title: Mutations of TP53 induce loss of DNA methylation and amplification of the TROP1 gene.
abstract: p53 and DNA methylation play key roles in the maintenance of genome stability. In this work, we demonstrate that the two mechanisms are linked and that p53 plays a role in the maintenance of the DNA methylation levels. The loss of p53 was shown to induce loss of DNA methylation in the TROP1 gene, a human cancer-expressed locus that undergoes amplification when hypomethylated. This demethylation was reverted by the reintroduction of a wild-type TP53 (wtTP53) in the TP53-null cells. Using a gene-amplification assay in vivo, we demonstrate that the loss of p53 leads to a demethylation-dependent TROP1 gene amplification. The induction of gene amplification was reverted by the expression of a wtTP53 gene or by in vitro methylation of the transfected DNA with the Sss I DNA methylase. Taken together, these findings demonstrate that the inactivation of TP53 induces loss of DNA methylation and DNA methylation-dependent gene amplification.
authors.affiliation: Department of Cell Biology and Oncology, Instituto di Ricerche Farmacologiche' Mario Negri, Chieti, Italy.
authors.forename: Ashraf F
authors.initials: AF
authors.lastname: Nasr
authors.forename: Michele
authors.initials: M
authors.lastname: Nutini
authors.forename: Barbara
authors.initials: B
authors.lastname: Palombo
authors.forename: Emanuela
authors.initials: E
authors.lastname: Guerra
authors.forename: Savenio
authors.initials: S
authors.lastname: Alberti
mesh_terms: D000951:Antigens, Neoplasm / Q000235:genetics*; D015815:Cell Adhesion Molecules / Q000235:genetics*; D000071858:Epithelial Cell Adhesion Molecule; D005434:Flow Cytometry; D005784:Gene Amplification; D016158:Genes, p53; D006801:Humans; D016864:Li-Fraumeni Syndrome / Q000235:genetics; D009154:Mutation; D014162:Transfection
chemical_list: D000951:Antigens, Neoplasm; D015815:Cell Adhesion Molecules; D000071858:Epithelial Cell Adhesion Molecule