Spruck C H, Won K A, Reed S I
Department of Molecular Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
Nature. 1999 Sep 16;401(6750):297-300. doi: 10.1038/45836.
Cyclin E, a regulatory subunit of cyclin-dependent kinase 2 (Cdk2), is an important regulator of entry into S phase in the mammalian cell cycle. In normal dividing cells, cyclin E accumulates at the G1/S-phase boundary and is degraded as cells progress through S phase. However, in many human tumours cyclin E is overexpressed and the levels of protein and kinase activity are often deregulated relative to the cell cycle. It is not understood how alterations in expression of cyclin E contribute to tumorigenesis. Here we show that constitutive cyclin-E overexpression in both immortalized rat embryo fibroblasts and human breast epithelial cells results in chromosome instability (CIN). In contrast, analogous expression of cyclin D1 or A does not increase the frequency of CIN. Cyclin-E-expressing cells that exhibit CIN have normal centrosome numbers. However, constitutive overexpression of cyclin E impairs S-phase progression, indicating that aberrant regulation of this process may be responsible for the CIN observed. These results indicate that downregulation of cyclin-E/Cdk2 kinase activity following the G1/S-phase transition may be necessary for the maintenance of karyotypic stability.
细胞周期蛋白E是细胞周期蛋白依赖性激酶2（Cdk2）的调节亚基，是哺乳动物细胞周期进入S期的重要调节因子。在正常分裂细胞中，细胞周期蛋白E在G1/S期边界积累，并随着细胞进入S期而降解。然而，在许多人类肿瘤中，细胞周期蛋白E过度表达，其蛋白质水平和激酶活性相对于细胞周期常常失调。目前尚不清楚细胞周期蛋白E表达的改变如何促进肿瘤发生。在此我们表明，在永生化大鼠胚胎成纤维细胞和人乳腺上皮细胞中持续过表达细胞周期蛋白E会导致染色体不稳定（CIN）。相比之下，细胞周期蛋白D1或A的类似表达不会增加CIN的频率。表现出CIN的细胞周期蛋白E表达细胞具有正常的中心体数量。然而，细胞周期蛋白E的持续过表达会损害S期进程，表明该过程的异常调节可能是观察到的CIN的原因。这些结果表明，G1/S期转变后细胞周期蛋白E/Cdk2激酶活性的下调可能是维持核型稳定性所必需的。
