TP53 and hepatocellular carcinoma.
TP53 gene mutations occur in 30 to 55% hepatocellular carcinomas. Both the frequency and the type of p53 mutations in HCC vary according to geographical location of tumors. A specific mutation at codon 249 (AGG-->AGT) was found at high frequency in tumors from high aflatoxin-areas. TP53 mutations in other geographic locations are less frequent and scattered on the exons encoding the central region of the protein. TP53 mutations observed in hepatocellular carcinoma are accompanied by a loss of wild-type p53 function. Moreover, the p53-249ser mutant appears to display a gain of function at some degree. In addition to p53 inactivation by gene mutation, there is growing evidence that the wild-type p53 functions can be inactivated by the HBx protein of Hepatitis B Virus. The hepatocellular functions of wild-type p53 protein are not entirely known. The present data suggest that the DNA damaging agents induce p53-dependent cell cycle arrest or apoptosis in cell lines derived from normal liver or hepatocellular carcinoma. In contrast, the exposure of mice to genotoxic agents does not induce p53-dependent changes in normal adult liver. This could be due to the fact that the hepatocytes of the adult liver are quiescent cells.
Unité INSERM U453, Centre Léon, Bérard, Lyon, France.
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Puisieux
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Ozturk
D006528:Carcinoma, Hepatocellular / Q000235:genetics*; D016158:Genes, p53; D006801:Humans; D008099:Liver / Q000166:cytology / Q000378:metabolism; D008113:Liver Neoplasms / Q000235:genetics*; D009154:Mutation; D012016:Reference Values