Effects of Simultaneous Treatment with Growth Factors on DNA Synthesis, MAPK Activity, and G1 Cyclins in Rat Hepatocytes

Abstract

Several growth factors act in concert during liver regeneration in vivo. Once hepatic injury occurs, liver regeneration is stimulated by hepatocyte growth factor (HGF), transforming growth factor (TGF)-α, and heparin-binding epidermal growth factor-like growth factor (HB-EGF), whereas TGF-s1 terminates liver regeneration. Treatment with a combination of HGF and epidermal growth factor (EGF), in comparison with that with either HGF or EGF, was found to additively stimulate mitogen-activated protein kinase (MAPK) activity and cyclin D1 expression additively, resulting in additive stimulation of DNA synthesis. In contrast, TGF-s1 treatment completely inhibited DNA synthesis through a marked decrease in cyclin E expression, although growth factor-induced MAPK activity and cyclin D1 expression were not affected by TGF-s1. These results indicate that potent mitogens such as HGF, TGF-α, and HB-EGF can cooperatively induce the additive enhancement ofliver regeneration through an increase in Ras/MAPK activity followed by cyclin D1 expression, and that TGF-s1 suppresses the growth factor-induced signals between cyclin D1 and cyclin E, resulting in inhibition of DNA synthesis.