α-Catenin is an inhibitor of transcription
α-Catenin is an inhibitor of transcription
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DOI：
10.1073/pnas.1308663111
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发表时间：
2014-04-08
影响因子：
11.1
通讯作者：
Gottardi, Cara J.
中科院分区：
文献类型：
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作者：
Daugherty, Rebecca L.;Serebryannyy, Leonid;Gottardi, Cara J.
α-连环蛋白 (α-cat) 是细胞间凝聚所需的肌动蛋白结合蛋白。尽管α-cat的这种粘附功能已广为人知，但细胞含有大量可用于其他功能的非连接α-cat。我们证明α-cat是一种核蛋白，可以与β-连环蛋白（β-cat）和T细胞因子（TCF）相互作用，并且α-cat的核积累依赖于β-cat。使用过表达、敲低和染色质免疫沉淀方法，我们发现 α-cat 以启动子上加载的 β-cat/TCF 下游的方式减弱 Wnt/β-cat 反应基因。 α-cat 的 β-cat 和肌动蛋白结合域都是抑制 Wnt 信号传导所必需的。 α-cat 的核靶向形式诱导核丝状肌动蛋白的形成，而缺乏 α-cat 的细胞显示出改变的核肌动蛋白特性。核肌动蛋白丝的形成与 RNA 合成减少和染色质组织改变相关。相反，由缺乏 α-cat 的细胞制成的核提取物在体外显示出增强的一般转录，这种活性可以通过恢复 α-cat 的 C 端肌动蛋白结合区域来部分恢复。这些数据表明α-cat可能通过影响核肌动蛋白组织来限制基因表达。
alpha-Catenin (alpha-cat) is an actin-binding protein required for cell-cell cohesion. Although this adhesive function for alpha-cat is well appreciated, cells contain a substantial amount of nonjunctional alpha-cat that may be used for other functions. We show that alpha-cat is a nuclear protein that can interact with beta-catenin (beta-cat) and T-cell factor (TCF) and that the nuclear accumulation of alpha-cat depends on beta-cat. Using overexpression, knockdown, and chromatin immunoprecipitation approaches, we show that alpha-cat attenuates Wnt/beta-cat-responsive genes in a manner that is downstream of beta-cat/TCF loading on promoters. Both beta-cat- and actin-binding domains of alpha-cat are required to inhibit Wnt signaling. A nuclear-targeted form of alpha-cat induces the formation of nuclear filamentous actin, whereas cells lacking alpha-cat show altered nuclear actin properties. Formation of nuclear actin filaments correlates with reduced RNA synthesis and altered chromatin organization. Conversely, nuclear extracts made from cells lacking alpha-cat show enhanced general transcription in vitro, an activity that can be partially rescued by restoring the C-terminal actin-binding region of alpha-cat. These data demonstrate that alpha-cat may limit gene expression by affecting nuclear actin organization.