Genotoxic-activated G2-M checkpoint exit is dependent on CDC25B phosphatase expression.
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.
Bugler
Béatrix
B
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.
Quaranta
Muriel
M
Aressy
Bernadette
B
Brezak
Marie-Christine
MC
Prevost
Grégoire
G
Ducommun
Bernard
B
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004249:DNA Damage / Q000187:drug effects / Q000502:physiology; D005047:Etoposide / Q000494:pharmacology; D005434:Flow Cytometry; D019084:Fluorescent Antibody Technique, Indirect; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology; D013752:Tetracycline / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay; D020687:cdc25 Phosphatases / Q000235:genetics / Q000378:metabolism*
D000972:Antineoplastic Agents, Phytogenic; D018797:Cell Cycle Proteins; D005047:Etoposide; C517008:CDC25B protein, human; D020687:cdc25 Phosphatases; D013752:Tetracycline