Cell division cycle 25 (CDC25) phosphatases regulate key transitions between cell cycle phases during normal cell division, and in the event of DNA damage they are key targets of the checkpoint machinery that ensures genetic stability. Taking only this into consideration, it is not surprising that CDC25 overexpression has been reported in a significant number of human cancers. However, in light of the significant body of evidence detailing the stringent complexity with which CDC25 activities are regulated, the significance of CDC25 overexpression in a subset of cancers and its association with poor prognosis are proving difficult to assess. We will focus on the roles of CDC25 phosphatases in both normal and abnormal cell proliferation, provide a critical assessment of the current data on CDC25 overexpression in cancer, and discuss both current and future therapeutic strategies for targeting CDC25 activity in cancer treatment.

No abstract

CDC25B is one of the three human phosphatases that activate the CDK-cyclin complexes, thereby triggering cell-cycle progression and division. Commitment to early mitotic events depends on the activation of a centrosomal pool of CDK1–cyclin-B1, and CDC25B is thought to be involved in initiating this centrosomal CDK1–cyclin-B1 activity. Centrosome-associated checkpoint kinase 1 (CHK1) has been proposed to contribute to the proper timing of a normal cell division cycle by inhibiting the activation of the centrosomal pool of CDK1. Here, we show that CDC25B is phosphorylated by CHK1 in vitro on multiple residues, including S230 and S563. We demonstrate these phosphorylations occur in vivo and that they are dependent on CHK1 activity. S230 CHK1-mediated phosphorylation is detected in cell extracts during S phase and G2 phase in the absence of DNA damage. We show that the S230-phosphorylated form of CDC25B is located at the centrosome from early S phase until mitosis. Furthermore, mutation of S230 to alanine increases the mitotic-inducing activity of CDC25B. Our results support a model in which, under normal cell cycle conditions and in the absence of DNA damage, CHK1 constitutively phosphorylates CDC25B during interphase and thus prevents the premature initiation of mitosis by negatively regulating the activity of CDC25B at the centrosome.