Edelmann W, Yang K, Kuraguchi M, Heyer J, Lia M, Kneitz B, Fan K, Brown A M, Lipkin M, Kucherlapati R
Department of Molecular Genetics, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Cancer Res. 1999 Mar 15;59(6):1301-7.
An3 1 KAL I MutL homologue 1 (MLH1) is a member of the family of proteins required for DNA mismatch repair. Germ-line mutations in MLH1 lead to the cancer susceptibility syndrome hereditary nonpolyposis colorectal cancer (HNPCC). We generated mice carrying a null mutation in the Mlh1 gene. We showed that mice heterozygous and homozygous for the Mlh1 gene are predisposed to developing tumors of the gastrointestinal (GI) tract, lymphomas, and a number of other tumor types. We also examined the role of adenomatous polyposis coli gene (Apc) gene mutations in the GI tumors of Mlh1 mutant mice by different methods and showed that the GI tumors in Mlh1 mice express little or no adenomatous polyposis coli protein. When an Apc gene mutation was bred into the Mlh1 mutant mice, the GI tumor incidence increased 40-100-fold. The wild-type Apc allele in these tumors was found to contain mutations. Together, these results show that we have developed two mouse models for human HNPCC and that the mechanisms of tumor development in the GI tract of these mice involve loss of Apc gene function in a manner very similar to that seen in the GI tumors of HNPCC.
错配修复蛋白1（MLH1）是DNA错配修复所需蛋白质家族的成员。MLH1的种系突变会导致癌症易感性综合征——遗传性非息肉病性结直肠癌（HNPCC）。我们构建了Mlh1基因无效突变的小鼠。我们发现，Mlh1基因杂合和纯合的小鼠易患胃肠道（GI）肿瘤、淋巴瘤及其他多种肿瘤类型。我们还通过不同方法研究了腺瘤性息肉病（Apc）基因突变在Mlh1突变小鼠胃肠道肿瘤中的作用，结果表明Mlh1小鼠的胃肠道肿瘤很少表达或不表达腺瘤性息肉病蛋白。当将Apc基因突变引入Mlh1突变小鼠时，胃肠道肿瘤发病率增加了40至100倍。这些肿瘤中的野生型Apc等位基因被发现含有突变。这些结果共同表明，我们已经建立了两种人类HNPCC的小鼠模型，并且这些小鼠胃肠道肿瘤的发生机制涉及Apc基因功能的丧失，其方式与HNPCC胃肠道肿瘤中所见的非常相似。
