Deficiency of Mbd2 attenuates Wnt signaling
Deficiency of Mbd2 attenuates Wnt signaling
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DOI：
10.1128/mcb.00539-08
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发表时间：
2008-10-01
影响因子：
5.3
通讯作者：
Clarke, Alan R.
中科院分区：
文献类型：
--
作者：
Phesse, Toby J.;Parry, Lee;Clarke, Alan R.
我们以前已经表明，甲基结合结构域蛋白Mbd2的缺陷显着降低腺瘤负担的Apc（Min/+）背景。为了研究这种现象的机制，我们已经确定了Mbd2缺乏对小肠中Apc条件性缺失所施加的表型的影响。微阵列分析表明，在Mbd2的情况下，Wnt途径的部分抑制。Mbd2缺陷也影响了Apc丢失的一个直接细胞后果，使潘氏细胞定位正常化。从机理的角度来看，我们表明Mbd2的缺乏提高了已知Wnt靶点Lect 2的水平，并且我们在这里证实Mbd2结合与NuRD相关的Lect 2启动子。此外，我们表明，Lect 2是能够作为Wnt途径抑制剂。因此，这些结果提供了通过Mbd2介导的腺瘤形成的表观遗传控制的机制基础。
We have previously shown that deficiency of the methyl binding domain protein Mbd2 dramatically reduces adenoma burden on an Apc(Min/+) background. To investigate the mechanism underlying this phenomenon, we have determined the effect of Mbd2 deficiency upon the phenotypes imposed by the conditional deletion of Apc in the small intestine. Microarray analysis demonstrated a partial suppression of the Wnt pathway in the absence of Mbd2. Mbd2 deficiency also influenced one immediate cellular consequence of Apc loss, with normalization of Paneth cell positioning. From a mechanistic perspective, we show that deficiency of Mbd2 elevates levels of the known Wnt target Lect2, and we confirm here that Mbd2 binds the Lect2 promoter in association with NuRD. Furthermore, we show that Lect2 is capable of functioning as a Wnt pathway repressor. These results therefore provide a mechanistic basis for the epigenetic control of adenoma formation mediated through Mbd2.