TRANSGENIC RESCUE FROM EMBRYONIC LETHALITY AND RENAL CARCINOGENESIS IN THE EKER RAT MODEL BY INTRODUCTION OF A WILD-TYPE TSC2 GENE

We recently reported that a germ-line insertion in the rat homologue o f the human tuberous sclerosis gene (TSC2) gives rise to dominantly in herited cancer in the Eker rat model. In this study, we constructed tr ansgenic Eker rats with introduction of a wild-type Tsc2 gene to ascer tain whether suppression of the Eker phenotype is possible. Rescue fro m embryonic lethality of mutant homozygotes (Eker/Eker) and suppressio n of N-ethyl-N-nitrosourea-induced renal carcinogenesis in heterozygot es (Eker/+) were both observed, defining the germ-line Tsc2 mutation i n the Eker rat as embryonal lethal and tumor predisposing mutation. To the best of our knowledge, this is the first report of rescue from a naturally occurring dominantly inherited cancer. This transgenic rescu e system will be useful to analyze Tsc2 gene function, its relation to tumorigenesis in vivo, and genetic-environmental interactions in carc inogenesis.