The consequence of p53 overexpression for liver tumor development and the response of transformed murine hepatocytes to genotoxic agents

To analyse the effect of p53 on liver tumor development, we generated trans genic mice overexpressing wild-type p53 in the liver and crossed them with transgenic mice in which the expression of the SV40 large T antigen (TAg) i nduces hepatic tumors. Remarkably, whereas preneoplastic TAg liver exhibite d anisocaryosis and anisocytosis, TAg/p53 liver never presented any dysplas tic cells. Moreover, whereas expression of p53 did not affect hepatic devel opment, its constitutive expression in tumorigenic livers resulted in a sig nificantly enhanced apoptosis once nodules had appeared. In contrast, p53 o verexpression did not modify the elevated proliferation of TAg-transformed hepatocytes and had no effect on hepatocarcinoma progression. In vitro anal ysis of primary hepatocytes exposed to various genotoxic agents showed that p53 failed to sensitize normal or TAg-transformed hepatocytes to apoptosis , except when high doses of doxorubicin, UV-B and UV-C radiation were used. Our results confirmed that the hepatocyte cell type is very resistant to g enotoxic agents and showed that constitutive expression of p53 failed to im prove their responsiveness. In addition, our results showed that suppressio n of dysplastic cells, probably by restoring normal cytokinesis and karyoki nesis, and enhancement of apoptosis by means of p53 overexpression were ins ufficient to counteract or delay the TAg-induced liver tumoral progression.