ALLELE-SPECIFIC ACTIVATION AND EXPRESSION OF THE K-RAS GENE IN HYBRIDMOUSE LUNG-TUMORS INDUCED BY CHEMICAL CARCINOGENS

A mouse hybrid, (C3H X A/J)F1 or C3A, was developed by crossing male A /J mice (high lung tumor susceptibility) with female C3H mice (low lun g tumor susceptibility). The lung tumor responses of the C3A mice to d imethylnitrosamine (DMN) or benzo[a]pyrene (B[a]P) were found to be in termediate between those of the two parental strains. Mutational activ ation of the K-ras gene was found at a high frequency in both the B[a] P- and DMN-induced C3A lung tumors. To explore the genetic basis of th e K-ras gene involvement in mouse lung tumor susceptibility, the paren tal origin of the K-ras oncogene in the chemically induced C3A lung tu mors was determined. K-ras oncogenes were found on the allele inherite d from the susceptible A/J parent in 14/16 of DMN-induced tumors and 1 5/17 of B[a]P-induced tumors from C3A mice. Furthermore, the K-ras mRN A transcribed from the A/J allele was 5-20 times more than C3H K-ras t ranscripts in 10/10 DMN-induced and 10/10 B[a]P-induced C3A lung tumor s, These data suggest that an activated A/J K-ras allele could be more tumorigenic than an activated C3H allele due to the differential expr ession of the two alleles in lung cells.