Keck Jamie M, Summers Matthew K, Tedesco Donato, Ekholm-Reed Susanna, Chuang Li-Chiou, Jackson Peter K, Reed Steven I
Department of Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037.
J Cell Biol. 2007 Jul 30;178(3):371-85. doi: 10.1083/jcb.200703202.
Overexpression of cyclin E, an activator of cyclin-dependent kinase 2, has been linked to human cancer. In cell culture models, the forced expression of cyclin E leads to aneuploidy and polyploidy, which is consistent with a direct role of cyclin E overexpression in tumorigenesis. In this study, we show that the overexpression of cyclin E has a direct effect on progression through the latter stages of mitotic prometaphase before the complete alignment of chromosomes at the metaphase plate. In some cases, such cells fail to divide chromosomes, resulting in polyploidy. In others, cells proceed to anaphase without the complete alignment of chromosomes. These phenotypes can be explained by an ability of overexpressed cyclin E to inhibit residual anaphase-promoting complex (APC(Cdh1)) activity that persists as cells progress up to and through the early stages of mitosis, resulting in the abnormal accumulation of APC(Cdh1) substrates as cells enter mitosis. We further show that the accumulation of securin and cyclin B1 can account for the cyclin E-mediated mitotic phenotype.
细胞周期蛋白E（一种细胞周期蛋白依赖性激酶2的激活剂）的过表达与人类癌症有关。在细胞培养模型中，细胞周期蛋白E的强制表达会导致非整倍体和多倍体，这与细胞周期蛋白E过表达在肿瘤发生中的直接作用一致。在本研究中，我们表明细胞周期蛋白E的过表达对有丝分裂前中期后期（在染色体在中期板完全排列之前）的进程有直接影响。在某些情况下，此类细胞无法分离染色体，导致多倍体。在其他情况下，细胞在染色体未完全排列的情况下进入后期。这些表型可以通过过表达的细胞周期蛋白E抑制残余后期促进复合物（APC（Cdh1））活性的能力来解释，随着细胞进入并经历有丝分裂早期阶段，该活性持续存在，导致细胞进入有丝分裂时APC（Cdh1）底物异常积累。我们进一步表明，securin和细胞周期蛋白B1的积累可以解释细胞周期蛋白E介导的有丝分裂表型。
