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

Isabel Sánchez-Pérez, Montserrat Martínez-Gomariz, David Williams, Stephen M Keyse, Rosario Perona

    Research output: Contribution to journalArticlepeer-review

    124 Citations (Scopus)

    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.
    Original languageEnglish
    Pages (from-to)5142-52
    Number of pages11
    JournalOncogene
    Volume19
    Issue number45
    DOIs
    Publication statusPublished - 26 Oct 2000

    Keywords

    • Cisplatin
    • JNK1
    • CL100-MKP-1
    • hVH-5
    • Apoptosis

    Fingerprint Dive into the research topics of 'CL100/MKP-1 modulates JNK activation and apoptosis in response to cisplatin'. Together they form a unique fingerprint.

    Cite this