||Experiments were designed to investigate the expression of three cell-cycle-dependent proto-oncogenes in response to two different types of proliferative stimuli: compensatory cell proliferation after partial hepatectomy (PH) or CCl4 and liver hyperplasia induced by the mitogens ethylene dibromide (EDB) and cyproterone acetate (CPA). Steady-state levels of messenger RNAs for c-fos and c-myc were found to be elevated after PH or CCl4 with a maximum increase between 0.5 and 2 h for c-fos and at 2-3 h for c-myc and a rapid decline after 3 h. However, when liver cell proliferation was induced by mitogens, no increase in the expression of c-fos mRNA was observed with both EDB or CPA during the first 24 h. In addition, elevated expression of c-myc was found only in liver hyperplasia induced by EDB, but not with CPA. While the expression of c-myc mRNA and c-fos mRNA was different in the two types of proliferative stimuli, that of c-Ha-ras and c-Ki-ras was similar in all the experimental groups. Cell proliferation monitored by means of incorporation of labelled thymidine into DNA or mitotic index at 24 h following PH, EDB and CPA occurred at a similar extent in all the experimental groups. Our data indicate that the transient and sequential expression of cell-cycle-related genes may vary in response to proliferative stimuli of different nature and suggest that increased expression of cell-cycle-related genes may not be a necessary prerequisite for the entry of the cells into the cell cycle.