Comprehension and application of biological information system based on the analysis of molecular mechanisms of stress response

基于应激反应分子机制分析的生物信息系统理解与应用

• 批准号: 13854022
• 负责人: ICHIJO Hidenori
• 金额: $ 78.79万
• 依托单位: The University of Tokyo (2002-2005)Tokyo Medical and Dental University (2001)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (S)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13854022/
• 关键词: ASK1; MAP Kinase; Apoptosis; Stress; Calcium; 自然免疫; ASKファミリー; ASK2

This research program aimed at disclosing the molecular mechanisms by which cells convert quantitative difference of signals into qualitative difference of responses. We investigated the stress responses with main focuses on the regulatory mechanisms of ASK family proteins by physico-chemical stresses. More concretely, following studies have been performed ; 1)oxidative stress- and endoplasmic reticulum stress-induced activation mechanisms of ASK1, 2)development of monitoring system of ASK1 activity, 3)search for small compounds which inhibit ASK1 activity, 4)activation mechanisms of ASK family proteins, 5)establishment of knockout mice of ASK family genes, 6)the effects of ASK1 gene deletion on the gene expression, protein modification and cell fate. Based on these experiments, we found that durations of activated proteins downstream of ASK1 play important roles in generation of qualitative differences of cellular responses. These excellent results suggested that the studies of stress responses through ASK family may lead to the development of revolutionary therapeutic drugs for neurodegenerative diseases and inflammation.

本研究旨在揭示细胞将信号的量的差异转化为反应的质的差异的分子机制。我们研究了植物的胁迫反应，主要集中在物理化学胁迫对ASK家族蛋白的调控机制。更具体地说，进行了以下研究：1）氧化应激和内质网应激诱导的ASK 1激活机制，2）ASK 1活性监测系统的开发，3）寻找抑制ASK 1活性的小分子化合物，4）ASK家族蛋白的激活机制，5）ASK家族基因敲除小鼠的建立，6）ASK 1基因缺失对基因表达的影响，蛋白质修饰和细胞命运。基于这些实验，我们发现ASK 1下游活化蛋白的持续时间在细胞反应的质的差异的产生中起重要作用。这些优异的结果表明，通过ASK家族研究应激反应可能会导致神经退行性疾病和炎症的革命性治疗药物的开发。

项目成果

Sustained activation of the JNK cascade and rapamycin-induced apoptosis are suppressed by p53/p21^Cip1

p53/p21^Cip1 抑制 JNK 级联的持续激活和雷帕霉素诱导的细胞凋亡

• 发表时间: 2003
• 期刊: Mol. Cell 11
• 作者: Huang;H. et al.
• 通讯作者: H. et al.

Signal Transduction by Reactive Oxygen and Nitrogen Species : Pathways and Chemical Principles

活性氧和氮的信号转导：途径和化学原理

• 发表时间: 2003
• 作者: Matsuzawa;A. at al.
• 通讯作者: A. at al.

Takeda, K., et al.: "Roles of MAPKKK ASK1 in Stress-Induced Cell Death"Cell Struct Funct.. 28. 23-29 (2003)

Takeda，K.，等人：“MAPKKK ASK1 在应激诱导的细胞死亡中的作用”Cell Struct Funct.. 28. 23-29 (2003)

Roles of MAPKKK ASK1 in stress-induced cell death.

• DOI: 10.1247/csf.28.23
• 发表时间: 2003-02
• 期刊: Cell structure and function
• 影响因子: 1.5
• 作者: K. Takeda;A. Matsuzawa;H. Nishitoh;H. Ichijo

Matsuura, H. et al.: "Phosphorylation-dependent scaffolding role of JSAP1/JIP3 in the ASK1-JNK signaling pathway : a new mode of regulation of the MAP kinase cascade"J. Biol. Chem.. 277. 40703-40709 (2002)

Matsuura, H. 等人：“ASK1-JNK 信号通路中 JSAP1/JIP3 的磷酸化依赖性支架作用：MAP 激酶级联调节的新模式”J.