《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：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 Quan^1，3*

(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: 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