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p14ARF triggers G2 arrest through ERK-mediated Cdc25C phosphorylation, ubiquitination and proteasomal degradation

Beatrice Eymin1, Paule Claverie, Caroline Salon

  • 1INSERM U578, Groupe de Recherche sur le Cancer du Poumon, Université Joseph Fourier, La Tronche, France. Beatrice.Eymin@ujf-grenoble.fr

Cell Cycle (Georgetown, Tex.)
|April 4, 2006
PubMed

Insights

The p14ARF tumor suppressor triggers a p53-independent G2 arrest by activating ERK1/2 MAP kinases. This pathway phosphorylates Cdc25C at Ser216, leading to its degradation and cell cycle arrest.

Area of Science:

  • Cell Biology
  • Molecular Oncology
  • Signal Transduction

Background:

  • Cdc25C phosphatase regulates mitotic entry, with phosphorylation at Ser216 inducing inactivation via 14-3-3 binding.
  • p14ARF, a tumor suppressor, previously shown to induce inactive Cdc25C(Ser216) and p53-independent G2 arrest.

Purpose of the Study:

  • Investigate the signaling pathways mediating p14ARF-induced G2 arrest.
  • Identify the role of ERK1/2 MAP kinases in this process.
  • Determine if Cdc25C is a direct target of ERK1/2.

Main Methods:

  • Utilized pharmacological inhibitors to probe signaling pathways.
  • Assessed protein levels and phosphorylation status of Cdc25C and ERK1/2.
  • Investigated protein-protein interactions and ubiquitination/degradation pathways.

Main Results:

  • p14ARF expression activates the ERK1/2 MAP kinase pathway, inducing a p53-independent G2 checkpoint.
  • Activated ERK1/2 directly phosphorylates Cdc25C at Ser216, identifying Cdc25C as a novel ERK1/2 target.
  • Phosphorylation at Ser216 by ERK1/2 promotes Cdc25C ubiquitination and proteasomal degradation, essential for sustained G2 arrest.

Conclusions:

  • The MAPK ERK signaling pathway is crucial for p14ARF's p53-independent antiproliferative functions.
  • p14ARF-induced G2 arrest involves ERK1/2-mediated phosphorylation and subsequent degradation of Cdc25C.
  • This study reveals a new mechanism for Cdc25C inactivation through Ser216 phosphorylation and proteolysis.

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