Lack of c-Jun activity increases survival to cisplatin

Antineoplasic agents such as cisplatin and adriamycin execute their pharmac ological role by triggering apoptosis. We have studied the mechanism of apo ptosis induction by cisplatin and adriamycin. Both drugs activated JNK with slow and persistent kinetics, Adriamycin activated caspase-3 before the ri se in JNK activity, while the response to cisplatin occurs hours after JNK activation, The increase in JNK activity was necessary for cisplatin-mediat ed apoptosis but it was dispensable for adriamycin-induced cell death. Cell s derived from c-jun knock out mice were more resistant to cisplatin cell d eath than normal cells, but no difference was observed in response to adria mycin. Activation of JNK and cell death by cisplatin is mediated by the MEK K1/SEK1 cascade, since expression of dominant negative expression vectors o f these kinases blocked both processes. p38 was also activated by cisplatin with similar kinetics as JNK. AP-1 complexes were activated by cisplatin i ncluding mainly c-jun/ATF-2 heterodimers suggesting that AP-1-dependent tra nscription partially mediated cisplatin-induced apoptosis. (C) 1999 Federat ion of European Biochemical Societies.