Carcinogenesis, Vol 19, 1503-1508, Copyright © 1998 by Oxford University Press
SE Jones-Bolin, E Johansson, WA Palmisano, MW Anderson, JS Wiest and SA Belinsky
Differences in tumor formation among inbred mouse strains with high (A/J)
and low (C3H) susceptibility for lung cancer have been linked to a
repetitive element within the second intron of the K-ras gene. The purpose
of this investigation was to determine whether differences within the K-ras
gene promoter region or the intron 2 polymorphism affect K-ras gene
expression in lung tumors and target alveolar type II cells isolated from
A/J and C3H mice. Ribonuclease protection assays were performed using RNA
isolated from 4-(methylnitrosamino)-1-(3- pyridyl)-1-butanone (NNK)-induced
lung tumors from each mouse strain and alveolar type II cells isolated from
A/J and C3H mice. An 838 bp fragment of the murine K-ras gene promoter
region was amplified by PCR, cloned and sequenced from both mouse strains.
Promoter regions from both mouse strains were inserted into a luciferase
reporter gene vector, with and without the second intron polymorphism, and
transfected into sensitive, intermediate and resistant lung tumor cell
lines. No significant differences in K-ras gene promoter activity was found
between the two strains using these specific reporter gene constructs.
Consistent with these results, levels of K-ras expression did not differ
between alveolar type II cells, whole lung or tumors induced by NNK in A/J
or C3H mice. Moreover, in lung tumor cell lines derived from mice with
differing susceptibility for lung cancer, K-ras expression did not
correlate with the growth rate of tumors induced in nude mice from these
cell lines. These results indicate that factors involved in modulating the
rapid clonal expansion of the mutated K-ras allele from A/J mice are not
directly linked to expression of this gene. Other genetic changes or losses
in conjunction with hypothesized modifier loci, such as the Par1 locus,
must play a significant role in establishing the phenotypic strain
differences for lung tumor formation.
ARTICLES
Effect of promoter and intron 2 polymorphisms on murine lung K-ras gene expression
Lovelace Respiratory Research Institute, Albuquerque, NM 87185, USA.
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