Regulatory Mechanism of Stress-Responsive Signal Transduction Pathway

应激反应信号转导通路的调控机制

• 批准号: 14086101
• 负责人: SAITO Haruo
• 金额: $ 13.89万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research on Priority Areas
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14086101/
• 关键词: gene; environment; enzyme; intracellular signal transduction; stress; 細胞内シグナル伝達; ストレス応答; MAPキナーゼ; 分子生物学; 細胞生物学

Stress-responsive signal transduction pathway is an important cellular defence mechanism. Its central core is the so-called Stress-Activated MAP Kinase cascade (SAPK cascade). Defects in mammalian SAPK pathways cause, not only abnormalities at the molecular and cellular levels, but also systemic diseases such as autoimmunity and cancer. In order to aide developments of new treatments for these difficult diseases, this project focused on various important subjects concerning SAPK pathways, using human, mouse, nematode, yeast, and cyanobacterium.Through this project, the novel activation mechanisms of several MAP3K enzymes, namely mammalian MTK1 and ASK1/2 and yeast Ssk2 and Ste11, were elucidated. Furthermore, we obtained numerous new findings concerning positive and negative regulations of SAPK pathways by protein phosphatases, adaptor and binding proteins, and docking interactions. Studies using nematode has revealed new roles of SAPK pathways at systemic level, such as innate immunity, tolerance to oxidative stress, and tolerance to heavy metals. The regulatory mechanism of the yeast HOG osmoregulatory SAPK pathway has been elucidated to the point that it is now considered as one of the best understood signaling pathways.Mammalian MAPK and SAPK pathways are intimately related to pathogenesis of various diseases such as autoimmunity, cancer, and infection. Thus, results from this projects are expected to aide developments of new treatments for these difficult diseases, by identifying prospective target molecules for drug development. Because the yeast SAPK pathway is an important determinant for virulence of pathogenic yeasts such as Blastomyces and Candida, the findings from this project will be also useful to develop new anti-fungal drugs.In conclusion, this project not only contributed to advancement of the immediate field of SAPK signaling in mammalian, nematode, yeast and cyanobacterium, but it also had a significant influence on other related fields.

应力响应信号转导途径是重要的细胞防御机制。它的中心是所谓的应力激活的MAP激酶级联反应（SAPK Cascade）。哺乳动物SAPK途径的缺陷导致不仅在分子和细胞水平下异常，而且还引起自身免疫性和癌症等全身性疾病。 In order to aide developments of new treatments for these difficult diseases, this project focused on various important subjects concerning SAPK pathways, using human, mouse, nematode, yeast, and cyanobacterium.Through this project, the novel activation mechanisms of several MAP3K enzymes, namely mammalian MTK1 and ASK1/2 and yeast Ssk2 and Ste11, were elucidated.此外，我们获得了许多有关蛋白质磷酸酶，衔接子和结合蛋白以及对接相互作用的SAPK途径正和负法规的新发现。使用线虫的研究揭示了SAPK途径在系统水平上的新作用，例如先天免疫力，对氧化应激的耐受性以及对重金属的耐受性。已经阐明了酵母猪OSMoregulatory SAPK途径的调节机制，以至于它被认为是最能理解的信号通路之一。MammalianMAPK和SAPK途径与诸如自身免疫，癌症和感染等各种疾病的发病机理密切相关。因此，通过鉴定前瞻性靶标分子来开发药物开发，预计该项目的结果有助于这些困难疾病的新疗法发展。因为酵母SAPK途径是毒性毒性（例如爆炸性酵母菌和念珠菌）的重要决定因素，因此该项目的发现对于开发新的抗真菌药物也将很有用。在结论中，该项目不仅有助于在哺乳动物，Nemalian，Nematode，Yeast，Yeast，Yeast，Yeast，Yeast，Yeast，Yeast，Yeast，Yeast和CyAn a A a A a A a A An It It It and It and In It and In It and In It and In It and It and It and It and It and It and It and It and It and It It to and It It to and It and It It It。

项目成果

Caspase-mediated cleavage of JN during stress-induced apoptosis.

应激诱导的细胞凋亡过程中 Caspase 介导的 JN 裂解。

• 发表时间: 2003
• 期刊: Biochemical and Biophysical Research Communications 306
• 作者: Enomoto;Atsushi
• 通讯作者: Atsushi

Stomach-specific calpain, nCL-2, localizes in mucus cells and proteolyzes the b-subunit of coatomer complex, b-COP.

胃特异性钙蛋白酶 nCL-2 定位于粘液细胞并蛋白水解外壳复合物 b-COP 的 b 亚基。

• 发表时间: 2006
• 期刊: J. Biol. Chem. 281
• 作者: Hata;S.;Koyama;S.;Kawahara;H.;Doi;N.;Maeda;T.;Toyama-Sorimachi;N.;Abe;K.;Suzuki;K.;^*Sorimachi;H.
• 通讯作者: H.

Expression and distribution of JNK/SAPK-assoclated scaffold protein JSAP1 in developing and adult mouse brain.

JNK/SAPK 相关支架蛋白 JSAP1 在发育中和成年小鼠大脑中的表达和分布。

• 发表时间: 2006
• 期刊: Journal of Neurochemistry 97
• 作者: Miura;Eriko
• 通讯作者: Eriko

Scaffold protein JSAP1 is transported to growth cones of neuritis independent of JNK signaling pathways in PC12h cells.

支架蛋白 JSAP1 在 PC12h 细胞中独立于 JNK 信号通路转运至神经炎生长锥。

• 发表时间: 2004
• 期刊: Gene 329
• 作者: Sato;Shinji
• 通讯作者: Shinji

Conserved docking site is essential for activation of mammalian MAP kinase by specific MAP kinase kinase kinases.

保守的对接位点对于特定 MAP 激酶激酶激活哺乳动物 MAP 激酶至关重要。

• 发表时间: 2005
• 期刊: Molecular Cell 18
• 作者: Takekawa;Mutsuhiro
• 通讯作者: Mutsuhiro