Presence of potent transcriptional activation domains in the predisposing tuberous sclerosis (Tsc2) gene product of the Eker rat model.

The Eker rat hereditary renal carcinoma is an excellent example of Mendelian dominant predisposition to a specific cancer in an experimental animal. We recently reported that a germline insertion in the rat homologue of the human tuberous sclerosis gene (TSC2) gives rise to dominantly inherited cancer in the Eker rat model, as well as a tumor suppressor nature for the Tsc2 gene function. We also showed a strong conservation between the rat and human gene products. The molecular function of the Tsc2 gene product (called "tuberin" in the human case) is not yet understood, although it contains a short amino acid sequence homologous to ras family GTPase-activating proteins (Rap1GAP). Here, we describe transcriptional activation domains (AD1 and AD2) in the carboxyl terminus of the Tsc2 product (in exons 30 and 32 and exon 41, respectively). The Eker insertional mutation (intron 30) disrupts their transcriptional activity. Whereas a COOH-terminal truncated Tsc2 protein was localized in the nucleus, the full-length protein is found predominantly in the perinuclear region of cytoplasm. The present demonstration of transcriptional activation domains in the Tsc2 gene provides clues for studying its role in renal carcinogenesis.