Inhibition of rat hepatocyte proliferation by transforming growth factor beta and glucagon is associated with inhibition of ERK2 and p70 S6 kinase.

Stimulation of hepatocyte proliferation by epidermal growth factor (EGF) and insulin is inhibited by transforming growth factor beta (TGF-beta) and by glucagon. It is also suppressed by inhibitors of various protein kinases, including rapamycin, which blocks activation of p70 S6 kinase (p70(S6k)), PD98059, which inhibits the activation of extracellular-regulated kinase (ERK), and SB 203580, an inhibitor of the p38 mitogen-activated protein kinase (p38 MAPK). In this study, we investigated whether the inhibition of proliferation by TGF-beta involves these protein kinase cascades. Culture of hepatocytes with TGF-beta for 16 hours decreased the stimulation by EGF of ERK2 and p70(S6k) (by 50% and 35%, respectively), but did not affect the stimulation of either p38 MAPK, c-jun NH2-terminal kinase (JNK), or protein kinase B (PKB). Culture of hepatocytes with glucagon for 16 hours also inhibited the stimulation by EGF of activation of ERK2 and p70(S6k) (by approximately 50%). The inhibitory effects of glucagon were observed when the hormone was added either 10 minutes or 60 minutes before EGF addition, whereas no effects of TGF-beta were observed after 10-minute or 60-minute incubation. These results suggest that the inhibition of hepatocyte proliferation by TGF-beta may be in part mediated by inhibition of ERK2 and p70(S6k), but does not involve PKB, JNK, or p38 MAPK. Unlike glucagon, the effects of TGF-beta are not elicited in response to short-term treatment.