c-Jun-N-terminal kinase drives cyclin D1 expression and proliferation during liver regeneration.
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.
Schwabe
Robert F
RF
Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Bradham
Cynthia A
CA
Uehara
Tetsuya
T
Hatano
Etsuro
E
Bennett
Brydon L
BL
Schoonhoven
Robert
R
Brenner
David A
DA
D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006498:Hepatectomy / Q000379:methods / Q000401:mortality; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases; D008099:Liver / Q000187:drug effects / Q000473:pathology*; D008115:Liver Regeneration / Q000502:physiology*; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015996:Survival Rate
D000873:Anthracenes; D004791:Enzyme Inhibitors; D019938:Cyclin D1; C432165:pyrazolanthrone; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases