Inappropriate activation of cyclin-dependent kinases by the phosphatase Cdc25b results in premature mitotic entry and triggers a p53-dependent checkpoint.
The dual specificity phosphatase Cdc25B is capable of inhibiting cellular proliferation, and this occurs in a manner dependent upon its catalytic activity. Here it is shown that this is accompanied by inappropriate cyclin-dependent kinase activation and premature mitotic entry, leading to both p53-dependent and independent checkpoints. Forced expression of Cdc25B inappropriately up-regulated the activity of Cdk1 and Cdk2, by reducing levels of inhibitory phosphorylation. In cells lacking p14ARF, p53 is induced, and components of the ATM and ATR pathways are activated. Cdc25B triggers cell cycle arrest in the G(1) and G(2) phases that is p53- and p21-dependent and is inhibited by caffeine. Cdc25B also causes cells with an S phase DNA content to enter mitosis prematurely in a p53-independent manner. Synchronization of cells with aphidicolin results in these cells undergoing apoptosis. Thus, inappropriate cell cycle progression and premature mitotic entry via dysregulation of cyclin-dependent kinases results in activation of both p53-dependent and independent responses. Because Cdc25B is known to have oncogenic activity, this provides insight into the multistep nature of cancer development and why there is p53 loss during tumorigenesis.
Varmeh
Shohreh
S
Department of Oncological Sciences, Mount Sinai School of Medicine, New York, New York 10029, USA.
Manfredi
James J
JJ
D016203:CDC2 Protein Kinase / Q000378:metabolism*; D002110:Caffeine / Q000494:pharmacology; D002453:Cell Cycle; D002460:Cell Line; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism*; D004789:Enzyme Activation; D006801:Humans; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D020687:cdc25 Phosphatases / Q000235:genetics / Q000378:metabolism*
D016159:Tumor Suppressor Protein p53; D019000:Phosphotyrosine; D002110:Caffeine; D017346:Protein Serine-Threonine Kinases; D016203:CDC2 Protein Kinase; D051357:Cyclin-Dependent Kinase 2; D020687:cdc25 Phosphatases