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Control of mouse hepatocyte proliferation and ploidy by p53 and p53ser246 mutation in vivo

✍ Scribed by Li Yin; Nader Ghebranious; Subhendu Chakraborty; Christine E. Sheehan; Zoran Ilic; Stewart Sell

Publisher: John Wiley and Sons
Year: 1998
Tongue: English
Weight: 220 KB
Volume: 27
Category: Article
ISSN: 0270-9139
DOI: 10.1002/hep.510270113

No coin nor oath required. For personal study only.

✦ Synopsis

The effect of expression of the p53 gene, in the presence or absence of the p53ser246 mutation (p53*), on ploidization (image cytometry), proliferation (expression of proliferating cell nuclear antigen and radioactive thymidine histoautoradiography), and apoptosis (in situ detection of DNA fragments) is determined in hepatocytes of p53-null and p53*-transgenic mice. The mouse p53ser246 mutation is equivalent to the p53ser249 mutation found in human hepatomas associated with hepatitis B virus infection and aflatoxin exposure. The hepatocytes of heterozygous or homozygous p53-knockout mice (p53؉/؊; p53؊/؊), as well as knockout mice expressing one allele of p53ser246 (p53؉/؊, p53*; p53؊/؊, p53*), do not undergo normal polyploidization with aging and show an increase in the number of cycling (G 1 -, S-, and M-phase) cells. In addition, p53ser246-transgenic mice (p53؉/؉, p53*; p53؉/؊, p53*; and p53؊/؊, p53*) have a greatly increased number of hepatocytes in the G 1 phase. No differences in rates of apoptotic hepatocytes are found among any 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 p53ser246 mutation stimulates G 0 to G 1 and/or M to G 1 transition of hepatocytes. Increased proliferation of hepatocytes, combined with no concomitant increase in apoptosis, may in part explain the enhanced development of hepatocellular carcinomas in p53-knockout and p53*-transgenic mice exposed to aflatoxin.

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