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Activation of ERK1/2 by ΔRaf-1 : ER* represses Bim expression independently of the JNK or PI3K pathways

Oncogene volume 22, pages 1281–1293 (2003)Cite this article

Abstract

CC139 fibroblasts are one of several model systems in which the Raf→MEK→ERK1/2 pathway can inhibit apoptosis independently of the PI3K pathway; however, the precise mechanism for this protective effect is not known. Serum withdrawal from CC139 fibroblasts resulted in the rapid onset of apoptosis, which was prevented by actinomycin D or cycloheximide. Serum withdrawal promoted the rapid, de novo accumulation of BimEL, a proapoptotic ‘BH3-only’ member of the Bcl-2 protein family. BimEL expression was an early event, occurring several hours prior to caspase activation. In contrast to studies in neurons, activation of the JNK→c-Jun pathway was neither necessary nor sufficient to induce BimEL expression. Selective inhibition of either the ERK pathway (with U0126) or the PI3K pathway (with LY294002) caused an increase in the expression of BimEL. Furthermore, selective activation of the ERK1/2 pathway by ΔRaf-1:ER* substantially reduced BimEL expression, abolished conformational changes in Bax and blocked the appearance of apoptotic cells. The ability of ΔRaf-1:ER* to repress BimEL expression required the ERK pathway but was independent of the PI3K→PDK→PKB pathway. Thus, serum withdrawal-induced expression of BimEL occurs independently of the JNK→c-Jun pathway and can be repressed by the ERK pathway independently of the PI3K pathway. This may contribute to Raf- and Ras-induced cell survival at low serum concentrations.

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Acknowledgements

We thank members of the Cook Group and Inositide Laboratory for discussions and comments on the study. We are grateful to Jonathan Ham and Jonathan Whitfield for discussion of their results prior to publication, Martin McMahon for provision of the ΔRaf-1:ER* cDNA, Michela Marani for advice on the N-20 Bax IP protocol and Paul Evans for advice on real-time RT–PCR analysis. We thank Geoff Morgan for maintenance of the Babraham Institute Flow Cytometry Facility and timely advice throughout this study. CW thanks the MRC and CC and SM the BBSRC for PhD studentships. This work was funded by Cancer Research UK (SP2458/0201), a project grant from the BBSRC (202/C15785) and a Competitive Strategic Grant from the BBSRC. SJC is a Senior Cancer Research Fellow of Cancer Research UK.

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  1. Claire R Weston, Kathryn Balmanno: These authors contributed equally to this study

Authors and Affiliations

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

    Claire R Weston, Kathryn Balmanno, Claire Chalmers, Kathryn Hadfield, Sarah A Molton, Rebecca Ley & Simon J Cook

  2. Research Institute of Molecular Pathology (IMP), Dr Bohr-Gasse 7, Vienna, A-1030, Austria

    Erwin F Wagner

  3. Howard Hughes Medical Institute, University of Massachusetts Medical School, Suite 306, 373 Plantation St., Worcester, MA 01605, USA

    Claire R Weston

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Correspondence to Simon J Cook.

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Weston, C., Balmanno, K., Chalmers, C. et al. Activation of ERK1/2 by ΔRaf-1 : ER* represses Bim expression independently of the JNK or PI3K pathways. Oncogene 22, 1281–1293 (2003). https://doi.org/10.1038/sj.onc.1206261

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