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首页> 外文期刊>Molecular biology of the cell >Aurora kinase inhibitor ZM447439 blocks chromosome-induced spindle assembly, the completion of chromosome condensation, and the establishment of the spindle integrity checkpoint in Xenopus egg extracts
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Aurora kinase inhibitor ZM447439 blocks chromosome-induced spindle assembly, the completion of chromosome condensation, and the establishment of the spindle integrity checkpoint in Xenopus egg extracts

机译：Aurora激酶抑制剂ZM447439阻止非洲爪蟾卵提取物中染色体诱导的纺锤体组装，染色体浓缩的完成以及纺锤体完整性检查点的建立

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摘要

The Aurora family kinases contribute to accurate progression through several mitotic events. ZM447439 ("ZM"), the first Aurora family kinase inhibitor to be developed and characterized, was previously found to interfere with the mitotic spindle integrity checkpoint and chromosome segregation. Here, we have used extracts of Xenopus eggs, which normally proceed through the early embryonic cell cycles in the absence of functional checkpoints, to distinguish between ZM's effects on the basic cell cycle machinery and its effects on checkpoints. ZM clearly had no effect on either the kinetics or amplitude in the oscillations of activity of several key cell cycle regulators. It did, however, have striking effects on chromosome morphology. In the presence of ZM, chromosome condensation began on schedule but then failed to progress properly; instead, the chromosomes underwent premature decondensation during mid-mitosis. ZM strongly interfered with mitotic spindle assembly by inhibiting the formation of microtubules that are nucleated/stabilized by chromatin. By contrast, ZM had little effect on the assembly of microtubules by centrosomes at the spindle poles. Finally, under conditions where the spindle integrity checkpoint was experimentally induced, ZM blocked the establishment, but not the maintenance, of the checkpoint, at a point upstream of the checkpoint protein Mad2. These results show that Aurora kinase activity is required to ensure the maintenance of condensed chromosomes, the generation of chromosome-induced spindle microtubules, and activation of the spindle integrity checkpoint.
机译：Aurora家族激酶通过一些有丝分裂事件有助于准确的进程。 ZM447439（“ ZM”）是第一个要开发和表征的Aurora家族激酶抑制剂，先前发现可干扰有丝分裂纺锤体完整性检查点和染色体分离。在这里，我们使用非洲爪蟾卵的提取物来区分ZM对基本细胞周期机制的影响和对检查点的影响，这些提取物通常在没有功能性检查点的情况下经历早期胚胎细胞周期。 ZM显然对几种关键细胞周期调节因子的动力学或振幅没有影响。但是，它确实对染色体形态具有显着影响。在存在ZM的情况下，染色体凝结如期开始，但随后无法正常进行。取而代之的是，染色体在有丝分裂中期经历过早的缩聚。 ZM通过抑制染色质成核/稳定的微管的形成，强烈干扰了有丝分裂纺锤体的组装。相比之下，ZM对纺锤极的中心体对微管的组装影响很小。最终，在实验诱导了主轴完整性检查点的条件下，ZM阻止了检查点蛋白质Mad2上游点的建立，但没有维护检查点。这些结果表明，需要Aurora激酶活性来确保凝聚染色体的维持，染色体诱导的纺锤体微管的产生以及纺锤体完整性检查点的激活。

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