p53 alterations in plutonium-induced F344 rat lung tumors.
The tumor suppressor gene p53 plays a critical role in the cellular response to genetic damage caused by radiation. In addition, mutations in this gene are often encountered in cells in lung tumors resected from uranium miners whose exposure to radon daughters exceeded 450 working level months. However, most of these miners also smoked tobacco products. Thus whether this gene is of specific importance in lung cancer is unclear. In this study, aberrations in the p53 gene were investigated using an immunohistochemical assay on 38 lung tumors (26 squamous cell carcinomas, 9 adenocarcinomas and 3 adenosquamous carcinomas) from rats that had inhaled 239PuO2 aerosols. Only 2 tumors exhibited detectable levels of staining of p53 products; both were large, well-differentiated squamous cell carcinomas that had invaded the pleural cavity or mediastinum. Direct DNA sequence analysis was used to characterize the mutations in these two tumors, and both exhibited G-->A transition mutations. One tumor was mutated in the first position of codon 283, resulting in a lysine for glutamine substitution; the other tumor was mutated at the second position of codon 280, resulting in a histidine to arginine substitution. No alterations in exons 5-7 of the p53 gene were found in a representative sample of tumors that did not exhibit elevated levels of the protein by immunohistochemistry. Further, no detectable polymorphisms or deletions were observed within the rat p53 gene after Southern blot analysis of 18 randomly selected 239Pu-induced tumors. These results suggest that p53 mutations are relatively unimportant in the development of lung tumors induced in the rat by high-linear energy transfer radiation.
Kelly
G
G
Inhalation Toxicology Research Institute, Lovelace Biomedical and Environmental Research Institute, Albuquerque, New Mexico 87185, USA.
Stegelmeier
B L
BL
Hahn
F F
FF
D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology; D000336:Aerosols; D000595:Amino Acid Sequence; D000818:Animals; D015139:Blotting, Southern; D018196:Carcinoma, Adenosquamous / Q000235:genetics / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000473:pathology; D017931:DNA Primers; D004273:DNA, Neoplasm / Q000032:analysis; D005091:Exons; D005260:Female; D016158:Genes, p53 / Q000528:radiation effects*; D005973:Glutamine; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D008239:Lysine; D008969:Molecular Sequence Data; D016296:Mutagenesis; D009381:Neoplasms, Radiation-Induced / Q000235:genetics* / Q000473:pathology; D011005:Plutonium / Q000008:administration & dosage; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D051381:Rats; D011916:Rats, Inbred F344; D016159:Tumor Suppressor Protein p53 / Q000032:analysis / Q000096:biosynthesis
D000336:Aerosols; D017931:DNA Primers; D004273:DNA, Neoplasm; D016159:Tumor Suppressor Protein p53; D005973:Glutamine; C026885:plutonium dioxide; D011005:Plutonium; D008239:Lysine