Proto-oncogene expression and growth factors during liver regeneration.

When growth is stimulated in normally quiescent hepatocytes, steady-state levels of c-fos, c-myc, and p53 mRNAs increase sequentially and transiently before DNA replication. C-fos mRNA increases almost immediately after partial hepatectomy and decreases by 2 hr; c-myc mRNA reaches maximal levels between 30 min and 2 hr. In contrast, the p53 mRNA increase corresponds to the G1/S transition, and mRNAs from c-ras genes are elevated later, coinciding with DNA replication and mitosis. p53 and p21 proteins are elevated when their mRNAs are more abundant. This regulated response suggests that these genes either control key steps in the cell cycle or are responding to humoral or internal growth factors acting at specified growth stages. We propose that hepatocytes go through a "priming" stage during the first four hours after partial hepatectomy and that their progression through late G1, is likely to be controlled by autocrine or paracrine mechanisms, which may account for the precisely regulated growth of the liver after partial hepatectomy. Transforming growth factor beta (TGF beta) is a potent inhibitor of DNA synthesis in normal hepatocytes in vitro. We show that TGF beta mRNA increases in the regenerating liver at the time of hepatocyte DNA synthesis and mitosis. In normal or regenerating liver, the mRNA for this growth factor is contained in nonparenchymal cells but not in hepatocytes. We suggest that TGF beta may be a component of a paracrine regulatory loop that controls hepatocyte replication.