Laird P W, Jackson-Grusby L, Fazeli A, Dickinson S L, Jung W E, Li E, Weinberg R A, Jaenisch R
Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge 02142, USA.
Cell. 1995 Apr 21;81(2):197-205. doi: 10.1016/0092-8674(95)90329-1.
We have used a combination of genetics and pharmacology to assess the effects of reduced DNA methyltransferase activity on ApcMin-induced intestinal neoplasia in mice. A reduction in the DNA methyltransferase activity in Min mice due to heterozygosity of the DNA methyltransferase gene, in conjunction with a weekly dose of the DNA methyltransferase inhibitor 5-aza-deoxycytidine, reduced the average number of intestinal adenomas from 113 in the control mice to only 2 polyps in the treated heterozygotes. Hence, DNA methyltransferase activity contributes substantially to tumor development in this mouse model of intestinal neoplasia. Our results argue against an oncogenic effect of DNA hypomethylation. Moreover, they are consistent with a role for DNA methyltransferase in the generation of the C to T transitions seen at high frequency in human colorectal tumors.
我们运用遗传学与药理学相结合的方法，评估DNA甲基转移酶活性降低对ApcMin诱导的小鼠肠道肿瘤形成的影响。由于DNA甲基转移酶基因杂合性，Min小鼠的DNA甲基转移酶活性降低，再结合每周一次的DNA甲基转移酶抑制剂5-氮杂脱氧胞苷剂量，使肠道腺瘤的平均数量从对照小鼠的113个减少至经治疗的杂合子小鼠仅2个息肉。因此，在这种肠道肿瘤小鼠模型中，DNA甲基转移酶活性对肿瘤发展有显著作用。我们的结果反驳了DNA低甲基化的致癌作用。此外，它们与DNA甲基转移酶在人类结肠直肠癌中高频出现的C到T转变的产生过程中所起的作用是一致的。
