Prolonged Jun N-terminal kinase (JNK) activation and the upregulation of p53 and p2l(WAF1/CIP1) preceded apoptosis in hepatocytes after partial hepatectomy and cisplatin

Cisplatin induced apoptosis in regenerating liver after partial hepatectomy (PH). Apoptosis was determined by in situ end-labeling and gel electrophor esis 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 maintain ed up to 4 h after PH. The in vivo activation of JNK was confirmed by the i ncreased level of the phosphorylated c-Jun protein. Western blot analysis s howed 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 m RNA levels also markedly increased at 1 h after PH with cisplatin. The prot ein level of p53 increased after 1 h on cisplatin injection, but no signifi cant change in the mRNA level was observed. The rise in the p53 protein lev el was followed by the upregulation of p21(WAF1/CIP1) mRNA and protein leve ls. 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. (C) 2001 Elsevier Science B.V. All rights reserved.