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 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.
Mailand
Niels
N
Danish Cancer Society, Institute of Cancer Biology, Strandboulevarden 49, DK-2100 Copenhagen Ø, Denmark
Podtelejnikov
Alexandre V
AV
Groth
Anja
A
Mann
Matthias
M
Bartek
Jiri
J
Lukas
Jiri
J
D000595:Amino Acid Sequence; D000818:Animals; D016203:CDC2 Protein Kinase / Q000378:metabolism; D019926:Cyclin B / Q000378:metabolism; D004249:DNA Damage; D004795:Enzyme Stability; D016195:G2 Phase; D006801:Humans; D008938:Mitosis; D008969:Molecular Sequence Data; D010766:Phosphorylation; D012694:Serine / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism; D020687:cdc25 Phosphatases / Q000737:chemistry / Q000378:metabolism*
D019926:Cyclin B; D025801:Ubiquitin; D012694:Serine; D016203:CDC2 Protein Kinase; C517004:CDC25A protein, human; D020687:cdc25 Phosphatases