A Bax/Bak-independent mechanism of cytochrome c release
A Bax/Bak-independent mechanism of cytochrome c release
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DOI：
10.1074/jbc.m611060200
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发表时间：
2007-06-01
影响因子：
4.8
通讯作者：
Tsujimoto, Yoshihide
中科院分区：
文献类型：
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作者：
Mizuta, Takeshi;Shimizu, Shigeomi;Tsujimoto, Yoshihide
Bax和巴克是Bcl- 2蛋白家族的多结构域促细胞凋亡成员，其通过直接调节线粒体膜通透性来调节细胞凋亡介导的细胞凋亡。由于Bax和巴克缺陷的双敲除小鼠胚胎成纤维细胞对多种凋亡刺激具有抗性，因此Bax和巴克被认为是各种凋亡信号的重要通道。在这里，我们发现，钙离子载体A23187和花生四烯酸的组合诱导细胞色素c的释放和双敲除小鼠胚胎成纤维细胞的半胱天冬酶依赖性死亡，表明细胞色素c的释放存在其他机制。此外，A23187/花生四烯酸（ArA）诱导的caspase依赖性死亡被几种丝氨酸蛋白酶抑制剂包括4-（2-氨基乙基）苯磺酰氟和L-1-氯- 3-（4-甲苯磺酰氨基）-4-苯基-2-丁酮的治疗显着抑制，但不是抗凋亡Bcl- 2家族蛋白的过表达或线粒体膜通透性转换的抑制。这些结果表明，至少有两种细胞色素c释放导致半胱天冬酶活化的机制，Bax/Bak依赖性机制和Bax/巴克非依赖性但丝氨酸蛋白酶依赖性机制。
Bax and Bak are multidomain pro-apoptotic members of the Bcl- 2 family of proteins that regulate mitochondria-mediated apoptosis by direct modulation of mitochondrial membrane permeability. Since double-knock-out mouse embryonic fibroblasts with deficiency of Bax and Bak are resistant to multiple apoptotic stimuli, Bax and Bak are considered to be an essential gateway for various apoptotic signals. Here we showed that the combination of calcium ionophore A23187 and arachidonic acid induced cytochrome c release and caspase-dependent death of double-knock-out mouse embryonic fibroblasts, indicating that other mechanisms of cytochrome c release exist. Furthermore, A23187/arachidonic acid (ArA)induced caspase-dependent death was significantly suppressed by the treatment of several serine protease inhibitors including 4-(2-aminoethyl) benzenesulfonylfluoride and L-1-chloro- 3-(4-tosylamido)-4-phenyl-2-butanone but not the overexpression of anti-apoptotic Bcl- 2 family of proteins or the inhibition of mitochondrial membrane permeability transition. These results indicate that there are at least two mechanisms of cytochrome c release leading to caspase activation, a Bax/Bak-dependent mechanism and a Bax/Bak- independent, but serine protease(s)-dependent, mechanism.