Smad4 (homolog of human DPC4) and Smad2 (homolog of human JV18-1): candidates for murine lung tumor resistance and suppressor genes

In this study we investigated the mouse mad-related genes, Smad4/Dpc4 and Smad2 (homolog of JV18-1), as candidates for involvement in lungtumor resistance and suppression. These genes are located in a region of mouse chromosome 18that is syntenic with human 18q21.1, where several genes that are mutated in various cancers have been mapped. A newly identified murine lungtumor resistance locus, Par2 has also been mapped to this region of chromosome 18. We found no mutations in the coding regionsof either gene in 11 lungtumors from B6CF1 (C57BL/ 6xBALB/c) mice by RT-PCR and SSCP/RFLP, suggesting that these genes are not mutated in lungcarcinogenesis in this strain. Moreover, lossof heterozygosityin this region of chromosome 18was not detected in 28 lungadenocarcinomas from B6CF1 mice, 17 lungadenocarcinomas from B6C3F1 mice or 18 lungadenocarcinomas from AB6F1 mice. These data provide evidence that a 'classical' tumor suppressor genefor mouse lungcarcinogenesis in these strains does not reside in this region. In order to investigate Smad4/Dpc4 and Smad2 as candidates for the Par2 resistance locus mapped to this region, we also sequenced the coding regionsof both genes in cDNA from normal lungsof A/J, BALB/c and C57BL/6 inbred strains of mice. No polymorphisms were detected in the coding regionof Smad4. In Smad2, two sequence polymorphisms were identified that are not in the conserved regions of the gene. Northern blot analysis revealed no differential expression in normal lungtissue among the three strains for either gene. Thus, in this study we found no evidence that either Smad4 or Smad2 represents the Par2 lungtumor resistance locus or is a lung tumor suppressor genein the B6CF1 mice.