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 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 (G1-, 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 G1 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 G0 to G1 and/or M to G1 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.
Yin
L
L
Department of Pathology and Laboratory Medicine, Albany Medical College, NY 12208-3479, USA.
Ghebranious
N
N
Chakraborty
S
S
Sheehan
C E
CE
Ilic
Z
Z
Sell
S
S
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002452:Cell Count; D002453:Cell Cycle / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D008099:Liver / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic / Q000235:genetics / Q000502:physiology; D009154:Mutation; D011003:Ploidies; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000502:physiology*
D016159:Tumor Suppressor Protein p53