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 genes associated with growth control in response to two types of cell proliferation stimuli in the livers of male F344 rats. Regenerative hepatocyte proliferation after partial hepatectomy or a single dose of carbon tetrachloride, and mitogenic liver hyperplasia induced by a single dose of phenobarbital or WY-14,643 were assessed by thymidine incorporation and quantitative autoradiography. The expression of myc, fos, and Ha-ras was evaluated by Northern blot analysis of liver derived poly(A)(+) mRNA from these same animals. After each treatment, the level of hepatocyte proliferation (labelling index 4-32%) was observed to peak 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 expression was seen at 0.5-2h but only with the cytotoxic and regenerative proliferative treatments partial hepatectomy or carbon tetrachloride. A broad peak in Ha-ras expression was observed 12 to 36h after each treatment. These data demonstrate transient expression of these genes following the synchronous induction of hepatocyte proliferation. The increased expression of fos upon treatment with cytotoxicants, but not mitogens, suggests different modes of growth regulation that may be important in understanding the induction of cell proliferation by these two types of agents.