Aressy Bernadette, Bugler Béatrix, Valette Annie, Biard Denis, Ducommun Bernard
LBCMCP-CNRS-IFR109 Institut d'Exploration Fonctionnelle des Génomes, University of Toulouse, Toulouse, France.
Cell Cycle. 2008 Jul 15;7(14):2234-40. doi: 10.4161/cc.7.14.6305. Epub 2008 May 14.
CDC25B, one of the three members of the CDC25 dual-specificity phosphatase family, plays a critical role in the control of the cell cycle and in the checkpoint response to DNA damage. CDC25B is responsible for the initial dephosphorylation and activation of the cyclin-dependent kinases, thus initiating the train of events leading to entry into mitosis. The critical role played by CDC25B is illustrated by the fact that it is specifically required for checkpoint recovery and that unscheduled accumulation of CDC25B is responsible for illegitimate entry into mitosis. Here, we report that in p53(-/-) colon carcinoma cells, a moderate increase in the CDC25B level is sufficient to impair the DNA damage checkpoint, to increase spontaneous mutagenesis, and to sensitize cells to ionising radiation and genotoxic agents. Using a tumour cell spheroid assay as an alternative to animal studies, we demonstrate that the level of CDC25B expression modulates growth inhibition and apoptotic death. Since CDC25B overexpression has been observed in a significant number of human cancers, including colon carcinoma, and is often associated with high grade tumours and poor prognosis, our work suggests that the expression level of CDC25B might be a potential key parameter of the cellular response to cancer therapy.
细胞周期蛋白磷酸酶25B（CDC25B）是CDC25双特异性磷酸酶家族的三个成员之一，在细胞周期调控以及对DNA损伤的检查点反应中发挥关键作用。CDC25B负责细胞周期蛋白依赖性激酶的初始去磷酸化和激活，从而启动导致进入有丝分裂的一系列事件。CDC25B发挥的关键作用体现在以下事实上：检查点恢复特别需要它，而且CDC25B的异常积累会导致异常进入有丝分裂。在此，我们报告在p53基因敲除的结肠癌细胞中，CDC25B水平的适度升高足以损害DNA损伤检查点、增加自发突变，并使细胞对电离辐射和基因毒性剂敏感。使用肿瘤细胞球体测定法替代动物研究，我们证明CDC25B的表达水平调节生长抑制和凋亡性死亡。由于在包括结肠癌在内的大量人类癌症中都观察到了CDC25B的过表达，并且它通常与高级别肿瘤和不良预后相关，我们的研究表明CDC25B的表达水平可能是细胞对癌症治疗反应的一个潜在关键参数。
