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

EMBO J. 2002 Nov 1;21(21):5911-20. doi: 10.1093/emboj/cdf567.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • CDC2 Protein Kinase / metabolism
  • Cyclin B / metabolism
  • DNA Damage
  • Enzyme Stability
  • G2 Phase*
  • Humans
  • Mitosis*
  • Molecular Sequence Data
  • Phosphorylation
  • Serine / metabolism
  • Ubiquitin / metabolism
  • cdc25 Phosphatases / chemistry
  • cdc25 Phosphatases / metabolism*


  • Cyclin B
  • Ubiquitin
  • Serine
  • CDC2 Protein Kinase
  • CDC25A protein, human
  • cdc25 Phosphatases