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首页> 外文期刊>Cell cycle >CDK1 inhibitors antagonize the immediate apoptosis triggered by spindle disruption but promote apoptosis following the subsequent rereplication and abnormal mitosis.
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CDK1 inhibitors antagonize the immediate apoptosis triggered by spindle disruption but promote apoptosis following the subsequent rereplication and abnormal mitosis.

机译:CDK1抑制剂可拮抗纺锤体破坏触发的立即凋亡,但在随后的复制和异常有丝分裂后可促进凋亡。

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摘要

Spindle-disrupting agents and CDK inhibitors are important cancer therapeutic agents. Spindle toxins activate the spindle-assembly checkpoint and lead to sustained activation of CDK1. Different published results indicate that CDK1 activity is either important or dispensable for the cytotoxicity associated with spindle disruption. Using live cell imaging and various approaches that uncoupled mitotic events, we show that apoptosis was induced by both prolonged nocodazole treatment as well as by inhibition of CDK1 activity after a transient nocodazole block. However, distinct mechanisms are involved in the two types of cell death. The massive apoptosis triggered by nocodazole treatment requires the continuous activation of cyclin B1-CDK1 and is antagonized by premature mitotic slippage. By contrast, apoptosis induced by nocodazole followed by CDK inhibitors occurred after rereplication and multipolar mitosis of the subsequent cell cycle. The presence of dual mechanisms of cytotoxicity mediated by spindle disruption and CDK inhibition may reconcile the various apparent inconsistent published results. These data underscore the essential role of cyclin B1-CDK1 as the basis of apoptosis during mitotic arrest, and the role of mitotic slippage and abnormal mitosis for apoptosis at later stages.
机译:纺锤体破坏剂和CDK抑制剂是重要的癌症治疗剂。主轴毒素激活主轴装配检查点,并导致CDK1持续激活。不同的已发表结果表明,CDK1活性对于与纺锤体破坏相关的细胞毒性很重要或可有可无。使用活细胞成像和解耦有丝分裂事件的各种方法,我们表明,细胞凋亡是由延长的诺考达唑治疗以及短暂的诺考达唑阻滞后抑制CDK1活性诱导的。但是,两种细胞死亡都涉及不同的机制。由诺考达唑治疗触发的大量凋亡需要细胞周期蛋白B1-CDK1的持续激活,并因有丝分裂过早而被拮抗。相比之下,诺考达唑继之以CDK抑制剂诱导的细胞凋亡在随后的细胞周期复制和多极有丝分裂后发生。由纺锤体破坏和CDK抑制介导的细胞毒性双重机制的存在可能会调和各种明显不一致的已发表结果。这些数据强调了细胞周期蛋白B1-CDK1作为有丝分裂阻滞过程中细胞凋亡的基础的重要作用,以及有丝分裂的滑移和异常有丝分裂对于后期细胞凋亡的作用。

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