Department of Gynecology and Obstetrics, Frankfurt, Germany.
1] Department of Hematology/Oncology, J W Goethe-University, Theodor-Stern-Kai 7, Frankfurt, Germany [2] Georg-Speyer-Haus, Frankfurt, Germany [3] German Cancer Consortium (DKTK), Heidelberg, Germany [4] German Cancer Research Center (DKFZ), Heidelberg, Germany.
Oncogene. 2014 Dec 11;33(50):5716-28. doi: 10.1038/onc.2013.518. Epub 2013 Dec 9.
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.
作为一种多功能分子，p21 在细胞周期调控、分化、凋亡、DNA 修复、衰老、老化和干细胞重编程中发挥着多种关键作用。p21 在细胞周期的间期的重要作用已经得到了深入研究。p21 在有丝分裂中的作用已经被提出，但没有系统地研究过。我们在这里表明，p21 在有丝分裂中丰富，并与 Cdk1/细胞周期蛋白 B1 结合并抑制其活性。p21 缺乏会通过延长中期、后期和胞质分裂来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，Aurora B 在中心纺锤体上的定位受到干扰。此外，HCT116 p21-/-, HeLa 和 Saos-2 细胞中 p21 的缺失会导致染色体分离和胞质分裂出现问题。温和抑制有丝分裂 Cdk1 或添加 p21 可挽救 HCT116 p21-/-细胞中的分离缺陷。我们的数据表明，p21 对于有丝分裂中 Cdk1 活性的精细调控非常重要，其正常功能有助于有丝分裂的顺利进行。鉴于 p21 在大多数肿瘤中都被下调，无论是由于肿瘤抑制因子如 p53 的缺失，还是由于癌基因如 c-myc 的过度激活，这一发现也为 p21 作为肿瘤抑制因子的分子机制提供了新的认识。
