Inactivation of Cdc2 increases the level of apoptosis induced by DNA damage.
A number of lines of evidence have suggested a possible involvement of the mitosis-promoting protein kinase Cdc2 in the process of apoptotic cell death, and one recent study concluded that premature activation of Cdc2 is required for apoptosis. Here we have used a temperature-sensitive murine Cdc2 mutant cell line and Cdc2 inhibitor compounds to study the effect of inhibition of this protein kinase on apoptosis induced by DNA-damaging drugs. Inhibition of Cdc2 activity before or during exposure to DNA strand break-inducing drugs had the effect of increasing the level of subsequent apoptosis, as assessed by electron microscopy and flow cytometry. We conclude that, far from being required for cell death, a form of mammalian Cdc2 suppresses apoptosis induced by DNA damage. This form of Cdc2 appears to be active in G2-arrested cells and is therefore presumably distinct from the mitosis-promoting Cdc2-cyclin B heterodimer.
Ongkeko
W
W
ICRF Molecular Oncology Laboratory, University of Oxford Institute of Molecular Medicine, UK.
Ferguson
D J
DJ
Harris
A L
AL
Norbury
C
C
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity; D017209:Apoptosis; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors*; D002453:Cell Cycle; D016923:Cell Death / Q000187:drug effects; D002467:Cell Nucleus / Q000648:ultrastructure; D004249:DNA Damage; D005260:Female; D005434:Flow Cytometry; D018922:HL-60 Cells; D006801:Humans; D008325:Mammary Neoplasms, Experimental; D051379:Mice; D008854:Microscopy, Electron; D008942:Mitoxantrone / Q000633:toxicity*; D008954:Models, Biological; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D008942:Mitoxantrone; D016203:CDC2 Protein Kinase