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CL100/MKP-1 modulates JNK activation and apoptosis in response to cisplatin

Oncogene volume 19, pages 5142–5152 (2000)Cite this article

Abstract

Treatment of cells with cisplatin induces a sustained activation of the stress activated protein kinase SAPK/JNK and the mitogen-activated protein kinase p38. Activation of JNK by cisplatin is necessary for the induction of apoptosis. Expression of the MAPK phosphatases CL100/MKP-1 and hVH-5 selectively prevents JNK/SAPK activation by cisplatin in a dose dependent fashion and results in protection against cisplatin-induced apoptosis. In contrast, expression of the ERK-specific phosphatase Pyst1 inhibits JNK/SAPK activity only when expressed at very high levels and does not confer protection against cisplatin. Furthermore, expression of a catalytically inactive mutant of CL100 in 293 cells decreases the IC50 for cisplatin and increases the toxicity of transplatin. This effect seems to be mediated by an increase in JNK activity since p38 activity is unaffected. These results suggest that dual-specificity MAPK phosphatases may be candidate drug targets in order to optimize cisplatin based therapeutic protocols.

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Acknowledgements

We thank L Sastre for critical reading of the manuscript and useful comments and to L Alvarez for technical advice. We also thank S Aznar for proof reading and A Fernández, R Uña and J Pérez for the artwork. I. Sánchez-Pérez is a P.D. fellow from Comunidad Autónoma de Madrid. This study was supported by grants from Fondo de Investigación Sanitaria 98/0514 and 00/0862 and Comunidad Autónoma de Madrid 08.1/0035/1998.

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  1. Instituto de Investigaciones Biomédicas C.S.I.C.-UAM, C/Arturo Duperier, 4, Madrid, 28029, Spain

    Isabel Sánchez-Pérez, Montserrat Martínez-Gomariz & Rosario Perona

  2. ICRF Molecular Pharmacology Unit, Biomedical Research Center, Ninewells Hospital, Dundee, 9SY, DDI, UK

    David Williams & Stephen M Keyse

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Sánchez-Pérez, I., Martínez-Gomariz, M., Williams, D. et al. CL100/MKP-1 modulates JNK activation and apoptosis in response to cisplatin. Oncogene 19, 5142–5152 (2000). https://doi.org/10.1038/sj.onc.1203887

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