title: Gene expression in the lung of p53 mutant mice exposed to cigarette smoke.
abstract: We showed previously that p53 mutations play a role in cigarette smoke-related carcinogenesis not only in humans but also in A/J mice. In fact, (UL53-3 x A/J)F(1) mice, carrying a dominant-negative germ-line p53 mutation, responded to exposure to environmental cigarette smoke more efficiently than their wild-type (wt) littermate controls in terms of molecular alterations, cytogenetic damage, and lung tumor yield. To clarify the mechanisms involved, we analyzed by cDNA array the expression of 1,185 cancer-related genes in the lung of the same mice. Neither environmental cigarette smoke nor the p53 status affected the expression of the p53 gene, but the p53 mutation strikingly increased the basal levels of p53 nuclear protein in the lung. Environmental cigarette smoke increased p53 protein levels in wt mice only. The p53 mutation enhanced the expression of positive cell cycle regulators in sham-exposed mice, which suggests a physiologic protective role of p53. In environmental cigarette smoke-exposed mice, the p53 mutation resulted in a lack of induction of proapoptotic genes and in overexpression of genes involved in cell proliferation, signal transduction, angiogenesis, inflammation, and immune response. Mutant mice and wt mice reacted to environmental cigarette smoke in a similar manner regarding genes involved in metabolism of xenobiotics, multidrug resistance, and protein repair. Irrespective of the p53 status, environmental cigarette smoke poorly affected the expression of oncogenes, tumor suppressor genes, and DNA repair genes. Taken together, these findings may explain the increased susceptibility of p53 mutant mice to smoke-related alterations of intermediate biomarkers and lung carcinogenesis.
authors.affiliation: Department of Health Sciences, University of Genoa, Genoa, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Izzotti
authors.forename: Cristina
authors.initials: C
authors.lastname: Cartiglia
authors.forename: Mariagrazia
authors.initials: M
authors.lastname: Longobardi
authors.forename: Maria
authors.initials: M
authors.lastname: Bagnasco
authors.forename: Andrea
authors.initials: A
authors.lastname: Merello
authors.forename: Ming
authors.initials: M
authors.lastname: You
authors.forename: Ronald A
authors.initials: RA
authors.lastname: Lubet
authors.forename: Silvio
authors.initials: S
authors.lastname: De Flora
mesh_terms: D000818:Animals; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D016158:Genes, p53 / Q000187:drug effects / Q000235:genetics*; D018095:Germ-Line Mutation; D008168:Lung / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008175:Lung Neoplasms / Q000209:etiology* / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008805:Mice, Inbred A; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014028:Tobacco Smoke Pollution / Q000009:adverse effects*; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics
chemical_list: D014028:Tobacco Smoke Pollution; D016159:Tumor Suppressor Protein p53