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Research Articles: Targets

Genotoxic-activated G₂-M checkpoint exit is dependent on CDC25B phosphatase expression

¹ Laboratoire de Biologie Cellulaire et Moléculaire du Contrôle de la Prolifération, Centre National de la Recherche Scientifique UMR5088- IFR109, Institut d'Exploration Fonctionnelle des Génomes, Université Paul Sabatier, Toulouse, France and ² IPSEN, Institut Henri Beaufour, Les Ulis, France

Requests for reprints: Bernard Ducommun, Laboratoire de Biologie Cellulaire et Moléculaire du Contrôle de la Prolifération, Centre National de la Recherche Scientifique UMR5088- IFR109, Institut d'Exploration Fonctionnelle des Génomes, Université Paul Sabatier, 118 route de narbonne, 31062 Toulouse, France. Phone: 33-5-61-55-62-10; Fax: 33-5-61-55-81-09. E-mail: ducommun{at}cict.fr

Cell cycle arrest at the G₂-M checkpoint is an essential feature of the mechanisms that preserve genomic integrity. CDC25 phosphatases control cell cycle progression by dephosphorylating and activating cyclin-dependent kinase/cyclin complexes. Their activities are, therefore, tightly regulated to modulate cell cycle arrest in response to DNA damage exposure. Here, we report that overexpression of CDC25B affects viability, reduces clonogenic efficiency, and increases sensitivity of cancer cells to a genotoxic agent. We show that ectopic expression of CDC25B results in bypass of a genotoxic-induced G₂-M checkpoint. In addition, cancer cells constitutively expressing high level of CDC25B are shown to be prone to exit prematurely from the G₂-M checkpoint arrest and to enter mitosis. Finally, we show that this exit is dependent on CDC25B expression. Together with previous results, our data strongly support a model in which CDC25B is the key phosphatase that controls entry into mitosis after DNA damage, thus emphasizing the relevance of its overexpression in many human tumors. [Mol Cancer Ther 2006;5(6):1446–51]

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Received 2/22/06; revised 4/12/06; accepted 4/21/06.