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

Treatment of cells with cisplatin induces a sustained activation of the str ess activated protein kinase SAPK/JNK and the mitogen-activated protein kin ase p38, Activation of JNK by cisplatin is necessary for the induction of a poptosis, Expression of the MAPK phosphatases CL100/MKP-1 and hVH-5 selecti vely 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 activit y only when expressed at very high levels and does not confer protection ag ainst cisplatin. Furthermore, expression of a catalytically inactive mutant of CL100 in 293 cells decreases the IC50 for cisplatin and increases the t oxicity of transplatin, This effect seems to be mediated by an increase in JNK activity since p38 activity is unaffected. These results suggest that d ual-specificity MAPK phosphatases may be candidate drug targets in order to optimize cisplatin based therapeutic protocols.