Drug development by the molecular mechanism-based analysis of stress signaling

通过基于分子机制的应激信号分析进行药物开发

• 批准号: 20229004
• 负责人: ICHIJO Hidenori
• 金额: $ 133.45万
• 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 (S)
• 财政年份: 2008
• 资助国家: 日本
• 起止时间: 2008-05-12 至 2013-03-31
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-20229004/
• 关键词: ストレス; ASKファミリー; MAPキナーゼ; アポトーシス; 浸透圧; PGAM5

The stress response is one of the most fundamental biological processes, and its disruption results in a wide variety of diseases. We demonstrated that ASK family kinases, including ASK1, ASK2 and ASK3, play pivotal roles in the recognition of physico-chemical stresses and induction of cellular stress responses. Here, we found through the analysis of ASK1 signalosome components that ASK1 activity is tightly regulated by ubiquitination by Roquin-2 E3 ligase and USP9X deubiquitinating enzyme. ASK3, a recently identified ASK family member, was found to exhibit a bidirectional change in its activity in response to osmotic stress. Furthermore, we have found the SOD1-Derlin-1 interaction functions as an intracellular zinc concentration sensor that converts zinc deficiency into mild ER stress and induces a physiological ER stress response to maintain zinc homeostasis. These findings will shed light on the development of diagnosis, prevention and treatment of various stress-related diseases.

压力反应是最基本的生物学过程之一，其破坏会导致多种疾病。我们证明，在识别物理化学应力和诱导细胞应力反应的识别中，包括Ask1，Ask2和Ask3在内的ASK家族激酶，包括Ask1，Ask2和Ask3。在这里，我们通过对ASK1信号组成分的分析发现，Roquin-2 E3连接酶和USP9X去泛素化酶受到泛素化的严格调节。 Ask3是最近确定的ASK家族成员，发现其活性在响应渗透压时表现出双向变化。此外，我们发现SOD1-DERLIN-1相互作用起着细胞内锌浓度传感器的作用，可将锌缺乏转化为轻度的ER应激，并诱导生理ER应力反应以维持锌稳态。这些发现将阐明各种与压力相关疾病的诊断，预防和治疗的发展。

项目成果

細胞がストレスを感じる仕組みと疾患

细胞如何感受压力和疾病

• 发表时间: 2022
• 作者: 20.佐藤優子;内野哲志;伊藤由馬;前原一満;大川恭行;徳永万喜洋;木村宏;一條秀憲
• 通讯作者: 一條秀憲

ASK family kinases in stress response and disease

ASK 家族激酶在应激反应和疾病中的作用

• 发表时间: 2007
• 作者: Williams YN;et al.;Hidenori Ichijo
• 通讯作者: Hidenori Ichijo

Signaling pathways in invertebrate immune and stress response

无脊椎动物免疫和应激反应中的信号通路

• 发表时间: 2009
• 期刊: Invertebrate Survival Journal 6
• 作者: Hatanaka;R.;et al.
• 通讯作者: et al.

Regulation of cell death signals by ubiquitination and deubiquitination

通过泛素化和去泛素化调节细胞死亡信号

• 发表时间: 2013
• 作者: Ichijo;H.
• 通讯作者: H.

Stress-Activated MAP Kinass Cascades in Cellular Senescence.

细胞衰老中应激激活的 MAP Kinass 级联。

• 发表时间: 2009
• 期刊: Curr. Med. Chem. 16
• 作者: Maruyama;J. et al.
• 通讯作者: J. et al.