中国科技核心期刊
CN:31-1600/Q
ISSN:1004-0374
“健康与疾病的免疫”国际学术研讨会通知      关于有网站冒充本刊网站的声明
《生命科学》 2011, 23(11): 1076-1080
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
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*
(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)
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。
关键词:线粒体;Bcl-2 ;细胞凋亡;细胞色素C
 
Functional conversion of Bcl-2 into a pro-apoptotic molecule to regulate
ZHU Yu-Shan1, LU Tie-Yuan2, WANG Rui3, HUANG Li3, MA Qi3, ZHAO Li-Xia3, GAO Ping3, LEI Xiao-Bo3, NI Bi-Yun3, LIN Jia-Ling4, HAO Xiao-Jiang5, CHEN Quan1,3*
(1 State Key Laboratory of Medicinal Chemical Biology, School of Life Sciences, Nankai University, Tianjin 300071, China; 2 Department of Health and Exercise Science, Tianjin University of Sport, Tianjin 300381, China; 3 The State Key
    Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; 4 Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center,Oklahoma City, Oklahoma 73126, USA; 5 The State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650204, China)
Abstract: 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.
Key words: mitochondria; Bcl-2; apoptosis; cytochrome c
 
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