TY - JOUR
T1 - Regulation of G(2)/M events by Cdc25A through phosphorylation-dependent modulation of its stability.
AU - Mailand, Niels
AU - Podtelejnikov, Alexandre V
AU - Groth, Anja
AU - Mann, Matthias
AU - Bartek, Jiri
AU - Lukas, Jiri
N1 - Keywords: Amino Acid Sequence; Animals; CDC2 Protein Kinase; Cyclin B; DNA Damage; Enzyme Stability; G2 Phase; Humans; Mitosis; Molecular Sequence Data; Phosphorylation; Serine; Ubiquitin; cdc25 Phosphatases
PY - 2002
Y1 - 2002
N2 - 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.
AB - 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.
U2 - 10.1093/emboj/cdf567
DO - 10.1093/emboj/cdf567
M3 - Journal article
C2 - 12411508
VL - 21
SP - 5911
EP - 5920
JO - E M B O Journal
JF - E M B O Journal
SN - 0261-4189
IS - 21
ER -