EXPRESSION OF MYC, FOS AND HA-RAS ASSOCIATED WITH CHEMICALLY-INDUCED CELL-PROLIFERATION IN THE RAT-LIVER

Events secondary to induced cell proliferation may play a role in the carcinogenic process. These studies investigated the expression of gen es associated with growth control in response to two types of cell pro liferation stimuli in the livers of male F344 rats. Regenerative hepat ocyte proliferation after partial hepatectomy or a single dose of carb on tetrachloride, and mitogenic liver hyperplasia induced by a single dose of phenobarbital or WY-14,643 were assessed by thymidine incorpor ation and quantitative autoradiography. The expression of myc, fos, an d Ha-ras was evaluated by Northern blot analysis of liver derived poly (A)(+) mRNA from these same animals. After each treatment, the level o f hepatocyte proliferation (labelling index 4-32%) was observed to pea k between 24 and 48 h and return to control values by 8 days. In every case, a peak in myc expression was seen between 0.5 and 18h depending on the proliferative stimulus treatment. A large peak in fos expressi on was seen at 0.5-2h but only with the cytotoxic and regenerative pro liferative treatments partial hepatectomy or carbon tetrachloride. A b road peak in Ha-ras expression was observed 12 to 36h after each treat ment. These data demonstrate transient expression of these genes follo wing the synchronous induction of hepatocyte proliferation. The increa sed expression of fos upon treatment with cytotoxicants, but not mitog ens, suggests different modes of growth regulation that may be importa nt in understanding the induction of cell proliferation by these two t ypes of agents.