Alterations in the K-ras and p53 genes in rat lung tumors
- Inhalation Toxicology Research Institute, Albuquerque, NM (United States); and others
Activation of the K-ras protooncogene and inactivation of the p53 tumor suppressor gene are events common to many types of human cancers. Molecular epidemiology studies have associated mutational profiles in these genes with specific exposures. The purpose of this paper is to review investigations that have examined the role of the K-ras and p53 genes in lung tumors induced in the F344 rat by mutagenic and nonmutagenic exposures. Mutation profiles within the K-ras and p53 genes, if present in rat lung tumors, would help to define some of the molecular mechanisms underlying cancer induction by various environmental agents. Pulmonary adenocarcinomas or squamous cell carcinomas were induced by tetranitromethane (TNM), 4-methylnitrosamino-1-(3-pyridyl)-1-butanone (NNK), beryllium metal, plutonium-239, X-ray, diesel exhaust, or carbon black. These agents were chosen because the tumors they produced could arise via different types of DNA damage. Mutation of the K-ras gene was determined by approaches that included DNA transfection, direct sequencing, mismatch hybridization, and restriction fragment length polymorphism analysis. The frequency for mutation of the K-ras gene was exposure dependent. The transition mutations formed could have been derived from deamination of cytosine. Alteration in the p53 gene was assessed by immunohistochemical analysis for p53 protein and single-strand conformation polymorphism (SSCP) analysis of exons 4 to 9. None of the 93 adenocarinomas examined was immunoreactive toward the anti-p53 antibody CM1. In contrast, 14 of 71 squamous cell carcinomas exhibited nuclear p53 immunoreactivity with no correlation to type of exposure. However, SSCP analysis only detected mutations in 2 of 14 squamous cell tumors that were immunoreactive, suggesting that protein stabilization did not stem from mutations within the p53 gene. Thus, the p53 gene does not appear to be involved in the genesis of most rat lung tumors. 2 figs., 2 tabs., 48 refs.
- Sponsoring Organization:
- USDOE
- DOE Contract Number:
- AC04-76EV01013
- OSTI ID:
- 588650
- Journal Information:
- Environmental Health Perspectives, Vol. 105, Issue Suppl.4; Other Information: PBD: Jun 1997
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
BASIC STUDIES
56 BIOLOGY AND MEDICINE
APPLIED STUDIES
RATS
CARCINOMAS
RFLPS
MUTATION FREQUENCY
DNA SEQUENCING
LUNGS
CYTOSINE
GENETIC EFFECTS
DEAMINATION
DNA
EPIDEMIOLOGY
EXONS
ONCOGENES
DNA HYBRIDIZATION
INACTIVATION
PROTEINS
GENE MUTATIONS
STABILIZATION
GENETIC RADIATION EFFECTS
BERYLLIUM
CARBON BLACK
PLUTONIUM 239
X RADIATION
DIESEL FUELS