The small-molecule inhibitor BI 2536 reveals novel insights into mitotic roles of polo-like kinase 1
The small-molecule inhibitor BI 2536 reveals novel insights into mitotic roles of polo-like kinase 1
复制标题
DOI：
10.1016/j.cub.2006.12.046
复制
发表时间：
2007-02-20
期刊：
影响因子：
9.2
通讯作者：
Peters, Jan-Michael
中科院分区：
文献类型：
--
作者：
Lenart, Peter;Petronczki, Mark;Peters, Jan-Michael
背景资料：有丝分裂激酶Cdk 1、Aurora A/B和Polo样激酶1（Plk 1）已被广泛表征以进一步理解有丝分裂机制并作为癌症治疗的潜在靶点。Cdk 1和极光激酶的研究已经促进了小分子抑制剂，但很少，如果任何有效的Plk 1抑制剂已被identified.Results：我们描述了一种新的化合物，BI 2536，一种有效的和选择性的Plk 1抑制剂的细胞效应。BI 2536完全和瞬间阻断Plk 1活性的事实使我们能够研究Plk 1有争议和未知的功能。用BI 2536处理的细胞在前期延迟，但最终将Cdk 1-细胞周期蛋白B输入细胞核，进入前中期，并降解细胞周期蛋白A，尽管BI 2536阻止APC/C抑制剂PDK 1的降解。BI 2536处理的细胞缺乏前期微管星状体，因此只有在核膜破裂后才有丝分裂微管，并形成不能稳定附着于着丝粒的单极纺锤体。Mad 2在着丝粒处积累，并且细胞通过激活的纺锤体组装检查点而停滞。BI 2536防止Plk 1的富集在动粒和中心体，当添加到中期细胞，它诱导微管从动粒的分离，并导致纺锤体collaps.Conclusions：我们的研究结果表明，Plk 1的积累在中心体和动粒取决于它自己的活动，这种活动是需要维持中心体和动粒功能。我们的数据还表明，Plk 1是不需要的前期进入，但延迟过渡到前中期，并在前中期的APC/C-介导的细胞周期蛋白A降解，EST 1的破坏是不必要的。
Background: The mitotic kinases, Cdk1, Aurora A/B, and Polo-like kinase 1 (Plk1) have been characterized extensively to further understanding of mitotic mechanisms and as potential targets for cancer therapy. Cdk1 and Aurora kinase studies have been facilitated by small-molecule inhibitors, but few if any potent Plk1 inhibitors have been identified.Results: We describe the cellular effects of a novel compound, BI 2536, a potent and selective inhibitor of Plk1. The fact that BI 2536 blocks Plk1 activity fully and instantaneously enabled us to study controversial and unknown functions of Plk1. Cells treated with BI 2536 are delayed in prophase but eventually import Cdk1-cyclin B into the nucleus, enter prometaphase, and degrade cyclin A, although BI 2536 prevents degradation of the APC/C inhibitor Emi1. BI 2536-treated cells lack prophase microtubule asters and thus polymerize mitotic microtubules only after nuclear-envelope breakdown and form monopolar spindles that do not stably attach to kinetochores. Mad2 accumulates at kinetochores, and cells arrest with an activated spindie-assembly checkpoint. BI 2536 prevents Plk1's enrichment at kinetochores and centrosomes, and when added to metaphase cells, it induces detachment of microtubules from kinetochores and leads to spindle collapse.Conclusions: Our results suggest that Plk1's accumulation at centrosomes and kinetochores depends on its own activity and that this activity is required for maintaining centrosome and kinetochore function. Our data also show that Plk1 is not required for prophase entry, but delays transition to prometaphase, and that Emi1 destruction in prometaphase is not essential for APC/C-mediated cyclin A degradation.