Human Cdc14B Promotes Progression through Mitosis by Dephosphorylating Cdc25 and Regulating Cdk1/Cyclin B Activity
Human Cdc14B Promotes Progression through Mitosis by Dephosphorylating Cdc25 and Regulating Cdk1/Cyclin B Activity
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DOI：
10.1371/journal.pone.0014711
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发表时间：
2011-02-17
期刊：
影响因子：
3.7
通讯作者：
Voit, Renate
中科院分区：
文献类型：
--
作者：
Tumurbaatar, Indra;Cizmecioglu, Onur;Voit, Renate
进入和通过有丝分裂的进展取决于关键底物的磷酸化和去磷酸化。在酵母中，核仁磷酸酶Cdc 14是关键的退出有丝分裂抵消Cdk 1依赖的磷酸化。hCdc 14 B，酵母Cdc 14的人类同源物，是否在有丝分裂中发挥类似的功能尚不清楚。在这里，我们表明，hCdc 14 B通过有丝分裂，这是从hCdc 14 A不同的调节进程中发挥关键作用。hCdc 14 B的非程序性过表达延迟了有丝分裂的两个主要调节因子Cdc 25和Cdk 1的激活，并减缓了有丝分裂的进入。通过RNAi去除hCdc 14 B，阻止了Cdk 1/cyclin B的及时失活和Cdc 25的去磷酸化，导致严重的有丝分裂缺陷，如中期/后期转换延迟、染色体落后、多极纺锤体和双核化。结果表明，Cdc 25磷酸酶和Cdk 1/细胞周期蛋白B活性的hCdc 14 B依赖性调节与正确的染色体分离和双极纺锤体形成紧密相关，这些过程是通过有丝分裂和维持基因组稳定性进行适当进展所需的。
Entry into and progression through mitosis depends on phosphorylation and dephosphorylation of key substrates. In yeast, the nucleolar phosphatase Cdc14 is pivotal for exit from mitosis counteracting Cdk1-dependent phosphorylations. Whether hCdc14B, the human homolog of yeast Cdc14, plays a similar function in mitosis is not yet known. Here we show that hCdc14B serves a critical role in regulating progression through mitosis, which is distinct from hCdc14A. Unscheduled overexpression of hCdc14B delays activation of two master regulators of mitosis, Cdc25 and Cdk1, and slows down entry into mitosis. Depletion of hCdc14B by RNAi prevents timely inactivation of Cdk1/cyclin B and dephosphorylation of Cdc25, leading to severe mitotic defects, such as delay of metaphase/anaphase transition, lagging chromosomes, multipolar spindles and binucleation. The results demonstrate that hCdc14B-dependent modulation of Cdc25 phosphatase and Cdk1/cyclin B activity is tightly linked to correct chromosome segregation and bipolar spindle formation, processes that are required for proper progression through mitosis and maintenance of genomic stability.