Additive and inhibitory effects of simultaneous treatment with growth factors on DNA synthesis through MAPK pathway and G1 cyclins in rat hepatocytes

Biochem Biophys Res Commun. 2001 Jan 12;280(1):368-73. doi: 10.1006/bbrc.2000.4063.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Cyclin D1 / biosynthesis
  • Cyclin D1 / physiology*
  • DNA / biosynthesis*
  • Epidermal Growth Factor / pharmacology
  • G1 Phase
  • Growth Substances / pharmacology*
  • Hepatocyte Growth Factor / pharmacology
  • Hepatocytes / cytology
  • Hepatocytes / drug effects
  • Hepatocytes / physiology*
  • Kinetics
  • Liver / cytology
  • MAP Kinase Signaling System / physiology*
  • Male
  • Mitogen-Activated Protein Kinases / metabolism*
  • Rats
  • Rats, Wistar
  • Transforming Growth Factor beta / pharmacology


  • Growth Substances
  • Transforming Growth Factor beta
  • Cyclin D1
  • Epidermal Growth Factor
  • Hepatocyte Growth Factor
  • DNA
  • Mitogen-Activated Protein Kinases