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ERK1/2 and p38 cooperate to induce a p21CIP1-dependent G1 cell cycle arrest

Daniel E Todd1, Ruth M Densham, Sarah A Molton

  • 1Signalling Programme, The Babraham Institute, Babraham Hall, Cambridge CB2 4AT, UK.

Oncogene
|February 26, 2004
PubMed

Insights

Mitogen- and stress-activated protein kinases (MAPK/SAPK) regulate cell cycle re-entry. DeltaMEKK3:ER* activation causes G1 arrest, dependent on p21CIP1 expression, impacting cell proliferation.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Mitogen- and stress-activated protein kinases (MAPK/SAPK) are crucial regulators of cellular processes, including cell cycle progression.
  • Understanding how these kinases control cell cycle re-entry is vital for deciphering cell proliferation and arrest mechanisms.

Purpose of the Study:

  • To investigate the role of specific MAPK/SAPK cascades in regulating the G1 to S phase transition during cell cycle re-entry.
  • To elucidate the mechanisms by which DeltaMEKK3:ER* activation influences cell cycle progression and the involvement of p21CIP1.

Main Methods:

  • Utilized conditional kinases to activate defined MAPK/SAPK cascades (DeltaMEKK3:ER*, DeltaRaf-1:ER*, DeltaMEKK1:ER*) in quiescent cells.
  • Assessed cell cycle progression (G1 arrest, S phase entry) and molecular markers (cyclin D1, Cdc25A, p21CIP1, CDK2 activity) in different cell lines (CCl39, Rat-1) and knockout models (p21CIP1-/-).

Main Results:

  • Activation of DeltaMEKK3:ER* strongly induced JNK1 and p38alpha, leading to sustained G1 arrest in CCl39 cells via p21CIP1 upregulation and CDK2 inhibition.
  • In Rat-1 cells with silenced p21CIP1 and in p21CIP1-/- cells, DeltaMEKK3:ER* caused only transient delays, highlighting p21CIP1's necessity for sustained arrest.
  • ERK1/2 and p38 pathways cooperated for p21CIP1 induction; p38 inhibition partially reversed the arrest. Selective ERK1/2 or JNK activation did not inhibit cell cycle re-entry.

Conclusions:

  • Activated DeltaMEKK3:ER* inhibits G1 to S phase progression through distinct mechanisms, with p21CIP1 expression being essential for a sustained G1 arrest.
  • The interplay between ERK1/2 and p38 pathways is critical for inducing p21CIP1 and mediating the cell cycle arrest.
  • JNK signaling alone does not appear to be a major antagonist of the G1 to S transition.

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