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Selective activation of the c-Jun N-terminal kinase (JNK) pathway fails to elicit Bax activation or apoptosis unless the phosphoinositide 3′-kinase (PI3K) pathway is inhibited

Oncogene volume 22, pages 4690–4701 (2003)Cite this article

Abstract

c-Jun N-terminal kinase (JNK) is activated when cells are exposed to noxious stimuli. The role of JNK in apoptosis is subject to considerable debate; for example, JNK activation may promote or inhibit apoptosis depending on the cell type and stimulus involved. These conflicting results have arisen in part because few studies have successfully separated JNK activation from the primary stress-induced damage or from other stress-induced signalling pathways. Here we describe a conditional mutant, ΔMEKK1:ER*, which allows selective activation of the JNK cascade in the absence of any cellular stress. Activation of ΔMEKK1:ER* in CC139 fibroblasts resulted in the rapid and sustained activation of JNK without activating ERK or p38 or promoting IκBα phosphorylation. Activation of ΔMEKK1:ER* caused a reversible halt in cell growth but failed to induce apoptosis. In contrast, treatment of cells with LY294002, to inhibit phosphoinositide 3-kinase (PI3K), caused downregulation of Bcl-2 and Mcl-1 and allowed ΔMEKK1:ER* to elicit a robust apoptotic response characterized by activation of Bax and caspases. This PI3K-inhibitable, JNK-induced death response was not impeded, but actually accelerated, by cycloheximide. This suggests that JNK-induced activation of Bax and cell death does not require the upregulation of pro-death genes such as Bim or FasL, but rather proceeds through pre-existing components. However, if the PI3K cell survival pathway is not inhibited, even sustained activation of JNK exerts no overt proapoptotic effect in CC139 cells.

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Acknowledgements

We thank Kathy Balmanno, Andy Garner and Claire Weston for helpful discussions and encouragement. We thank Martin McMahon for provision of the pBP3:hbER* plasmid and Michela Marani for advice on the N-20 Bax IP protocol. We are grateful to Geoff Morgan for maintenance of the Babraham Institute FACS facility and timely advice. SAM was supported by a BBSRC PhD studentship. This work was funded by Cancer Research UK (SP2458/0201 and SP2382/0403) and by the BBSRC Science of Ageing Initiative (202/SAG 10012). SJC is a Senior Cancer Research Fellow of Cancer Research UK.

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Author notes

  1. Sarah A Molton

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

  2. Daniel E Todd

    Present address: BioFocus, Unit 10, Cambridge Science Park, Milton Road, Cambridge, CB4 0FG, UK

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

    Sarah A Molton, Daniel E Todd & Simon J Cook

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Correspondence to Simon J Cook.

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Molton, S., Todd, D. & Cook, S. Selective activation of the c-Jun N-terminal kinase (JNK) pathway fails to elicit Bax activation or apoptosis unless the phosphoinositide 3′-kinase (PI3K) pathway is inhibited. Oncogene 22, 4690–4701 (2003). https://doi.org/10.1038/sj.onc.1206692

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