The goal of this proposal is to identify the pulmonary adenoma susceptibility 1 gene (Pas 1), 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. A major quantitative trait locus (QTL) responsible for lung tumor susceptibility to chemical carcinogens has been mapped to distal chromosome 6 in mice which accounts for approximately 50% of variance in tumor multiplicity between the susceptible A/J mouse and the resistant C57BL/6J mouse. The existence of Pas 1 locus will be confirmed by the construction of congenic strains in which high lung tumor susceptibility (A/J) allele is substituted onto the genetic background of the C57BL/6J mouse. The congenic chromosomal segment containing the Pas 1 QTL will then be progressively reduced by congenic mouse strain construction until the region is small enough for positional cloning of the Pas 1 gene, which requires a congenic region of approximately 0.5 - 1 centiMorgan. Based on flanking marker sequences, the DNA sequences of the entire region will be obtained from Celera mouse genome database. New and known genes in the target region will also be identified through the annotated Celera sequence database and the annotated public mouse sequence database. Candidate genes will be sought based on known or deduced function and/or differences in expression between lungs from A/J mice and those from C57BL/6J mice. Finally, the functional role of the candidate Pas 1 gene will be evaluated by constructing knock-in mice with the A/J Pas 1 allele to be replaced with the C57BL/6J allele. The resulting mouse will be subjected to lung carcinogenesis assay to confirm the Pas 1 gene. The significance of these studies is that they will identify the Pas 1 gene whose human homologue may predispose some individuals to lung cancer.
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