Codon 12 of the K-ras gene is a generally recognized example of a mutational hot spot. By the approach of gel retardation and specific antibodies, a double-stranded oligonucleotide corresponding to the codon 12 region of the mouse K-ras gene (from 20 to 50 bp with respect to the exon 1 start) was found to be a site for cooperative binding of the transcription factors GATA-6 and NF-Y. GATA-6 and NF-Y were selectively activated with lung carcinogens 3-methylcholanthrene and nitrosoethylurea in mice of strains susceptible to lung tumorigenesis but not in animals of resistant strains. The interaction of GATA-6 and NF-Y with the codon 12 region of the K-ras gene is suggested to be involved in the mechanism of lung carcinogenesis.