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Regulation of S6-kinase Activity and Erc Expression in Tuberous Sclerosis 2 (Tsc2) Gene-Deficient Renal Tumor Cells

Tuberous sclerosis (TSC) is an autosomal dominantly inherited disease characterized by the development of hamartomas and tumors in various organs such as kidney, brain, lung and heart. Two causative genes for TSC. TSC1 on chromosome 9q34 and TSC2 on chromosome 16pl3.3, have been identified. Both genes act as tumor suppressors, and Knudson's two hit theory can be applied for the development of lesions in TSC. TSC1 encodes hamartin containing a coiled-coil domain, and TSC2 encodes tuberin showing weak Rapl-GAP homology. Recently, it was revealed that hamartin and tuberin form a complex and are involve in down-regulation of mTOR-p70 S6K pathway. However, activity of hamartin/tuberin complex and precise molecular mechanism undelying TSC disease remain to be determined. We identified a germline mutation of rat TSC2 homologue (Tsc2) as the predisposing mutation for the Eker rat model of dominantly inherited renal tumor. We also generated Tsc2 knockout mice and reported that heterozygous mutant mice develop renal tumors and hepatic hemangiomas. In addition, we generated Tsc1 knockout mice and demonstrated that phenotypes similar to Tsc2 knockout mice were developed in them. Currently, we are analyzing functions of hamartin and tuberin as well as molecular mechanism of pathogenesis of TSC using these mutant animal models. Recently, we generated renal tumor cell lines from a Tsc2 knockout mouse and analyzed mTOR-S6K signaling pathway in those cells. Tumor formation of those cells in nude mice was completely suppressed by rapamycin, a m TOR inhibitor, suggesting the involvement of mTOR-S6K pathway in tumorigenesis and potential therapeutic use of rapamycin for TSC. We are analyzing Erc/mesothelin expression, which is known to elevate in Tsc2-mutant renal tumor cells, and preliminarily found the suppressive effect of Tsc2 expression on Erc expression. Pathways other than mTOR-S6K may be regulated by tuberin. Through analyses using cell lines and animal models desribed here, molecular mechanism of TSC will be elucidated.