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Molecular mechanism of CHOP dependent cell death induced by extracellular stresses

细胞外应激诱导CHOP依赖性细胞死亡的分子机制

基本信息

批准号：
16590057
负责人：
HAYASHI Hidetoshi
金额：
$ 2.3万
依托单位：
Nagoya City University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16590057/
关键词：
TRB3 CHOP ATF4 p300 endoplasmic reticulum stress apoptosis diabetes neurodegenerative diseases ネガティブ・フィードバック Akt

项目摘要

The endoplasmic reticulum(ER) stress is induced by the accumulation of misfolding or malfolding proteins in ER caused by genetic mutation or abnormal modification of proteins. Recently, it is clarified that the ER stress-induced apoptosis cause the neurodegenerative diseases and the diabetes. Applicants are advancing the study of analysis on transcription factor CHOP to which are induced at the ER stress, and are related of apoptosis. Here we have shown that the TRB3, one of the human homologs of a Drosophila kinase like molecule Tribbles, is induced by ER stress and its promoter is activated via ER stress-induced transcription factors, CHOP and ATF4. TRB3 proteins suppress the transcriptional activities of CHOP and ATF4, suggesting CHOP(probably also ATF4)signaling is strictly regulated by TRB3 via a negative feedback mechanism.In addition, overexpression of TRB3 enhances the ER stress-induced cell death, while the knockdown of TRB3 by a siRNA method decreased the cell death. We have … More also observed the association between TRB3 and CHOP by the immunoprecipitaion-Western blot methods. Inhibitory effect of TRB3 on the transcriptional activity of CHOP is Independent of protein degradation. Moreover, the expression of TRB3 did not influence the dimer formation and DNA binding activities of CHOP. However, TRB3 associated with CHOP through its transcriptional domain and this domain is overlapped with a p300 binding domain. Overexpression of TRB3 remarkably inhibited the formation of p300-CHOP complex. These results suggest that TRB3 may function as an antagonist to replace the p300 from CHOP, and control its transcriptional effect. Moreover, transactivational activity of ATF4 is also suppressed by TRB3 probably by the decrease in its stability and by the dissociation of p300 from ATF4.It is well known that some products necessary for cell survival are the downstream targets of ATF4, suggesting that the downregulation of ATF4 by TRB3 may greatly contribute the apoptosis according to the ER stress. Less

内质网应激是由基因突变或蛋白质异常修饰引起的内质网错误折叠或异常折叠蛋白质的积累引起的。近年来，内质网应激诱导的细胞凋亡与神经退行性疾病和糖尿病有关。申请者正在推进内质网应激诱导的转录因子CHOP的分析研究，该转录因子与细胞凋亡有关。在这里，我们已经证明TRB3是果蝇激酶样分子Tribbles的人类同源物之一，可由内质网应激诱导，其启动子可通过内质网应激诱导的转录因子CHOP和ATF4激活。TRB3蛋白抑制CHOP和ATF4的转录活性，提示CHOP（也可能是ATF4）信号通路受TRB3通过负反馈机制严格调控。此外，TRB3过表达增强内质网应激诱导的细胞死亡，而通过siRNA方法敲低TRB3可降低细胞死亡。More还通过免疫沉淀- western blot方法观察到TRB3与CHOP之间的关联。TRB3对CHOP转录活性的抑制作用与蛋白质降解无关。TRB3的表达不影响CHOP二聚体的形成和DNA结合活性。然而，TRB3通过其转录结构域与CHOP相关，并且该结构域与p300结合结构域重叠。TRB3过表达显著抑制p300-CHOP复合物的形成。这些结果表明TRB3可能作为拮抗剂取代CHOP中的p300，并控制其转录作用。此外，ATF4的交易活性也受到TRB3的抑制，可能是由于其稳定性降低和p300与ATF4的分离。众所周知，一些细胞生存所必需的产物是ATF4的下游靶点，这表明TRB3下调ATF4可能在很大程度上促进了内质网应激导致的细胞凋亡。少