title: Additive and inhibitory effects of simultaneous treatment with growth factors on DNA synthesis through MAPK pathway and G1 cyclins in rat hepatocytes.
abstract: Several growth factors play an important role in liver regeneration. Once hepatic injury occurs, liver regeneration is stimulated by hepatocyte growth factor (HGF), transforming growth factor (TGF)-alpha, and heparin-binding epidermal growth factor-like growth factor (HB-EGF), whereas TGF-beta1 terminates liver regeneration. In this study, we analyzed the effect of a combination of HGF and epidermal growth factor (EGF) on mitogen-activated protein kinase (MAPK) activity and G1 cyclin expression in primary cultured rat hepatocytes. Treatment with a combination of HGF and EGF, in comparison with that of either HGF or EGF, induced tyrosine phosphorylation of both c-Met and EGF receptor (EGFR) independently and additively stimulated MAPK activity and cyclin D1 expression, resulting in additive stimulation of DNA synthesis. On the other hand, although TGF-beta1 treatment did not affect tyrosine phosphorylation of c-Met and EGFR, MAPK activity, and cyclin D1 expression, which were stimulated by HGF and EGF, DNA synthesis was completely inhibited through a marked decrease in cyclin E expression. These results indicate that potent mitogens, such as HGF, TGF-alpha, and HB-EGF, could induce the additive enhancement of liver regeneration cooperatively through an increase in Ras/MAPK activity followed by cyclin D1 expression, and that TGF-beta1 suppresses the growth factor-induced signals between cyclin D1 and cyclin E, resulting in the inhibition of DNA synthesis.
authors.affiliation: Department of Internal Medicine II, Miyazaki Medical College, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Moriuchi
authors.forename: S
authors.initials: S
authors.lastname: Hirono
authors.forename: A
authors.initials: A
authors.lastname: Ido
authors.forename: T
authors.initials: T
authors.lastname: Ochiai
authors.forename: T
authors.initials: T
authors.lastname: Nakama
authors.forename: H
authors.initials: H
authors.lastname: Uto
authors.forename: T
authors.initials: T
authors.lastname: Hori
authors.forename: K
authors.initials: K
authors.lastname: Hayashi
authors.forename: H
authors.initials: H
authors.lastname: Tsubouchi
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000096:biosynthesis / Q000502:physiology*; D004247:DNA / Q000096:biosynthesis*; D004815:Epidermal Growth Factor / Q000494:pharmacology; D016193:G1 Phase; D006133:Growth Substances / Q000494:pharmacology*; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D007700:Kinetics; D008099:Liver / Q000166:cytology; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D016212:Transforming Growth Factor beta / Q000494:pharmacology
chemical_list: D006133:Growth Substances; D016212:Transforming Growth Factor beta; D019938:Cyclin D1; D004815:Epidermal Growth Factor; D017228:Hepatocyte Growth Factor; D004247:DNA; D020928:Mitogen-Activated Protein Kinases