Université de Toulouse, LBCMCP, Toulouse, France.
Mol Cancer. 2010 Feb 4;9:29. doi: 10.1186/1476-4598-9-29.
CDC25B phosphatase is a cell cycle regulator that plays a critical role in checkpoint control. Up-regulation of CDC25B expression has been documented in a variety of human cancers, however, the relationships with the alteration of the molecular mechanisms that lead to oncogenesis still remain unclear. To address this issue we have investigated, in model cell lines, the consequences of unscheduled and elevated CDC25B levels.
We report that increased CDC25B expression leads to DNA damage in the absence of genotoxic treatment. H2AX phosphorylation is detected in S-phase cells and requires active replication. We also report that CDC25B expression impairs DNA replication and results in an increased recruitment of the CDC45 replication factor onto chromatin. Finally, we observed chromosomal aberrations that are also enhanced upon CDC25B expression.
Overall, our results demonstrate that a moderate and unscheduled increase in CDC25B level, as observed in a number of human tumours, is sufficient to overcome the S-phase checkpoint efficiency thus leading to replicative stress and genomic instability.
CDC25B 磷酸酶是一种细胞周期调节剂，在检查点控制中起着关键作用。已经在多种人类癌症中记录了 CDC25B 表达的上调，然而，与导致癌变的分子机制改变的关系仍然不清楚。为了解决这个问题，我们在模型细胞系中研究了未计划和升高的 CDC25B 水平的后果。
我们报告说，在没有遗传毒性处理的情况下，增加 CDC25B 的表达会导致 DNA 损伤。在 S 期细胞中检测到 H2AX 磷酸化，这需要活跃的复制。我们还报告说，CDC25B 的表达会损害 DNA 复制，并导致 CDC45 复制因子更多地招募到染色质上。最后，我们观察到染色体异常，这些异常在 CDC25B 表达时也会增强。
总的来说，我们的结果表明，在许多人类肿瘤中观察到的 CDC25B 水平的适度和未计划的增加足以克服 S 期检查点效率，从而导致复制应激和基因组不稳定性。
