Regulation of Tcf7l1 DNA binding and protein stability as principal mechanisms of Wnt/β-catenin signaling.
Regulation of Tcf7l1 DNA binding and protein stability as principal mechanisms of Wnt/β-catenin signaling.
复制标题
DOI：
10.1016/j.celrep.2013.06.001
复制
发表时间：
2013-07-11
期刊：
影响因子：
8.8
通讯作者：
Merrill BJ
中科院分区：
文献类型：
--
作者：
Shy BR;Wu CI;Khramtsova GF;Zhang JY;Olopade OI;Goss KH;Merrill BJ
Wnt/β-catenin信号转导需要β-catenin与Tcf/Lef蛋白的直接结合，这是一个典型的与通过募集共激活因子刺激转录相关的事件。这种分子级联通过影响干细胞特征和肿瘤形成在整个胚胎发育和正常出生后生活中起着关键作用。在这里，我们表明，这一途径利用一个根本不同的机制来调节Tcf 7 l1（以前称为Tcf 3）的活动。β-连环蛋白通过将Tcf 7 l1从DNA中去除而使Tcf 7 l1失活，而无需转换为辅激活因子复合物，这导致Tcf 7 l1蛋白降解。小鼠遗传学实验表明，Tcf 7 l1失活是Tcf 7 l1-β-catenin相互作用的唯一必需效应。考虑到Tcf 7 l1在多能胚胎干细胞和成体干细胞以及低分化乳腺癌中的表达，这些发现为乳腺癌中多能性的调节和Wnt/β-连环蛋白的作用提供了机制见解。
Wnt/β-catenin signal transduction requires direct binding of β-catenin to Tcf/Lef proteins, an event that is classically associated with stimulating transcription by recruiting coactivators. This molecular cascade plays critical roles throughout embryonic development and normal postnatal life by affecting stem cell characteristics and tumor formation. Here, we show that this pathway utilizes a fundamentally different mechanism to regulate Tcf7l1 (formerly named Tcf3) activity. β-catenin inactivates Tcf7l1 without a switch to a coactivator complex by removing it from DNA, which leads to Tcf7l1 protein degradation. Mouse genetic experiments demonstrate that Tcf7l1 inactivation is the only required effect of the Tcf7l1-β-catenin interaction. Given the expression of Tcf7l1 in pluripotent embryonic and adult stem cells, as well as in poorly differentiated breast cancer, these findings provide mechanistic insights into the regulation of pluripotency and the role of Wnt/β-catenin in breast cancer.
登录
查看更多内容
影响因子：
64.8
作者：
Ishitani, T;Ninomiya-Tsuji, J;Matsumoto, K
通讯作者：
Matsumoto, K
影响因子：
4.8
作者：
Filali, M;Cheng, NL;Engelhardt, JF
通讯作者：
Engelhardt, JF
影响因子：
64.8
作者：
NUSSE, R;VANOOYEN, A;VARMUS, H
通讯作者：
VARMUS, H
影响因子：
11.4
作者：
Aberle, H;Bauer, A;Kemler, R
通讯作者：
Kemler, R
影响因子：
4.8
作者：
Hikasa, Hiroki;Sokol, Sergei Y.
通讯作者：
Sokol, Sergei Y.