The second intron of the K-ras gene contains regulatory elements associated with mouse lung tumor susceptibility.
We have previously demonstrated the preferential activation of the K-ras gene from the susceptible A/J parent in lung tumors from F1 mouse hybrids. In the present study, the mechanism of this observation is further investigated. Higher levels of expression of A/J K-ras allele were detected in lung adenomas (30 of 30) from the C3A mouse. In addition, three K-ras alleles, designated as susceptible (Ks), intermediate (Ki), or resistant (Kr), were identified by sequence analysis of the second intron of the K-ras gene from 32 strains of mice. These K-ras alleles are associated with differences in mouse lung tumor susceptibility. All Kr alleles have a tandem 37-bp direct repeat (nt 282-355) in the second intron of the K-ras gene. Ks and Ki alleles have only one copy of the 37-bp sequence (nt 282-318). Ks strains have three base variations at nt 288, 296, and 494, and Ki strains have two base variations at nt 288 and 494 in the second intron of the K-ras gene. Differential protein-binding patterns were observed in gel-mobility-shift experiments between the duplicated 37-bp sequence of the Kr allele and the single 37-bp sequence of the Ks and Ki alleles. DNase I footprinting assay revealed protein binding sites in the second intron of the K-ras gene that correspond to the tandem repeat sequences. Our data suggest that higher expression of the A/J allele relative to C3H allele may be responsible for the allele-specific activation of the K-ras gene in lung tumors from F1 hybrid mice.
Chen
B
B
Medical College of Ohio, Toledo 43699.
Johanson
L
L
Wiest
J S
JS
Anderson
M W
MW
You
M
M
D000236:Adenoma / Q000209:etiology / Q000235:genetics*; D000483:Alleles; D000818:Animals; D004273:DNA, Neoplasm / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D007438:Introns / Q000235:genetics*; D008175:Lung Neoplasms / Q000209:etiology / Q000235:genetics*; D051379:Mice; D008815:Mice, Inbred Strains; D009687:Nuclear Proteins / Q000378:metabolism; D011485:Protein Binding; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics*; D012091:Repetitive Sequences, Nucleic Acid; D017422:Sequence Analysis, DNA; D013045:Species Specificity
D004273:DNA, Neoplasm; D009687:Nuclear Proteins