Stevens F E, Beamish H, Warrener R, Gabrielli B
Cancer Biology Program, Diamantina Institute for Cancer Research, Immunology and Metabolic Medicine, University of Queensland, Princess Alexandra Hospital, Brisbane, Queensland, Australia.
Oncogene. 2008 Feb 28;27(10):1345-54. doi: 10.1038/sj.onc.1210779. Epub 2007 Sep 10.
Chromosomal passenger proteins have emerged as key players in the regulation of mitosis and cytokinesis. Histone deacetylase inhibitors (HDACi) are a class of anticancer drugs that induce aberrant mitosis and can overcome the spindle assembly checkpoint. Here, we investigate the mechanism by which HDACi disrupt normal mitotic progression and checkpoint function. We demonstrate that HDACi treatment temporarily delays mitotic progression through prometaphase due to activation of the spindle assembly checkpoint. Despite failing to congress chromosomes to the metaphase plate, cells aberrantly segregate their chromosomes and exit mitosis to undergo a failed cytokinesis. We show that this premature exit from mitosis is a form of mitotic slippage. Chromosomal passenger proteins fail to accumulate at the centromere following HDACi treatment. This results in inadequate concentrations of chromosomal passenger proteins at the centromere, which are insufficient to regulate the phosphorylation of the kinetochore checkpoint component BubR1, and an inability to maintain the mitotic arrest. Thus, the centromeric accumulation of chromosomal passenger complex components is critical for regulating kinetochore but not centromeric processes, and failure of this accumulation underlies the HDACi-induced mitotic slippage.
染色体乘客蛋白已成为有丝分裂和胞质分裂调控中的关键因子。组蛋白去乙酰化酶抑制剂（HDACi）是一类抗癌药物，可诱导异常有丝分裂并能克服纺锤体组装检查点。在此，我们研究HDACi破坏正常有丝分裂进程和检查点功能的机制。我们证明，由于纺锤体组装检查点的激活，HDACi处理会暂时延迟有丝分裂通过前中期的进程。尽管未能使染色体排列到中期板，但细胞仍异常地分离其染色体并退出有丝分裂，从而经历失败的胞质分裂。我们表明，这种过早退出有丝分裂是有丝分裂滑脱的一种形式。HDACi处理后，染色体乘客蛋白无法在着丝粒处积累。这导致着丝粒处染色体乘客蛋白浓度不足，不足以调节动粒检查点组分BubR1的磷酸化，并且无法维持有丝分裂停滞。因此，染色体乘客复合体组分在着丝粒处的积累对于调节动粒而非着丝粒过程至关重要，而这种积累的失败是HDACi诱导的有丝分裂滑脱的基础。
