Role of cyclin B1/Cdc2 up-regulation in the development of mitotic prometaphase arrest in human breast cancer cells treated with nocodazole.
Role of cyclin B1/Cdc2 up-regulation in the development of mitotic prometaphase arrest in human breast cancer cells treated with nocodazole.
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DOI：
10.1371/journal.pone.0024312
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Zhu BT
中科院分区：
文献类型：
--
作者：
Choi HJ;Fukui M;Zhu BT
在正常的细胞周期中，从G2期到有丝分裂期的转变是由细胞周期蛋白B1依赖性Cdc 2激酶的激活触发的。在这里，我们报告我们的发现，治疗MCF-7人乳腺癌细胞与诺考达唑，一种原型微管抑制剂，在强烈的上调细胞周期蛋白B1和Cdc 2的水平，其增加所需的有丝分裂前中期阻滞和特征表型的发展。据观察，有一个时间依赖性的早期增加细胞周期蛋白B1和Cdc 2蛋白水平（峰值之间的12和24小时后处理），和他们的水平开始下降后，最初的增加。细胞周期蛋白B1和Cdc 2的这种早期上调与诺考达唑诱导的有丝分裂前中期阻滞的时间密切相关。选择性敲除细胞周期蛋白B1或Cdc 2，分别废除诺考达唑诱导的前中期细胞的积累。诺考达唑诱导的前中期阻滞也被废除的细胞与roscovitine，细胞周期蛋白依赖性激酶的抑制剂，或与放线菌酮，蛋白质合成抑制剂，被发现抑制细胞周期蛋白B1和Cdc 2上调预处理。此外，我们发现，MAD 2敲除nocodazole诱导的细胞周期蛋白B1和Cdc 2蛋白的积累，这是伴随着nocodazole诱导的前中期阻滞衰减。这些观察结果表明，细胞周期蛋白B1和Cdc 2的强烈的早期上调至关重要的贡献的快速和选择性的积累的前中期停滞的细胞，与暴露于微管抑制剂的现象。
During a normal cell cycle, the transition from G2 phase to mitotic phase is triggered by the activation of the cyclin B1-dependent Cdc2 kinase. Here we report our finding that treatment of MCF-7 human breast cancer cells with nocodazole, a prototypic microtubule inhibitor, results in strong up-regulation of cyclin B1 and Cdc2 levels, and their increases are required for the development of mitotic prometaphase arrest and characteristic phenotypes. It was observed that there was a time-dependent early increase in cyclin B1 and Cdc2 protein levels (peaking between 12 and 24 h post treatment), and their levels started to decline after the initial increase. This early up-regulation of cyclin B1 and Cdc2 closely matched in timing the nocodazole-induced mitotic prometaphase arrest. Selective knockdown of cyclin B1or Cdc2 each abrogated nocodazole-induced accumulation of prometaphase cells. The nocodazole-induced prometaphase arrest was also abrogated by pre-treatment of cells with roscovitine, an inhibitor of cyclin-dependent kinases, or with cycloheximide, a protein synthesis inhibitor that was found to suppress cyclin B1 and Cdc2 up-regulation. In addition, we found that MAD2 knockdown abrogated nocodazole-induced accumulation of cyclin B1 and Cdc2 proteins, which was accompanied by an attenuation of nocodazole-induced prometaphase arrest. These observations demonstrate that the strong early up-regulation of cyclin B1 and Cdc2 contributes critically to the rapid and selective accumulation of prometaphase-arrested cells, a phenomenon associated with exposure to microtubule inhibitors.
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