Lack of c-Jun activity increases survival to cisplatin.
Antineoplasic agents such as cisplatin and adriamycin execute their pharmacological role by triggering apoptosis. We have studied the mechanism of apoptosis induction by cisplatin and adriamycin. Both drugs activated JNK with slow and persistent kinetics. Adriamycin activated caspase-3 before the rise in JNK activity, while the response to cisplatin occurs hours after JNK activation. The increase in JNK activity was necessary for cisplatin-mediated apoptosis but it was dispensable for adriamycin-induced cell death. Cells derived from c-jun knock out mice were more resistant to cisplatin cell death than normal cells, but no difference was observed in response to adriamycin. Activation of JNK and cell death by cisplatin is mediated by the MEKK1/SEK1 cascade, since expression of dominant negative expression vectors of these kinases blocked both processes. p38 was also activated by cisplatin with similar kinetics as JNK. AP-1 complexes were activated by cisplatin including mainly c-jun/ATF-2 heterodimers suggesting that AP-1-dependent transcription partially mediated cisplatin-induced apoptosis.
Instituto de Investigaciones Bioméicas C.S.I.C./U.A.M., Madrid, Spain.
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Sánchez-Pérez
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Perona
D051698:Activating Transcription Factor 2; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival; D002945:Cisplatin / Q000494:pharmacology*; D017362:Cyclic AMP Response Element-Binding Protein / Q000302:isolation & purification; D004317:Doxorubicin / Q000494:pharmacology; D004789:Enzyme Activation; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D048728:MAP Kinase Kinase Kinase 1; D051379:Mice; D018345:Mice, Knockout; D020929:Mitogen-Activated Protein Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000302:isolation & purification; D016755:Proto-Oncogene Proteins c-jun / Q000172:deficiency* / Q000235:genetics; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000302:isolation & purification; D014157:Transcription Factors / Q000302:isolation & purification
D051698:Activating Transcription Factor 2; D000970:Antineoplastic Agents; D017362:Cyclic AMP Response Element-Binding Protein; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D004317:Doxorubicin; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048728:MAP Kinase Kinase Kinase 1; C482578:Map3k1 protein, mouse; D048670:MAP Kinase Kinase 4; C482562:Map2k4 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D002945:Cisplatin