The c-Jun-N-terminal kinase (JNK) pathway is strongly activated after partial 
hepatectomy (PH), but its role in hepatocyte proliferation is not known. In this 
study, JNK activity was blocked with the small molecule inhibitor JNK SP600125 
in vivo and in vitro as shown by a reduction of c-Jun phosphorylation, AP-1 DNA 
binding activity, and c-jun messenger RNA (mRNA) expression. SP600125 inhibited 
proliferating cell nuclear antigen (PCNA) expression, cyclin D1 mRNA and protein 
expression and reduced mitotic figures after PH. Survival was reduced 
significantly 3 days after PH in SP600125-treated versus vehicle-treated rats (3 
of 11 vs. 8 of 9, P <.01). In epidermal growth factor (EGF)-treated primary 
cultures of rat hepatocytes, SP600125 decreased (3)H-thymidine uptake, cyclin D1 
mRNA and protein expression, and inhibited the EGF-induced transcription of a 
cyclin D1 promoter-driven reporter gene. The defective regeneration and the 
decreased survival in SP600125-treated rats did not result from a major increase 
in apoptosis as shown by normal levels of caspase 3 activity and only slight 
increases in apoptotic figures. In conclusion, our data show that JNK drives G0 
to G1 transition in hepatocytes and that cyclin D1 is a downstream target of the 
JNK pathway during liver regeneration.