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首页> 外文期刊>Developmental cell >APCCdc20 suppresses apoptosis through targeting Bim for ubiquitination and destruction
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APCCdc20 suppresses apoptosis through targeting Bim for ubiquitination and destruction

机译：APCCdc20通过靶向Bim进行泛素化和破坏来抑制细胞凋亡

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摘要

Anaphase-promoting complex Cdc20 (APCCdc20) plays pivotal roles in governing mitotic progression. By suppressing APCCdc20, antimitotic agents activatethe spindle-assembly checkpoint and induce apoptosis after prolonged treatment, whereas depleting endogenous Cdc20 suppresses tumorigenesis in part by triggering mitotic arrest and subsequent apoptosis. However, the molecular mechanism(s) underlying apoptosis induced by Cdc20 abrogation remains poorly understood. Here, we report the BH3-only proapoptotic protein Bim as an APCCdc20 target, such that depletion of Cdc20 sensitizes cells to apoptotic stimuli. Strikingly, Cdc20 and multiple APC-core components were identified in a small interfering RNA screen that, upon knockdown, sensitizes otherwise resistant cancer cells to chemoradiation in a Bim-dependent manner. Consistently, human adult Tcell leukemia cells that acquire elevated APCCdc20 activity via expressing the Tax viral oncoprotein exhibit reduced Bim levels and resistance to anticancer agents. These results reveal an important role for APCCdc20 in governing apoptosis, strengthening the rationale for developing specific Cdc20 inhibitors as effective anticancer agents.
机译：后期促进复合物Cdc20（APCCdc20）在控制有丝分裂进程中起关键作用。通过抑制APCCdc20，抗有丝分裂剂可在延长的治疗后激活纺锤体装配检查点并诱导凋亡，而耗尽内源性Cdc20则部分通过触发有丝分裂阻滞和随后的凋亡来抑制肿瘤发生。但是，尚不清楚由Cdc20废除诱导的细胞凋亡的分子机制。在这里，我们报告仅BH3促凋亡蛋白Bim作为APCCdc20靶标，因此Cdc20的耗尽会使细胞对凋亡刺激敏感。引人注目的是，在一个小的干扰RNA筛选中鉴定出了Cdc20和多个APC核心组件，该组件在敲除后以Bim依赖性方式使原本具有抗性的癌细胞对化学放射敏感。一致地，通过表达Tax病毒癌蛋白获得升高的APCCdc20活性的人类成年T细胞白血病细胞表现出降低的Bim水平和对抗癌药的耐药性。这些结果揭示了APCCdc20在调控细胞凋亡中的重要作用，加强了开发特定Cdc20抑制剂作为有效抗癌药的原理。

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