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.

应激反应是最基本的生物学过程之一，它的破坏导致各种疾病。我们证明了ASK家族激酶，包括ASK 1，ASK 2和ASK 3，在识别物理化学应激和诱导细胞应激反应中起关键作用。在这里，我们通过分析ASK 1信号体组分发现，ASK 1活性受到Roquin-2 E3连接酶和USP 9 X去泛素化酶的泛素化的严格调控。ASK 3是一个新近发现的ASK家族成员，在渗透胁迫下其活性表现出双向变化。此外，我们已经发现SOD 1-Derlin-1相互作用作为细胞内锌浓度传感器，将锌缺乏转化为轻度ER应激，并诱导生理性ER应激反应以维持锌稳态。这些发现将为各种压力相关疾病的诊断、预防和治疗的发展提供启示。

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

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.

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

Ubiquitin-like sequence in ASKI plays critical roles in the recognition and stabilization by USP9X and oxidative stress-induced cell death.

ASKI 中的泛素样序列在 USP9X 的识别和稳定以及氧化应激诱导的细胞死亡中发挥着关键作用。

• 发表时间: 2009
• 期刊: Mol. Cell 36
• 作者: Nagai;H.;Noguchi;T.;Homma;K.;Katagiri;K.;Takeda;K.;Matsuzawa;A.;Ichijo H.
• 通讯作者: Ichijo 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.