title: Inhibition of rat hepatocyte proliferation by transforming growth factor beta and glucagon is associated with inhibition of ERK2 and p70 S6 kinase.
abstract: 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.
authors.affiliation: Centre for Liver Research, University of Newcastle, Newcastle upon Tyne, UK.
authors.forename: M
authors.initials: M
authors.lastname: Dixon
authors.forename: L
authors.initials: L
authors.lastname: Agius
authors.forename: S J
authors.initials: SJ
authors.lastname: Yeaman
authors.forename: C P
authors.initials: CP
authors.lastname: Day
mesh_terms: D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005934:Glucagon / Q000494:pharmacology*; D006133:Growth Substances / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases; D008099:Liver / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1; D020928:Mitogen-Activated Protein Kinases; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology*; D051381:Rats; D019893:Ribosomal Protein S6 Kinases / Q000037:antagonists & inhibitors*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D004791:Enzyme Inhibitors; D006133:Growth Substances; D011500:Protein Synthesis Inhibitors; D016212:Transforming Growth Factor beta; D004815:Epidermal Growth Factor; D004247:DNA; D005934:Glucagon; D019893:Ribosomal Protein S6 Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases