ERK1/2 and p38 cooperate to delay progression through G1 by promoting cyclin D1 protein turnover

Ruth M Densham, Daniel E Todd, Kathy Balmanno, Simon J Cook

Research output: Contribution to journalArticlepeer-review

14 Citations (Scopus)


The conditional kinase DeltaMEKK3:ER allows activation of JNK, p38 and ERK1/2 without overt cellular stress or damage and has proved useful in understanding how these pathways regulate apoptosis and cell cycle progression. We have previously shown that activation of DeltaMEKK3:ER causes a sustained G(1) cell cycle arrest which requires p21(CIP1), with ERK1/2 and p38 cooperating to promote p21(CIP1) expression. In cells lacking p21(CIP1), DeltaMEKK3:ER causes only a transient delay in cell cycle re-entry. We now show that this delay in cell cycle re-entry is due to a reduction in cyclin D1 levels. Activation of DeltaMEKK3:ER promotes the proteasome-dependent turnover of cyclin D1; this requires phosphorylation of threonine 286 (T(286)) and expression of cyclin D1T(286)A rescues the delay in G(1)/S progression. DeltaMEKK3:ER-dependent phosphorylation of T(286) does not appear to be mediated by GSK3beta but requires activation of the ERK1/2 and p38 pathways. ERK1/2 can physically associate with cyclin D1 but activation of ERK1/2 alone is not sufficient for phosphorylation of T(286). Rather, cyclin D1 phosphorylation appears to require coincident activation of ERK1/2 and p38. Thus activation of DeltaMEKK3:ER promotes a sustained G(1) cell cycle arrest by a bipartite mechanism involving the rapid destruction of cyclin D1 and the slower more prolonged expression of p21(CIP1). This has parallels with the bipartite response to ionizing radiation and p53-independent mechanisms of G(1) cell cycle arrest in simple organisms such as yeast.
Original languageEnglish
Pages (from-to)1986-94
Number of pages9
JournalCellular Signalling
Issue number11
Publication statusPublished - Nov 2008


  • Amino Acid Motifs
  • Animals
  • Cell Line
  • Cyclin D1
  • Cyclin-Dependent Kinase Inhibitor p21
  • Down-Regulation
  • Enzyme Activation
  • G1 Phase
  • Glycogen Synthase Kinase 3
  • Humans
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mutation
  • Phosphorylation
  • Phosphothreonine
  • Proteasome Endopeptidase Complex
  • RNA, Messenger
  • Rats
  • p38 Mitogen-Activated Protein Kinases
  • raf Kinases


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