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Molecular mechanisms involved in non-apoptotic programmed cell death regulation

非凋亡程序性细胞死亡调节的分子机制

基本信息

批准号：
14580708
负责人：
KITANAKA Chifumi
金额：
$ 2.18万
依托单位：
National Cancer Center Research Institute
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2003
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14580708/
关键词：
Ras Apoptosis ミトコンドリア

项目摘要

We used the in vitro model system for Ras-dependent non-apoptotic programmed cell death and dissected the molecular mechanism involved in the regulation of Ras-induced non-apoptotic programmed cell death. In general, caspase-independent, non-apoptotic programmed cell deaths are known to be mitochondria-dependent We therefore examined whether mitochondria is involved in Ras-induced non-apoptotic programmed cell death. We found no evidence of increased permeability of mitochondrial membrane during Ras-induced cell death, and Ras-induced cell death was inhibited neither by Bcl-xL nor by vMIA, which are known to be potent inhitibors of mitochondrial cell death. These results indicated that Ras-induced cell death belongs to a novel type of non-apoptotic programmed cell death that has never been reported. Dissection of the intracellular signaling pathway activated by Ras using Ras effector loop mutant revealed that the Pl3K pathway plays a critical role in the transduction of the death signal. Screening of pharmacological agents that inhibit or promote Ras-induced cell death identified Toxin B of Clostridium difficile as a potent inhibitor of Ras-induced cell death, suggesting that the Rho family of proteins may play an important role in the regulation of Ras-induced cell death. Use of dominant-negative mutants of the Rho family proteins revealed that Rac among others may have a key role in Ras-induced non-apoptotic programmed cell death.

我们利用ras依赖性非凋亡程序性细胞死亡的体外模型系统，解剖了ras诱导非凋亡程序性细胞死亡的调控分子机制。一般来说，不依赖caspase的非凋亡程序性细胞死亡是线粒体依赖的。因此，我们研究了线粒体是否参与ras诱导的非凋亡程序性细胞死亡。在ras诱导的细胞死亡过程中，我们没有发现线粒体膜通透性增加的证据，并且Bcl-xL和vMIA都不能抑制ras诱导的细胞死亡，这两种物质都是线粒体细胞死亡的有效抑制剂。这些结果表明，ras诱导的细胞死亡属于一种从未报道过的新型非凋亡程序性细胞死亡。利用Ras效应环突变体对Ras激活的细胞内信号通路进行解剖，发现Pl3K通路在死亡信号的转导中起关键作用。筛选抑制或促进ras诱导细胞死亡的药理学药物，发现艰难梭菌毒素B是ras诱导细胞死亡的有效抑制剂，提示Rho蛋白家族可能在ras诱导细胞死亡的调控中发挥重要作用。Rho家族蛋白的显性阴性突变体的使用表明，Rac等可能在ras诱导的非凋亡程序性细胞死亡中起关键作用。