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p21CIP1 and Cdc25A: competition between an inhibitor and an activator of cyclin-dependent kinases

P Saha1, Q Eichbaum, E D Silberman

  • 1Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.

Molecular and Cellular Biology
|August 1, 1997
PubMed

Insights

The oncogene Cdc25A counterbalances growth suppressors by competing for cyclin-dependent kinases (cdks). A novel motif in Cdc25A mediates cyclin binding, protecting cdks from inhibitors like p21CIP1.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Oncogenesis

Background:

  • Cdc25A phosphatase is crucial for cell cycle progression at the G1-S transition.
  • Cyclin-dependent kinase (cdk) inhibitors p21CIP1 and p27 are induced by growth-suppressive signals.
  • Oncogenic pathways involving Myc and Cdc25A can counteract tumor-suppressive pathways mediated by p53 and TGF-beta.

Purpose of the Study:

  • To elucidate the mechanism by which Cdc25A interacts with cyclin-cdks.
  • To investigate the functional significance of a newly identified cyclin binding motif in Cdc25A.
  • To understand how Cdc25A and p21CIP1 regulate cyclin-cdk activity and DNA replication.

Main Methods:

  • Site-directed mutagenesis of the Cdc25A cyclin binding motif.
  • In vitro and in vivo association assays for Cdc25A and cyclin-cdks.
  • Peptide inhibition assays using a p21CIP1-derived motif.
  • Xenopus egg extract assays to assess DNA replication inhibition.

Main Results:

  • A novel N-terminal cyclin binding motif (Cy motif) was identified in Cdc25A.
  • Mutations in this motif disrupted Cdc25A association with cyclin E-cdk2 and cyclin A-cdk2.
  • The Cy motif peptide inhibited Cdc25A-cyclin-cdk association and kinase dephosphorylation.
  • Cdc25A protected cyclin-cdks and DNA replication from p21CIP1 inhibition.

Conclusions:

  • Cdc25A utilizes a Cy motif to bind and activate cyclin-cdks, promoting cell cycle progression.
  • Cdc25A antagonizes the inhibitory effects of p21CIP1 on cyclin-cdks.
  • This competitive interaction between oncogenic Cdc25A and tumor-suppressive p21CIP1 provides a mechanism for pathway counterbalance.

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