p21Waf1/Cip1 deficiency causes multiple mitotic defects in tumor cells
p21Waf1/Cip1 deficiency causes multiple mitotic defects in tumor cells
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DOI：
10.1038/onc.2013.518
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发表时间：
2014-12-11
期刊：
影响因子：
8
通讯作者：
Yuan, J.
中科院分区：
文献类型：
--
作者：
Kreis, N-N;Sanhaji, M.;Yuan, J.
作为一个多方面的分子，p21在细胞周期调控、分化、凋亡、DNA修复、衰老、衰老和干细胞重编程中起着多个关键作用。p21在细胞周期的间期中的重要作用已被深入研究。p21在有丝分裂中的功能已被提出，但尚未系统研究。我们在这里表明，p21是丰富的有丝分裂和结合，并抑制Cdk 1/细胞周期蛋白B1的活性。p21蛋白的缺失通过延长有丝分裂中期、后期和胞质分裂期延长有丝分裂的持续时间。在没有p21的后期细胞中，Aurora B的活性降低，并且Aurora B在中央纺锤体上的定位受到干扰。此外，缺失p21的HCT 116 p21（-/-）、HeLa和Saos-2细胞在染色体分离和胞质分裂中遇到问题。温和地抑制有丝分裂Cdk 1或p21的反向添加挽救了HCT 116 p21（-/-）细胞中的分离缺陷。我们的数据表明，p21是重要的微调控制的Cdk 1活性在有丝分裂，其适当的功能有利于顺利的有丝分裂进程。鉴于p21在大多数肿瘤中被下调，无论是通过肿瘤抑制因子如p53的丢失还是通过过度活跃的癌基因如c-myc，这一发现也为p21作为肿瘤抑制因子发挥作用的分子机制提供了新的线索。
As a multifaceted molecule, p21 plays multiple critical roles in cell cycle regulation, differentiation, apoptosis, DNA repair, senescence, aging and stem cell reprogramming. The important roles of p21 in the interphase of the cell cycle have been intensively investigated. The function of p21 in mitosis has been proposed but not systematically studied. We show here that p21 is abundant in mitosis and binds to and inhibits the activity of Cdk1/cyclin B1. Deficiency of p21 prolongs the duration of mitosis by extending metaphase, anaphase and cytokinesis. The activity of Aurora B is reduced and the localization of Aurora B on the central spindle is disturbed in anaphase cells without p21. Moreover, HCT116 p21(-/-), HeLa and Saos-2 cells depleted of p21 encounter problems in chromosome segregation and cytokinesis. Gently inhibiting the mitotic Cdk1 or add-back of p21 rescues segregation defect in HCT116 p21(-/-) cells. Our data demonstrate that p21 is important for a fine-tuned control of the Cdk1 activity in mitosis, and its proper function facilitates a smooth mitotic progression. Given that p21 is downregulated in the majority of tumors, either by the loss of tumor suppressors like p53 or by hyperactive oncogenes such as c-myc, this finding also sheds new light on the molecular mechanisms by which p21 functions as a tumor suppressor.