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 lung t umor resistance and suppression, These genes are located in a region o f mouse chromosome 18 that is syntenic with human 18q21.1, where sever al genes that are mutated in various cancers have been mapped. A newly identified murine lung tumor resistance locus, Par2 has also been map ped to this region of chromosome 18, We found no mutations in the codi ng regions of either gene in 11 lung tumors from B6CF1 (C57BL/6xBALB/c ) mice by RT-PCR and SSCP/RFLP, suggesting that these genes are not mu tated in lung carcinogenesis in this strain, Moreover, loss of heteroz ygosity in this region of chromosome 18 was not detected in 28 lung ad enocarcinomas from B6CF1 mice, 17 lung adenocarcinomas from B6C3F1 mic e or 18 lung adenocarcinomas from AB6F1 mice, These data provide evide nce that a 'classical' tumor suppressor gene for mouse lung carcinogen esis in these strains does not reside in this region, In order to inve stigate Smad4/Dpc4 and Smad2 as candidates for the Par2 resistance loc us mapped to this region, we also sequenced the coding regions of both genes in cDNA from normal lungs of A/J, BALB/c and C57BL/6 inbred str ains of mice, No polymorphisms were detected in the coding region of S mad4. In Smad2, two sequence polymorphisms were identified that are no t in the conserved regions of the gene, Northern blot analysis reveale d no differential expression in normal lung tissue among the three str ains for either gene, Thus, in this study we found no evidence that ei ther Smad4 or Smad2 represents the Par2 lung tumor resistance locus or is a lung tumor suppressor gene in the B6CF1 mice.