Treatment with EGF increases the length of S-Phase after partial hepatectomy in rat, changing the activities of cdks

Abstract

Liver proliferation occurs in the presence of mitogenic stimuli such as partial hepatectomy or growth factors. In this work we investigate how partial hepatectomy and Epidermal Growth Factor (EGF) affect hepatocyte proliferation by modulating cell cycle regulators. EGF administered to non-operated rats increased PCNA (proliferating cell nuclear antigen) expression, whereas when EGF was administered to partially hepatectomized rats it was able to anticipate the increase in PCNA expression to 18h after PH and to prolong it to 34h. Cell cycle progression was examined by monitoring specific markers of late G1- and S-phases. Western blot analysis showed that both treatment with EGF alone and treatment with EGF after PH induce the expression of cyclins D1 and A and of p21(cip1), but inhibites the expression of cyclin E and p27(kip1). EGF administration after PH also significantly affected the activity of the cyclin D1-cdk4 and cyclin E-cdk2 complexes, mainly by changing their time progression: it accelerated the increase in activity to 18h and caused a subsequent drop in activity after 34h; it delayed the activity of the cyclin A-cdk2 complex to 34h. In conclusion we observed that EGF modulates the activity of cdk complexes and induces a different linkage with inhibitory proteins that demonstrates their dual role, depending on their association with different cyclin-cdk complexes.