Oshima M, Oshima H, Kobayashi M, Tsutsumi M, Taketo M M
Banyu Tsukuba Research Institute (Merck), Japan.
Cancer Res. 1995 Jul 1;55(13):2719-22.
Mutations in the adenomatous polyposis coli (APC) gene are responsible for not only familial adenomatous polyposis but also many sporadic cancers of the digestive tract. Most mutations found in familial adenomatous polyposis patients are of the truncation type, and the phenotype is affected by the mutation sites in the gene. Truncated APC proteins can associate with the wild-type protein. Accordingly, it has been proposed that the polyposis is caused by a dominant negative mechanism. To test this possibility, we constructed transgenic mice that contained mutant minigenes. They expressed the APC protein truncated either at codon 716 (Apc delta 716) or 1287 (Apc delta 1287) at high levels in the intestinal epithelium. Contrary to our expectation, no intestinal polyps or tumors were found in any of such mice, even after 7 months. These results rule out any dominant negative mechanisms in which the truncated APC protein is directly involved in the formation of intestinal polyps in the mouse.
腺瘤性结肠息肉病（APC）基因的突变不仅导致家族性腺瘤性息肉病，还引发许多散发性消化道癌症。在家族性腺瘤性息肉病患者中发现的大多数突变属于截短型，其表型受基因中突变位点的影响。截短的APC蛋白可与野生型蛋白结合。因此，有人提出息肉病是由显性负性机制引起的。为了验证这种可能性，我们构建了含有突变小基因的转基因小鼠。它们在肠上皮细胞中高水平表达在密码子716（Apc delta 716）或1287（Apc delta 1287）处截短的APC蛋白。与我们的预期相反，即使在7个月后，在任何此类小鼠中都未发现肠息肉或肿瘤。这些结果排除了截短的APC蛋白直接参与小鼠肠息肉形成的任何显性负性机制。
