Analysis of the K-ras and p53 pathways in x-ray-induced lung tumors in the rat

Journal Article · Mon Apr 01 04:00:00 EST 1996 · Radiation Research

DOI:https://doi.org/10.2307/3579066· OSTI ID:387382

Belinsky, S A; Middleton, S K; Hahn, F F; Nikula, K J ^[1]; Picksley, S M ^[2]

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1. Inhalation Toxicology Research Inst., Albuquerque, NM (United States)
2. Medical Sciences Inst., Dundee (United Kingdom)

The risk from exposure to low-dose radiation in conjunction with cigarette smoking has not been estimated due in part to lmited knowledge surrounding the molecular mechanisms underlying radiation-induced cancers. The purpose of this investigation was to determine the frequency for alterations in genes within the K-ras and p53 signal and cell cycle regulatory pathways, respectively, in X-ray-induced lung tumors in the F344/N rat. These tumors were examined for genetic alterations in the K-ras, c-raf-1, p53, mdm2 and cip1 genes. No K-ras mutations were detected by sequencing in 18 squamous cell carcinomas (SCCs) or 17 adenocarcinomas. However, using a K-ras codon 12 mutation selection assay, a codon 12 GGT {r_arrow} GAT mutation was detected in one SCC, suggesting that activation of the K-ras proto-oncogene is both a rare and late event. Single-strand conformation polymorphism (SSCP) analysis of the kinase-binding domain of the c-raf-1 gene did not detect any polymorphisms. Three of 18 SCCs but none of the adenocarcinomas showed p53 nuclear immunoreactivity. Single-strand conformation polymorphism analysis of exons 4-9 of the p53 gene detected only an exon 9 mutation in one SCC. Mutations were not detected in the three SCCs with immunoreactive p53 protein. No amplification of the mdm2 gene was detected; however, nuclear mdm2 immunoreactivity was present in one of the three SCCs that stained positive for the p53 protein. The complete cDNA of the rat cip1 gene comprising 810 bases was cloned and sequenced. The frequency of somatic mutations in exon 2 of the cip1 gene was determined by SSCP analysis. No alterations in electrophoretic mobility were detected. The results of this investigation indicate that alterations in the K-ras and p53 pathways do not play a major role in the genesis of X-ray-induced lung tumors in the rat. 49 refs., 5 figs.

• Sponsoring Organization: USDOE
• DOE Contract Number: AC04-76EV01013
• OSTI ID: 387382
• Journal Information: Radiation Research, Journal Name: Radiation Research Journal Issue: 4 Vol. 145; ISSN 0033-7587; ISSN RAREAE
• Country of Publication: United States
• Language: English

Related Subjects

56 BIOLOGY AND MEDICINE
APPLIED STUDIES
BIOLOGICAL PATHWAYS
CARCINOMAS
GENES
GENETIC RADIATION EFFECTS
LUNGS
RADIOINDUCTION
RATS
SOMATIC MUTATIONS