title: Moderate variations in CDC25B protein levels modulate the response to DNA damaging agents.
abstract: 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.
authors.affiliation: LBCMCP-CNRS-IFR109 Institut d'Exploration Fonctionnelle des Génomes, University of Toulouse, Toulouse, France.
authors.forename: Bernadette
authors.initials: B
authors.lastname: Aressy
authors.forename: Béatrix
authors.initials: B
authors.lastname: Bugler
authors.forename: Annie
authors.initials: A
authors.lastname: Valette
authors.forename: Denis
authors.initials: D
authors.lastname: Biard
authors.forename: Bernard
authors.initials: B
authors.lastname: Ducommun
mesh_terms: D016923:Cell Death / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D004249:DNA Damage; D004317:Doxorubicin / Q000633:toxicity; D005047:Etoposide / Q000633:toxicity; D005720:Gamma Rays; D042822:Genomic Instability / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D009153:Mutagens / Q000633:toxicity*; D018874:Spheroids, Cellular / Q000187:drug effects / Q000201:enzymology / Q000528:radiation effects; D020687:cdc25 Phosphatases / Q000378:metabolism*
chemical_list: D009153:Mutagens; D005047:Etoposide; D004317:Doxorubicin; D020687:cdc25 Phosphatases