Gene expression in the lung of p53 mutant mice exposed to cigarette smoke

Alberto Izzotti, Cristina Cartiglia, Mariagrazia Longobardi, Maria Bagnasco, Andrea Merello, Ming You, Ronald A. Lubet, Silvio De Flora

Research output: Contribution to journalArticlepeer-review

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 × A/J)F, 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 thep55 status affected the expression of the p55 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 smokeexposed 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 xenobiptics, 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.

Original languageEnglish
Pages (from-to)8566-8572
Number of pages7
JournalCancer Research
Volume64
Issue number23
DOIs
Publication statusPublished - Dec 1 2004

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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