TIME-COURSE COMPARISON OF CELL-CYCLE PROTEIN EXPRESSION FOLLOWING PARTIAL-HEPATECTOMY AND WY14,643-INDUCED HEPATIC CELL-PROLIFERATION IN F344 RATS

During recent years, there has been an extensive research focus in the area of cell-cycle control in eukaryotes and the relationship that ex ists between cell proliferation and cancer, The eukaryotic cell-cycle is governed by signal transduction pathways mediated by complexes of c yclin dependent kinases (CDK) and their partner cyclin proteins, This study was performed to identify differences in cell-cycle control prot ein expression following physical and chemical stimuli of hepatic cell growth, Protein levels of cell cycle mediators, cyclin dependent kina ses (CDK 1,2,4,5), cyclin proteins (A,B,D1-D3 and E), proliferating ce ll nuclear antigen (PCNA), tumor suppressor proteins (p53 and Rb), and CDK inhibitory proteins (p16(Ink4), p21(Waf1) and p27(Kip1)) were exa mined in F344 rats following 70% partial hepatectomy or a single dose of WY14,643 over 96- and 48-h time courses, respectively, CDK1 (p34(cd c2)) and PCNA protein concentrations, quantified by ELISA, were signif icantly increased beginning at the 24-h time point and maximal at 48 h (6.9- and 3.7-fold for partial hepatectomy and 4.2- and 3.3-fold for WY14,643, respectively), Differential effects were observed with the G 1 cell-cycle mediators CDK4, CDK5, and cyclin D3, p21(Waf1) and p27(Ki p1) CDK inhibitory protein concentrations rose in accordance with the induction of DNA synthesis and histone H1 kinase activity, In addition , there were dramatic differences in p53 protein expression patterns f ollowing partial hepatectomy versus WY14,643 dosing, Because nongenoto xic hepatocarcinogens are known to induce cellular proliferation, data generated from this study may aid in elucidating the specific hepatoc arcinogenic signal transduction pathways stimulated by non-genotoxic c arcinogens.