Ja. Rininger et al., TIME-COURSE COMPARISON OF CELL-CYCLE PROTEIN EXPRESSION FOLLOWING PARTIAL-HEPATECTOMY AND WY14,643-INDUCED HEPATIC CELL-PROLIFERATION IN F344 RATS, Carcinogenesis, 18(5), 1997, pp. 935-941
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.