CDC25 phosphatases in cancer cells: key players? Good targets?

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Abstract
Cell division cycle 25 (CDC25) phosphatases are key regulators of the eukaryotic cell cycle. They are required to control cyclin-dependent kinase (CDK) dephosphorylation and activation in a strict spatio-temporal manner. CDC25A, B and C expression and activity is tightly regulated by many mechanisms, including alternative exon splicing, phosphorylation–dephosphorylation cycles, interactions with partners such as 14-3-3 proteins, intracellular localization and cell-cycle controlled degradation. CDC25 phosphatases are key targets of the checkpoint machinery activated in response to DNA damage. They are functionally inactivated or degraded to stop cell-cycle progression. CDC25B activity is required for checkpoint recovery. CDC25A and CDC25B overexpression are frequently found in many cancers, and are often associated with high-grade tumours and poor prognosis. The contribution of CDC25 phosphatases to tumorigenesis might be related to the genetic instability associated with the checkpoint-abrogating effect of their overexpression. Compounds that inhibit CDC25 phosphatase activities are currently being developed. The most potent quinonoid-based compounds identified so far are active on xenografted tumour models.