CONTROL OF MOUSE HEPATOCYTE PROLIFERATION AND PLOIDY BY P53 AND P53SER246 MUTATION IN-VIVO

The effect of expression of the p53 gene, in the presence or absence o f the p53ser246 mutation (p53), on ploidization (image cytometry), pr oliferation (expression of proliferating cell nuclear antigen and radi oactive thymidine histoautoradiography), and apoptosis (in situ detect ion of DNA fragments) is determined in hepatocytes of p53-null and p53 -transgenic mice. The mouse p53ser246 mutation is equivalent to the p S3ser249 mutation found in human hepatomas associated with hepatitis B virus infection and aflatoxin exposure, The hepatocytes of heterozygo us or homozygous p53-knockout mice (p53+/-; p53-/-), as well as knocko ut mice expressing one allele of p53ser246 (p53+/-, p53; p53-/-, p53* ), do not undergo normal polyploidization with aging and show an incre ase in the number of cycling (G(1)-, S-, and M-phase) cells. In additi on, p53ser246-transgenic mice (pS3+/+, p53; p53+/-, p53*; and p53-/-, p53) have a greatly increased number of hepatocytes in the G(1) phas e. No differences in rates of apoptotic hepatocytes are found among an y of the mouse groups studied, so the increased proliferation results in a hyperplasia manifested by a increased number of small periportal cells, We conclude that loss of p53 removes blocks in the cell cycle, leading to increased proliferation, whereas expression of the p53ser24 6 mutation stimulates G(0) to G(1) and/or M to G(1) transition of hepa tocytes. Increased proliferation of hepatocytes, combined with no conc omitant increase in apoptosis, may in part explain the enhanced develo pment of hepatocellular carcinomas in p53-knockout and p53-transgenic mice exposed to aflatoxin.