title: Functional inactivation but not structural mutation of p53 causes liver cancer.
abstract: Structural mutations in the p53 gene are seen in virtually every form of human cancer. To determine whether such mutations are important for initiating tumorigenesis, we have been studying hepatocellular carcinoma, in which most cases are associated with chronic hepatitis B virus infections. Using a transgenic mouse model where expression of a single HBV gene product, the HBx protein, induces progressive changes in the liver, we show that tumour development correlates precisely with p53 binding to HBx in the cytoplasm and complete blockage of p53 entry into the nucleus. Analysis of tumour cell DNA shows no evidence for p53 mutation, except in advanced tumours where a small proportion of cells may have acquired specific base substitutions. Our results suggest that genetic changes in p53 are late events which may contribute to tumour progression.
authors.affiliation: Department of Virology, Jerome H. Holland Laboratory, Rockville, Maryland 20855.
authors.forename: H
authors.initials: H
authors.lastname: Ueda
authors.forename: S J
authors.initials: SJ
authors.lastname: Ullrich
authors.forename: J D
authors.initials: JD
authors.lastname: Gangemi
authors.forename: C A
authors.initials: CA
authors.lastname: Kappel
authors.forename: L
authors.initials: L
authors.lastname: Ngo
authors.forename: M A
authors.initials: MA
authors.lastname: Feitelson
authors.forename: G
authors.initials: G
authors.lastname: Jay
mesh_terms: D000818:Animals; D001483:Base Sequence; D006528:Carcinoma, Hepatocellular / Q000209:etiology / Q000235:genetics*; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D016158:Genes, p53; D006509:Hepatitis B / Q000150:complications; D006801:Humans; D008113:Liver Neoplasms / Q000209:etiology / Q000235:genetics*; D008114:Liver Neoplasms, Experimental / Q000209:etiology / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D017354:Point Mutation; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D054334:Viral Regulatory and Accessory Proteins
chemical_list: D017931:DNA Primers; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein