DIFFERENTIAL REGULATION OF HEPATOCYTE DNA-SYNTHESIS BY CAMP IN-VITRO AND IN-VIVO

Adenosine 3',5'-cyclic monophosphate (cAMP) prevents epidermal growth factor (EGF)-induced DNA synthesis in many types of cultured cells, in cluding hepatocytes, but its effects on cellular proliferation in vivo are unknown. This study compares the effects of supplemental cAMP on hepatocyte proliferation induced in vivo by 70% partial hepatectomy (P H) and in vitro by EGF and determines the effects of cAMP on AP-1, a f amily of growth-regulatory transcription factors, and the kinase casca des that normally activate AP-1. Although injection of dibutyryladenos ine 3',5'-cyclic monophosphate (30 mg/kg ip) at the time of PH increas ed liver cAMP concentrations at least 100-fold for several hours, it d id not inhibit hepatic incorporation of [H-3]thymidine or proliferatin g cell nuclear antigen expression 24 h after PH. cAMP treatment led to a complete inhibition of extracellular signal-related kinase (ERK) ac tivity and transiently reduced NH2-terminal Jun nuclear kinase (JNK) a ctivity after PH but did not decrease the expression of c-jun mRNA or protein. Consistent with the known cAMP stimulation of jun-B in cultur ed cells, cAMP treatment increased jun-B mRNA, protein, and DNA bindin g activity post-PH. Surprisingly, cAMP treatment enhanced Raf kinase a ctivity after PH in rats. In primary hepatocyte cultures, supplemental cAMP inhibited JNK and ERK activity, total AP-1 and c-Jun transcripti onal activities, and DNA synthesis. Thus elevated cAMP inhibited ERK a nd JNK activity in culture and in vivo and inhibited hepatocyte prolif eration in culture but not in vivo. This suggests that in vivo mechani sms compensate for cAMP inhibition of certain growth-related signaling cascades and emphasizes potential risks of extrapolating from simple cell culture systems to explain physiology in intact animals.