CL100/MKP-1 modulates JNK activation and apoptosis in response to cisplatin.
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.
Sánchez-Pérez
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I
Instituto de Investigaciones Biomédicas C.S.I.C.-UAM, C/Arturo Duperier, 4, 28029 Madrid, Spain.
Martínez-Gomariz
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M
Williams
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Keyse
S M
SM
Perona
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R
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D018797:Cell Cycle Proteins; D002945:Cisplatin / Q000494:pharmacology*; D054638:Dual Specificity Phosphatase 1; D054642:Dual Specificity Phosphatase 6; D054637:Dual-Specificity Phosphatases; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009154:Mutation; D010749:Phosphoprotein Phosphatases; D011485:Protein Binding; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism*; D013237:Stereoisomerism; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D017874:Immediate-Early Proteins; C034697:transplatin; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; C517019:DUSP1 protein, human; C517035:DUSP6 protein, human; C517038:DUSP8 protein, human; D054638:Dual Specificity Phosphatase 1; D054642:Dual Specificity Phosphatase 6; D054637:Dual-Specificity Phosphatases; D017027:Protein Tyrosine Phosphatases; D002945:Cisplatin