Alkylation-induced colon tumorigenesis in mice deficient in the Mgmt and Msh6 proteins.
Alkylation-induced colon tumorigenesis in mice deficient in the Mgmt and Msh6 proteins.
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烷基化诱导的MGMT和MSH6蛋白缺乏小鼠的结肠肿瘤发生。
DOI：
10.1038/onc.2008.426
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发表时间：
2009-02-05
期刊：
影响因子：
8
通讯作者：
Samson, L. D.
中科院分区：
文献类型：
--
作者：
Bugni, J. M.;Meira, L. B.;Samson, L. D.
O6-甲基鸟嘌呤 DNA 甲基转移酶 (MGMT) 可抑制烷基化损伤导致的突变和细胞死亡。在多种人类癌症中，包括近一半的散发性结直肠癌，MGMT 表达因表观遗传沉默而丢失，这表明这种丢失可能是因果关系。使用靶向破坏 Mgmt 基因的小鼠，我们测试了 Mgmt 是否可以预防氧化偶氮甲烷 (AOM) 诱导的结肠异常隐窝病灶 (ACF)、AOM 和葡聚糖硫酸钠 (DSS) 诱导的结直肠腺瘤以及 ApcMin 小鼠的自发性肠腺瘤。我们还检查了 Mgmt 无效基因与 DNA 错配修复无效基因（即 Msh6）的遗传相互作用。 Mgmt 和 Msh6 均独立抑制 AOM 诱导的 ACF，并且两个突变等位基因的组合具有倍增效应。这种协同作用完全可以通过当 Msh6 缺失时烷基化诱导的细胞凋亡受到抑制来解释。此外，在 AOM+DSS 治疗后，Mgmt 防止腺瘤形成的程度与防止 AOM 诱导的 ACF 形成的程度相同。最后，Mgmt 缺乏并不影响 ApcMin/+ 小鼠自发性肠腺瘤的发展，这表明 Mgmt 抑制与外源性烷化剂相关的肠癌，并且内源性烷基化不会促进 ApcMin/+ 小鼠肿瘤的快速发展。
O6-methylguanine DNA methyltransferase (MGMT) suppresses mutations and cell death that result from alkylation damage. MGMT expression is lost by epigenetic silencing in a variety of human cancers including nearly half of sporadic colorectal cancers, suggesting that this loss maybe causal. Using mice with a targeted disruption of the Mgmt gene we tested whether Mgmt protects against azoxymethane (AOM) induced colonic aberrant crypt foci (ACF), against AOM and dextran sulfate sodium (DSS) induced colorectal adenomas, and against spontaneous intestinal adenomas in ApcMin mice. We also examined the genetic interaction of the Mgmt null gene with a DNA mismatch repair null gene, namely Msh6. Both Mgmt and Msh6 independently suppress AOM-induced ACF, and combination of the two mutant alleles had a multiplicative effect. This synergism can be explained entirely by the suppression of alkylation-induced apoptosis when Msh6 is absent. In addition, following AOM+DSS treatment Mgmt protected against adenoma formation to the same degree as it protected against AOM-induced ACF formation. Finally, Mgmt deficiency did not affect spontaneous intestinal adenoma development in ApcMin/+ mice, suggesting that Mgmt suppresses intestinal cancer associated with exogenous alkylating agents, and that endogenous alkylation does not contribute to the rapid tumor development seen in ApcMin/+ mice.
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影响因子：
2.7
作者：
Glassner, BJ;Weeda, G;Samson, LD
通讯作者：
Samson, LD
影响因子：
5.8
作者：
Kaina, B
通讯作者：
Kaina, B
DOI：
10.1073/pnas.96.19.10764
发表时间：
1999-09-14
影响因子：
11.1
作者：
Hickman, MJ;Samson, LD
通讯作者：
Samson, LD
影响因子：
2.9
作者：
Fang, QM;Kanugula, S;Pegg, AE
通讯作者：
Pegg, AE
影响因子：
4.7
作者：
MYRNES, B;NORSTRAND, K;KROKAN, H
通讯作者：
KROKAN, H