Tsuchiya H, Orimoto K, Kobayashi K, Hino O
Department of Experimental Pathology, Cancer Institute, Tokyo, Japan.
Cancer Res. 1996 Feb 1;56(3):429-33.
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.
埃克大鼠遗传性肾癌是实验动物中孟德尔显性遗传易患特定癌症的一个典型例子。我们最近报道，人类结节性硬化症基因（TSC2）的大鼠同源基因中的种系插入导致了埃克大鼠模型中的显性遗传癌症，以及Tsc2基因功能的肿瘤抑制特性。我们还表明大鼠和人类基因产物之间有很强的保守性。尽管Tsc2基因产物（在人类中称为“结节蛋白”）含有一段与ras家族GTP酶激活蛋白（Rap1GAP）同源的短氨基酸序列，但其分子功能尚不清楚。在此，我们描述了Tsc2产物羧基末端（分别在外显子30、32和41中）的转录激活结构域（AD1和AD2）。埃克插入突变（内含子30）破坏了它们的转录活性。虽然羧基末端截短的Tsc2蛋白定位于细胞核，但全长蛋白主要存在于细胞质的核周区域。Tsc2基因中转录激活结构域的目前这一证明为研究其在肾癌发生中的作用提供了线索。
