Molecular mechanism of response of living body to environmental stress

生命体对环境应激反应的分子机制

• 批准号: 10470037
• 负责人: TAMURA Shinri
• 金额: $ 8.19万
• 依托单位: Tohoku University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-10470037/
• 关键词: 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

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.

蛋白质磷酸酶2C（PP2C）隐含在酵母和哺乳动物细胞中治疗激活蛋白激酶（SAPK）级联反应的阴性调节中。在这项研究中，我们确定了pp2cβ-1（哺乳动物PP2C的主要同工型）在TAK1信号通路中的作用，Tak1信号通路是一种SAPK CASCADE，它被白介素-1（IL-1）激活，从而转化生长因子-β或压力。 PP2Cβ-1的异位表达抑制了TAK1介导的有丝分裂原激活的蛋白激酶激酶4（MKK4）-C-J-JUN N末端激酶（JNK）和MKK6-P38信号通路。体外，PP2Cβ-1去磷酸化和灭活的TAK1。共免疫沉淀实验表明，PP2Cβ-1与TAK1的中央区域相关。 PP2Cβ-1，PP2Cβ-1（R/G）的磷酸酶阴性突变体，充当显性阴性突变体，在体外抑制了野生型PP2Cβ-1在体外抑制TAK1的去磷酸化。另外，PP2Cβ-1（R/G）的生态表达增强了IL-1诱导的AP-1报告基因的激活。总的来说，这些结果表明PP2Cβ通过直接去磷酸化的TAK1负面调节TAK1信号通路。

项目成果

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