Nuclear AXIN2 represses MYC gene expression.
Nuclear AXIN2 represses MYC gene expression.
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DOI：
10.1016/j.bbrc.2013.11.089
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发表时间：
2014-01-03
影响因子：
3.1
通讯作者：
Yochum, Gregory S.
中科院分区：
文献类型：
--
作者：
Rennoll, Sherri A.;Konsavage, Wesley M., Jr.;Yochum, Gregory S.
β-catenin转录共激活因子是经典Wnt信号通路的关键介质。在不存在Wnt的情况下，β-连环蛋白与胞质和多蛋白质破坏复合物缔合，其中其被磷酸化并靶向蛋白酶体降解。在Wnt的存在下，破坏复合物被灭活，β-连环蛋白易位到细胞核中。在细胞核中，β-连环蛋白结合T细胞因子（TCF）转录因子以激活c-MYC（MYC）和轴抑制蛋白2（AXIN 2）的表达。AXIN 2是破坏复合体的成员，因此在负反馈循环中起作用，控制Wnt/β-连环蛋白信号传导。AXIN 2也存在于细胞核中，但其在该隔室中的功能尚不清楚。在这里，我们证明，AXIN 2定位于正常和结肠肿瘤组织以及结直肠癌细胞系内的上皮细胞的细胞核。在细胞核中，AXIN 2抑制Wnt/β-连环蛋白应答荧光素酶报告基因的表达，并与β-连环蛋白和TCF形成复合物。我们证明AXIN 2共占据MYC启动子区域的β-catenin/TCF复合物。当组成型定位于细胞核时，AXIN 2改变MYC启动子处的染色质结构并直接抑制MYC基因表达。这些发现表明，核AXIN 2作为变阻器起作用，以响应Wnt/β-catenin信号传导来控制MYC表达。
The β-catenin transcriptional coactivator is the key mediator of the canonical Wnt signaling pathway. In the absence of Wnt, β-catenin associates with a cytosolic and multi-protein destruction complex where it is phosphorylated and targeted for proteasomal degradation. In the presence of Wnt, the destruction complex is inactivated and β-catenin translocates into the nucleus. In the nucleus, β-catenin binds T-cell factor (TCF) transcription factors to activate expression of c-MYC (MYC) and Axis inhibition protein 2 (AXIN2). AXIN2 is a member of the destruction complex and, thus, serves in a negative feedback loop to control Wnt/β-catenin signaling. AXIN2 is also present in the nucleus, but its function within this compartment is unknown. Here, we demonstrate that AXIN2 localizes to the nuclei of epithelial cells within normal and colonic tumor tissues as well as colorectal cancer cell lines. In the nucleus, AXIN2 represses expression of Wnt/β-catenin-responsive luciferase reporters and forms a complex with β-catenin and TCF. We demonstrate that AXIN2 co-occupies β-catenin/TCF complexes at the MYC promoter region. When constitutively localized to the nucleus, AXIN2 alters the chromatin structure at the MYC promoter and directly represses MYC gene expression. These findings suggest that nuclear AXIN2 functions as a rheostat to control MYC expression in response to Wnt/β-catenin signaling.
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影响因子：
5.3
作者：
Yochum, Gregory S.;Cleland, Ryan;Goodman, Richard H.
通讯作者：
Goodman, Richard H.
影响因子：
4.8
作者：
Konsavage, Wesley M., Jr.;Kyler, Sydney L.;Yochum, Gregory S.
通讯作者：
Yochum, Gregory S.
影响因子：
5.3
作者：
Lustig, B;Jerchow, B;Behrens, J
通讯作者：
Behrens, J
影响因子：
50.3
作者：
Murphy DJ;Junttila MR;Pouyet L;Karnezis A;Shchors K;Bui DA;Brown-Swigart L;Johnson L;Evan GI
通讯作者：
Evan GI
影响因子：
56.9
作者：
He, TC;Sparks, AB;Kinzler, KW
通讯作者：
Kinzler, KW