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

Oncogene volume 23, pages 3284–3295 (2004)Cite this article

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 ΔMEKK3:ER* during serum restimulation of quiescent cells causes a strong activation of JNK1 and p38α 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 p21CIP1 expression is silenced by methylation, ΔMEKK3: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 ΔMEKK3:ER*-induced G1 cell cycle arrest compared to their wild-type counterparts. These results suggest that activated ΔMEKK3: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 p38αβ pathways cooperated to induce p21CIP1 expression and inhibition of p38αβ caused a partial reversal of the cell cycle arrest. In contrast, selective activation of ERK1/2 by ΔRaf-1:ER* did not inhibit serum stimulated cell cycle re-entry. Finally, selective activation of JNK by ΔMEKK1: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.

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Acknowledgements

We thank Amer Mirza and Martin McMahon for provision of WT and p21CIP1−/− 3T3 cell lines and members of the Cook Lab for useful discussions and comments. We are grateful to Geoff Morgan for maintenance of the Babraham Institute FACS facility and for timely advice and help. This work was supported by Cancer Research UK (SP2458/0201), the BBSRC Science of Ageing Initiative (202/SAG10012) and a Competitive Strategic Grant from the BBSRC. CRW was supported by a MRC PhD studentship, SAM by a BBSRC PhD studentship and RMD by a BBSRC/CASE studentship with GSK. SJC is a Senior Cancer Research Fellow of Cancer Research UK.

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Author notes

  1. Daniel E Todd

    Present address: BioFocus Discovery, Cambridge Science Park, Cambridge, UK

  2. Sarah A Molton

    Present address: UCSF Cancer Centre, UCSF, Box 0128, San Francisco, CA, 94143, USA

  3. Claire R Weston

    Present address: Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, MA, 01605, USA

  4. Andrew P Garner

    Present address: Cancer and Infection Bioscience, AstraZeneca, Alderley Park, Macclesfield, SK10 4TG, UK

Authors and Affiliations

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

    Daniel E Todd, Ruth M Densham, Sarah A Molton, Kathryn Balmanno, Catherine Newson, Claire R Weston, Andrew P Garner & Simon J Cook

  2. The Beatson Institute for Cancer Research, Garscube Estate, Glasgow, G61 1BD, Scotland, UK

    Linda Scott

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Todd, D., Densham, R., Molton, S. et al. ERK1/2 and p38 cooperate to induce a p21CIP1-dependent G1 cell cycle arrest. Oncogene 23, 3284–3295 (2004). https://doi.org/10.1038/sj.onc.1207467

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