The long term goal of this proposal is to identify the Pas 1 gene which is responsible for lung tumor susceptibility to chemical carcinogens. Chemical carcinogenesis in mouse lung may involve changes in at least three classes of genes: tumor susceptibility genes, protooncogenes, and tumor suppressor genes. Quantitative trait loci (QTL) responsible for lung tumor susceptibility to chemical carcinogens have been mapped to chromosomes 6, 9, 17, and 19. QTLs linked to lung tumor resistance were mapped to chromosomes 4, 11, and 18. The Pas1 gene is located at distal chromosome 6, accounting for approximately 50% of variance in tumor multiplicities between the susceptible A/J mouse and the resistant C57BL/6J mouse. The K-ras protooncogene is the primary candidate for the Pas1 locus based on the following evidence: a) activation of the K-ras gene is an early event frequently found in both spontaneously occurring and chemically induced mouse lung tumors; b) polymorphisms detected in the K-ras promoter and enhancer regions in different mouse strains correlate with their susceptibility to chemical induction of lung tumors; c) these polymorphisms seem to be responsible for the observed allele-specific expression of the K-ras allele in hybrid mice; d) the allele-specific expression leads to allele-specific activation of the K-ras gene; and e) genetic linkage analyses indicate a major locus only when parental mice have distinct K-ras genotypes. In the first phase of this proposal the principal investigator and coworkers will evaluate the A/J K-ras allele as the Pas1 gene by both fine-structure mapping using congenic mice and the construction of transgenic mice carrying the A/J K-ras allele on a resistant C57BL/6J background. If K-ras is confirmed to be the Pas1 gene, a systematic characterization of transcriptional regulation of this gene will be conducted with both the mouse K-ras gene and the human K-ras gene to delineate the mechanism of A/J K-ras allele- induced lung tumor susceptibility. If the A/J K-ras allele is excluded, they will clone the Pas1 locus by fine mapping of the Pas1 QTL to a 1-2 cM subregion of the chromosome by congenic mice construction and generation of congenic substrains, and followed by positional cloning of the Pas1 QTL. The significance of these studies is that they will identify the Pas1 gene whose human homologue may predispose some individuals to lung cancer.
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