When the checkpoints have gone: insights into Cdc25 functional activation.
DNA-responsive checkpoints operate at the G(2)/M transition to prevent premature mitosis in the presence of incompletely replicated or damaged DNA. These pathways prevent mitotic entry, at least in part, by suppressing Cdc25, the phosphatase that activates Cdc2/Cyclin B. To gain insight into how checkpoint signaling controls Cdc25 function, we have carefully examined the individual steps in Cdc25 activation. We found that removal of the regulatory protein, 14-3-3, that binds to phosphorylated Cdc25 during interphase is one of the early steps in mitotic activation. Moreover, our studies unexpectedly implicated the phosphatase PP1 and the G(1)/S kinase Cdk2 in the process of Cdc25 activation. Here we integrate our findings and those of others to propose a model for Cdc25 activation in an effort to provide insight into novel loci of DNA-responsive checkpoint control of mitotic entry.
Margolis
Seth S
SS
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Kornbluth
Sally
S
D048948:14-3-3 Proteins; D000818:Animals; D042846:CDC2-CDC28 Kinases / Q000378:metabolism; D002384:Catalysis; D051357:Cyclin-Dependent Kinase 2; D004247:DNA / Q000378:metabolism; D004249:DNA Damage; D004789:Enzyme Activation; D016193:G1 Phase; D016195:G2 Phase; D007399:Interphase; D008938:Mitosis; D008954:Models, Biological; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D010766:Phosphorylation; D016196:S Phase; D015398:Signal Transduction; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D014981:Xenopus; D029867:Xenopus Proteins; D020687:cdc25 Phosphatases / Q000378:metabolism*
D048948:14-3-3 Proteins; D029867:Xenopus Proteins; D004247:DNA; D014446:Tyrosine 3-Monooxygenase; D042846:CDC2-CDC28 Kinases; C495891:Cdk2 protein, Xenopus; D051357:Cyclin-Dependent Kinase 2; D010744:Phosphoric Monoester Hydrolases; D020687:cdc25 Phosphatases