Bcl-2家族蛋白调控线粒体膜通透性和细胞色素C释放的新机制  

Functional conversion of Bcl-2 into a pro-apoptotic molecule to regulate mitochondrial cytochrome c release

作　　者：朱玉山[1] 卢铁元[2] 王蕊[3] 黄理[3] 马淇[3] 赵丽霞[3] 高平[3] 雷晓波[3] 倪碧云[3] 林家凌[4] 郝小江[5] 陈佺[1,3] 

机构地区：[1]南开大学生命科学学院药物化学生物学国家重点实验室,天津300071 [2]天津体育学院健康与运动系,天津300381 [3]中国科学院动物研究所生物膜与膜生物工程国家重点实验室,北京100101 [4]美国俄克拉荷马大学健康科学中心,诺曼56581 [5]中国科学院昆明植物研究所,昆明650204

出　　处：《生命科学》2011年第11期1076-1080,共5页Chinese Bulletin of Life Sciences

基　　金：国家自然科学基金国际合作项目(30910103910)

摘　　要：Bcl-2家族蛋白在调控线粒体功能和细胞色素C释放中起重要作用。最近发现Bcl-2分子通过与其他促凋亡分子相互作用调控线粒体外膜通透性,其具体分子机制尚不完全清楚。本课题组采用化学生物学方法,在研究Bax/Bak非依赖的细胞凋亡途径中,发现了一些小分子化合物能够诱导Bim表达量急剧升高,Bim能转位到线粒体上,与Bcl-2相互作用增强,并直接促进Bcl-2构象变化。有意义的是,Bim可以诱导Bcl-2功能发生转换并能够形成大的复合体通道来介导细胞色素C释放。研究结果提示Bcl-2分子可变成促凋亡分子,参与Bax/Bak非依赖的细胞色素C释放和细胞凋亡。Bcl-2 and its family proteins play pivotal roles in the regulation of the cytochrome c release and mitochondria functions.However,the mechanism on how Bcl-2 regulates mitochondrial outer membrane permeability is still not fully understood.We undertook a chemical biology approach to understand whether and how Bcl-2 regulates cytochrome c release in the absence of Bax and Bak.We identified several small compounds,such as gossypol,S-3 and PAO,that induced typical apoptosis in the bax/bak deficient cells.Mechanistic studies further revealed that these compounds are able to induce functional conversion of Bcl-2 into a Bax or Bak-like molecules.In particular,S-3 and PAO could induce the up-regulation of Bim which physically interacts with Bcl-2 at the MOM changing its conformation to form Bax-like pores which release cytochrome c and induce apoptosis.Since previous studies have generated overwhelming evidence showing that Bcl-2 is an anti-apoptotic molecule,it is surprising to find that Bim,a BH3-only protein and well known physiological inducer of apoptosis converts Bcl-2 to a Bax-like pro-apoptotic protein.

关 键 词：线粒体 BCL-2 细胞凋亡 细胞色素C 

分 类 号：Q244[生物学—细胞生物学] Q255