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

Research output: Contribution to journalArticle

Authors

  • Daniel E Todd
  • Sarah A Molton
  • Kathryn Balmanno
  • Catherine Newson
  • Claire R Weston
  • Andrew P Garner
  • Linda Scott
  • Simon J Cook

Abstract

To study the mechanisms by which mitogen- and stress-activated protein kinases regulate cell cycle re-entry, we have used a panel of conditional kinases that stimulate defined MAPK or SAPK cascades. Activation of DeltaMEKK3:ER* during serum restimulation of quiescent cells causes a strong activation of JNK1 and p38alpha but only a modest potentiation of serum-stimulated ERK1/2 activity. In CCl39 cells this promoted a sustained G1 arrest that correlated with decreased expression of cyclin D1 and Cdc25A, increased expression of p21CIP1 and inhibition of CDK2 activity. In Rat-1 cells, in which p21(CIP1) expression is silenced by methylation, DeltaMEKK3:ER* activation caused only a transient delay in the S phase entry rather than a sustained G1 arrest. Furthermore, p21CIP1-/- 3T3 cells were defective for the DeltaMEKK3:ER*-induced G1 cell cycle arrest compared to their wild-type counterparts. These results suggest that activated DeltaMEKK3:ER* inhibits the G1 --> S progression by two kinetically distinct mechanisms, with expression of p21CIP1 being required to ensure a sustained G1 cell cycle arrest. The ERK1/2 and p38alphabeta pathways cooperated to induce p21CIP1 expression and inhibition of p38alphabeta caused a partial reversal of the cell cycle arrest. In contrast, selective activation of ERK1/2 by DeltaRaf-1:ER* did not inhibit serum stimulated cell cycle re-entry. Finally, selective activation of JNK by DeltaMEKK1:ER* failed to inhibit cell cycle re-entry, even in cells that retained wild-type p53, arguing against a major role for JNK alone in antagonizing the G1 --> S transition.

Bibliographic note

Copyright 2004 Nature Publishing Group

Details

Original languageEnglish
Pages (from-to)3284-95
Number of pages12
JournalOncogene
Volume23
Issue number19
Publication statusPublished - 22 Apr 2004

Keywords

  • 3T3 Cells, Animals, Cyclin-Dependent Kinase Inhibitor p21, Cyclins, G1 Phase, Mice, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Mitogen-Activated Protein Kinases, Phosphorylation, RNA, Messenger, Rats, Retinoblastoma Protein, S Phase, Tamoxifen, Tumor Suppressor Protein p53, p38 Mitogen-Activated Protein Kinases