Prolonged Jun N-terminal kinase (JNK) activation and the upregulation of p53 and p21 WAF1/ CIP1 preceded apoptosis in hepatocytes after partial hepatectomy and cisplatin

Abstract

Cisplatin induced apoptosis in regenerating liver after partial hepatectomy (PH). Apoptosis was determined by in situ end-labeling and gel electrophoresis of DNA fragmentation. Characteristic DNA fragmentation was obvious at 4 h and peaked at 8 h after PH. The activity of Jun N-terminal kinase (JNK) transiently increased at 1 h after PH. However, in cisplatin-injected rats, the JNK activity increased at 30 min and the increased level was maintained up to 4 h after PH. The in vivo activation of JNK was confirmed by the increased level of the phosphorylated c-Jun protein. Western blot analysis showed that the phosphorylated c-Jun level increased at 1 h and reached more than 30-fold the control level at 2 h after PH with cisplatin. The c-jun mRNA levels also markedly increased at 1 h after PH with cisplatin. The protein level of p53 increased after 1 h on cisplatin injection, but no significant change in the mRNA level was observed. The rise in the p53 protein level was followed by the upregulation of p21 WAF1/ CIP1 mRNA and protein levels. These results suggested that the enhanced and sustained JNK activation and the upregulation of p53 and p21 WAF1/ CIP1 were involved in hepatocyte apoptosis induced by PH with cisplatin.