Dulić V, Stein G H, Far D F, Reed S I
CNRS-UMR 134, Université de Nice-Sophia Antipolis, Nice, France.
Mol Cell Biol. 1998 Jan;18(1):546-57. doi: 10.1128/MCB.18.1.546.
Cell cycle arrest in G1 in response to ionizing radiation or senescence is believed to be provoked by inactivation of G1 cyclin-cyclin-dependent kinases (Cdks) by the Cdk inhibitor p21(Cip1/Waf1/Sdi1). We provide evidence that in addition to exerting negative control of the G1/S phase transition, p21 may play a role at the onset of mitosis. In nontransformed fibroblasts, p21 transiently reaccumulates in the nucleus near the G2/M-phase boundary, concomitant with cyclin B1 nuclear translocation, and associates with a fraction of cyclin A-Cdk and cyclin B1-Cdk complexes. Premitotic nuclear accumulation of cyclin B1 is not detectable in cells with low p21 levels, such as fibroblasts expressing the viral human papillomavirus type 16 E6 oncoprotein, which functionally inactivates p53, or in tumor-derived cells. Moreover, synchronized E6-expressing fibroblasts show accelerated entry into mitosis compared to wild-type cells and exhibit higher cyclin A- and cyclin B1-associated kinase activities. Finally, primary embryonic fibroblasts derived from p21-/- mice have significantly reduced numbers of premitotic cells with nuclear cyclin B1. These data suggest that p21 promotes a transient pause late in G2 that may contribute to the implementation of late cell cycle checkpoint controls.
细胞周期因电离辐射或衰老而停滞于G1期，据信是由细胞周期蛋白依赖性激酶（Cdk）抑制剂p21（Cip1/Waf1/Sdi1）使G1期细胞周期蛋白-Cdk失活所引发的。我们提供的证据表明，除了对G1/S期转换发挥负调控作用外，p21可能在有丝分裂开始时发挥作用。在未转化的成纤维细胞中，p21在靠近G2/M期边界处的细胞核中短暂重新积累，这与细胞周期蛋白B1的核转位同时发生，并与一部分细胞周期蛋白A-Cdk和细胞周期蛋白B1-Cdk复合物相关联。在p21水平较低的细胞中，如表达病毒人乳头瘤病毒16型E6癌蛋白（其在功能上使p53失活）的成纤维细胞或肿瘤来源的细胞中，无法检测到有丝分裂前细胞周期蛋白B1的核积累。此外，与野生型细胞相比，同步化的表达E6的成纤维细胞进入有丝分裂的速度加快，并且表现出更高的细胞周期蛋白A和细胞周期蛋白B1相关激酶活性。最后，来自p21基因敲除小鼠的原代胚胎成纤维细胞中，有丝分裂前细胞核中含有细胞周期蛋白B1的细胞数量显著减少。这些数据表明，p21促进G2晚期的短暂停顿，这可能有助于实施细胞周期后期检查点控制。
