Tobacco smoke-induced lung tumorigenesis in mutant A/J mice with alterations in K-ras, p53, or Ink4a/Arf

Oncogene. 2005 Apr 21;24(18):3042-9. doi: 10.1038/sj.onc.1208390.

Abstract

A/J mice with genetic alterations in K-ras, p53, or Ink4a/Arf were employed to investigate whether mice carrying these germline mutations would be susceptible to tobacco smoke-induced lung tumorigenesis. Transgenic mice of both genders and their wild-type littermates were exposed to environmental cigarette smoke for 6 months, followed by recovery in air for 5 months. A significant increase of lung tumor multiplicity was observed in K-ras, p53, or Ink4a/Arf mutant mice when compared with wild-type mice. Furthermore, an additive effect was observed between the mice with a mutant p53 transgene and an Ink4A/Arf deletion during tobacco smoke-induced lung tumorigenesis. Sequence analysis of the K-ras gene indicated that the mutations had occurred at either codon 12/13 or 61 in both spontaneously occurring (air control) and tobacco smoke-induced lung tumors. K-ras mutations were found in 62% of the tumors from air-control animals and 83% in those exposed to tobacco smoke. The mutation spectrum found in tumors from mice exposed to tobacco smoke is somewhat similar to that in tumors from air-control mice. In addition, we identified three novel mutations at codon 12: GGT (Gly) --> TTT (Phe), ATT (Ile), and CTT (Leu). These findings provide evidence that K-ras, p53, and Ink4a/Arf mutations play a role in tobacco smoke-related lung carcinogenesis. The similarity of the mutation spectra in the K-ras oncogene observed in tobacco smoke-induced tumors, as compared to spontaneous tumors, suggests that tobacco smoke enhances lung tumorigenesis primarily through promoting spontaneously occurring K-ras mutations.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics*
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism
  • Genes, ras*
  • Lung Neoplasms / etiology*
  • Lung Neoplasms / pathology
  • Mice
  • Mutation
  • Smoking / adverse effects*
  • Tumor Suppressor Protein p53 / genetics*
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Cyclin-Dependent Kinase Inhibitor p16
  • Tumor Suppressor Protein p53