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.

应激反应信号转导通路是一种重要的细胞防御机制。其中心核心是所谓的应激激活的MAP-Kinase级联(SAPK Casade)。哺乳动物SAPK通路的缺陷不仅会导致分子和细胞水平的异常，还会导致自身免疫和癌症等全身性疾病。为了帮助开发治疗这些疑难疾病的新方法，本项目以人、小鼠、线虫、酵母和蓝藻为研究对象，重点研究了SAPK途径的各种重要课题，并通过该项目阐明了哺乳动物MTK1和ASK1/2以及酵母Ssk2和Ste11等几种MAP3K酶的新的激活机制。此外，我们还获得了许多关于蛋白磷酸酶、接头蛋白和结合蛋白以及对接相互作用对SAPK通路的正负调控的新发现。利用线虫的研究揭示了SAPK通路在系统水平上的新作用，如天然免疫、对氧化应激的耐受和对重金属的耐受。酵母猪渗透压调节SAPK通路的调节机制已被阐明，目前被认为是最被理解的信号通路之一。哺乳动物MAPK和SAPK通路与自身免疫、癌症和感染等多种疾病的发病机制密切相关。因此，这一项目的结果有望通过确定药物开发的预期目标分子，帮助开发针对这些疑难疾病的新疗法。由于酵母菌SAPK通路是芽孢杆菌和念珠菌等致病酵母菌毒力的重要决定因素，本项目的研究结果也将有助于开发新的抗真菌药物。总之，该项目不仅促进了哺乳动物、线虫、酵母和蓝藻SAPK信号转导领域的发展，而且对其他相关领域也有重大影响。

项目成果

Regulation of N-cadherin- based cell-cell interaction by JSAP1 scaffold in PC12h cells

PC12h 细胞中 JSAP1 支架对基于 N-钙粘蛋白的细胞间相互作用的调节

• 发表时间: 2007
• 期刊: Biochem. Biophys. Res. Commun 353
• 作者: Bayarsaikhan;M.;Takino;T.;Gantulga;D.;Sato;H.;Ito;T.;Yoshioka;K
• 通讯作者: K

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

In vitro development of mouse embryonic stem cells lacking JNK/stress-activated protein kinase-associated protein (JSAP1) scaffold protein revealed its requirement during early embryonic neurogenesis.

缺乏 JNK/应激激活蛋白激酶相关蛋白 (JSAP1) 支架蛋白的小鼠胚胎干细胞的体外发育揭示了其在早期胚胎神经发生过程中的需求。

• 发表时间: 2003
• 期刊: J. Biol. Chem. 278
• 作者: Xu;P.;Yoshioka;K.;Yoshimura;D.;Tominaga;Y.;Nishioka;T.;Ito;M.;^*Nakabeppu;Y.
• 通讯作者: Y.

Regulation of Lck and Fyn tyrosine kinase activities by transmembrane protein tyrosine phosphatase leukocyte common antigen-related molecule.

跨膜蛋白酪氨酸磷酸酶白细胞共同抗原相关分子对 Lck 和 Fyn 酪氨酸激酶活性的调节。

• 发表时间: 2002
• 期刊: Molecular Cancer Research 1
• 作者: Tsujikawa;Kazutake
• 通讯作者: Kazutake

Enomoto, Atsushi: "Caspase-mediated cleavage of JNK during stress-induced apoptosis."Biochemical and Biophysical Research Communication. 306. 837-842 (2003)

Enomoto，Atsushi：“应激诱导的细胞凋亡过程中，半胱天冬酶介导的 JNK 裂解。”生物化学和生物物理研究通讯。