東北大学, 加齢医学研究所, 助手 (90202366)
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| Project Period (FY) |
1998 – 2001
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| Project Status |
Completed (Fiscal Year 2001)
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| Budget Amount *help |
¥12,800,000 (Direct Cost: ¥12,800,000)
Fiscal Year 2001: ¥2,700,000 (Direct Cost: ¥2,700,000)
Fiscal Year 2000: ¥2,700,000 (Direct Cost: ¥2,700,000)
Fiscal Year 1999: ¥2,900,000 (Direct Cost: ¥2,900,000)
Fiscal Year 1998: ¥4,500,000 (Direct Cost: ¥4,500,000)
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| Keywords | SAPK / signaling pathway / IL-1 / TAK1 / PP2C / ストレス応答 / SAPKシグナル伝達路 / プロテインホスファターゼ2C / 環境ストレス / プロテインホスファターゼ / ストレス反応 / SAPKシステム |
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| Research Abstract |
Protein phosphatase 2C (PP2C) is implicated in the negative regulation of tress-activated protein kinase (SAPK) cascades in yeast and mammalian cells. In this study, we determined the role of PP2Cβ-1, a major isoform of mammalian PP2C, in the TAK1 signaling pathway, a SAPK cascade that is activated by interleukin-1 (IL-1), transforming growth factor-β or stress. Ectopic expression of PP2Cβ-1 inhibited the TAK1-mediated mitogen-activated protein kinase kinase 4 (MKK4)-c-Jun N-terminal kinase (JNK) and MKK6-p38 signaling pathways. In vitro, PP2Cβ-1 dephosphorylated and inactivated TAK1. Co-immunoprecipitation experiments indicated that PP2Cβ-1 associates with the central region of TAK1. A phosphatase-negative mutant of PP2Cβ-1, PP2Cβ-1(R/G), acted as a dominant negative mutant, inhibiting dephosphorylation of TAK1 by wild-type PP2Cβ-1 in vitro. In addition, ectopic expression of PP2Cβ-1(R/G) enhanced IL-1-induced activation of an AP-1 reporter gene. Collectively, these results indicate that PP2Cβ negatively regulates the TAK1 signaling pathway by direct dephosphorylation of TAK1.
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