Fodde R, Edelmann W, Yang K, van Leeuwen C, Carlson C, Renault B, Breukel C, Alt E, Lipkin M, Khan P M
Department of Genetics, Leiden University, The Netherlands.
Proc Natl Acad Sci U S A. 1994 Sep 13;91(19):8969-73. doi: 10.1073/pnas.91.19.8969.
Germ-line mutations in the human adenomatous polyposis coli (APC) gene result in familial adenomatous polyposis, an autosomal dominant disorder characterized by the early onset of multiple adenomatous polyps in the large bowel with a high likelihood of developing colorectal carcinomas. To understand the role of APC in intestinal tumor formation, we have introduced a chain-termination mutation in the 15th exon of the mouse Apc gene and employed it to modify the endogenous gene by homologous recombination in embryonic stem cells. Mice which are heterozygous for the Apc gene modification progressively develop intestinal tumors in a manner that is similar to that observed in patients with familial adenomatous polyposis and in mice which carry a mutation called multiple intestinal neoplasia (Min). Our results indicate that the Apc gene modification is a critical event in the initiation of intestinal tumor formation and results in an autosomal dominant predisposition toward development of spontaneous colonic and intestinal tumors in mice.
人类腺瘤性息肉病 coli（APC）基因的种系突变会导致家族性腺瘤性息肉病，这是一种常染色体显性疾病，其特征是大肠中早期出现多个腺瘤性息肉，且患结直肠癌的可能性很高。为了了解 APC 在肠道肿瘤形成中的作用，我们在小鼠 Apc 基因的第 15 外显子中引入了一个链终止突变，并利用它通过胚胎干细胞中的同源重组来修饰内源基因。对 Apc 基因进行修饰的杂合小鼠会逐渐发展出肠道肿瘤，其方式类似于在家族性腺瘤性息肉病患者以及携带一种名为多发性肠道肿瘤（Min）突变的小鼠中观察到的情况。我们的结果表明，Apc 基因修饰是肠道肿瘤形成起始中的一个关键事件，并导致小鼠出现常染色体显性倾向，易于自发发生结肠和肠道肿瘤。
