Regulation of G(2)/M events by Cdc25A through phosphorylation-dependent modulation of its stability

DNA replication in higher eukaryotes requires activation of a Cdk2 kinase by Cdc25A, a labile phosphatase subject to further destabilization upon genotoxic stress. We describe a distinct, markedly stable form of Cdc25A, which plays a previously unrecognized role in mitosis. Mitotic stabilization of...

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Bibliographic Details
Published in:The EMBO journal 2002-11, Vol.21 (21), p.5911
Main Authors: Mailand, Niels, Podtelejnikov, Alexandre V, Groth, Anja, Mann, Matthias, Bartek, Jiri, Lukas, Jiri
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Animals
CDC2 Protein Kinase - metabolism
cdc25 Phosphatases - chemistry
cdc25 Phosphatases - metabolism
Cyclin B - metabolism
DNA Damage
Enzyme Stability
G2 Phase
Humans
Mitosis
Molecular Sequence Data
Phosphorylation
Serine - metabolism
Ubiquitin - metabolism
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Summary:DNA replication in higher eukaryotes requires activation of a Cdk2 kinase by Cdc25A, a labile phosphatase subject to further destabilization upon genotoxic stress. We describe a distinct, markedly stable form of Cdc25A, which plays a previously unrecognized role in mitosis. Mitotic stabilization of Cdc25A reflects its phosphorylation on Ser17 and Ser115 by cyclin B-Cdk1, modifications required to uncouple Cdc25A from its ubiquitin-proteasome-mediated turnover. Cdc25A binds and activates cyclin B-Cdk1, accelerates cell division when overexpressed, and its downregulation by RNA interference (RNAi) delays mitotic entry. DNA damage-induced G(2) arrest, in contrast, is accompanied by proteasome-dependent destruction of Cdc25A, and ectopic Cdc25A abrogates the G(2) checkpoint. Thus, phosphorylation-mediated switches among three differentially stable forms ensure distinct thresholds, and thereby distinct roles for Cdc25A in multiple cell cycle transitions and checkpoints.
ISSN:0261-4189
DOI:10.1093/emboj/cdf567