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首页> 外文期刊>Molecular and Cellular Biology >Calpain-Mediated Bid Cleavage and Calpain-Independent Bak Modulation: Two Separate Pathways in Cisplatin-Induced Apoptosis
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Calpain-Mediated Bid Cleavage and Calpain-Independent Bak Modulation: Two Separate Pathways in Cisplatin-Induced Apoptosis

机译：钙蛋白酶介导的 bid 裂解和钙蛋白酶非依赖性 bak 调节：顺铂诱导的细胞凋亡中的两种独立途径

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Calpain is a ubiquitous protease with potential involvement in apoptosis. We report that in human melanoma cells, cisplatin-induced calpain activation occurs early in apoptosis. Calpain activation and subsequent apoptosis were inhibited by calpeptin and PD150606, two calpain inhibitors with different modes of action. Furthermore, cisplatin induced cleavage of the BH3-only protein Bid, yielding a 14-kDa fragment similar to proapoptotic, caspase-cleaved Bid. However, Bid cleavage was inhibited by inhibitors of calpain, but not by inhibitors of caspases or of cathepsin L. Recombinant Bid was cleaved in vitro by both recombinant calpain and by lysates of cisplatin-treated cells. Cleavage was calpeptin sensitive, and the cleavage site was mapped between Gly70 and Arg71. Calpain-cleaved Bid induced cytochrome c release from isolated mitochondria. While calpeptin did not affect cispplatin-induced modulation of Bak to its proapoptotic conformation, a dominant-negative mutant of MEKK1 (dnMEKK) inhibited Bak modulation. dnMEKK did not, however, block Bid cleavage. The combination of dnMEKK and calpeptin had an additive inhibitory effect on apoptosis. In summary, calpain-mediated Bid cleavage is important in drug-induced apoptosis, and cisplatin induces at least two separate apoptotic signaling pathways resulting in Bid cleavage and Bak modulation, respectively.
机译：钙蛋白酶是一种无处不在的蛋白酶，可能参与细胞凋亡。我们报告说，在人类黑色素瘤细胞中，顺铂诱导的钙蛋白酶活化发生在细胞凋亡的早期。钙蛋白酶激活和随后的细胞凋亡被钙肽素和PD150606抑制，这两种钙蛋白酶抑制剂具有不同的作用方式。此外，顺铂诱导仅 BH3 蛋白 Bid 的裂解，产生类似于促凋亡、半胱天冬酶裂解的 Bid 的 14-kDa 片段。然而，钙蛋白酶抑制剂抑制了 Bid 裂解，但不被半胱天冬酶或组织蛋白酶 L 的抑制剂抑制，重组 Bid 在体外被重组钙蛋白酶和顺铂处理的细胞裂解物裂解。裂解对钙肽素敏感，裂解位点位于 Gly70 和 Arg71 之间。钙蛋白酶裂解的 Bid 诱导细胞色素 c 从分离的线粒体释放。虽然卡肽素不影响顺铂诱导的 Bak 对其促凋亡构象的调节，但 MEKK1 的显性阴性突变体 （dnMEKK） 抑制了 Bak 调节。然而，dnMEKK 并没有阻止 Bid 分裂。dnMEKK与卡肽素联合使用对细胞凋亡具有累加抑制作用。总之，钙蛋白酶介导的 Bid 裂解在药物诱导的细胞凋亡中很重要，顺铂诱导至少两个独立的凋亡信号通路，分别导致 Bid 裂解和 Bak 调节。

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