Transforming Growth Factor-β1 Induced Epithelial Mesenchymal Transition is blocked by a chemical antagonist of translation factor eIF4E.
Transforming Growth Factor-β1 Induced Epithelial Mesenchymal Transition is blocked by a chemical antagonist of translation factor eIF4E.
复制标题
DOI：
10.1038/srep18233
复制
发表时间：
2015-12-18
影响因子：
4.6
通讯作者：
Bitterman PB
中科院分区：
文献类型：
--
作者：
Smith KA;Zhou B;Avdulov S;Benyumov A;Peterson M;Liu Y;Okon A;Hergert P;Braziunas J;Wagner CR;Borok Z;Bitterman PB
上皮细胞向间质细胞转化（EMT）赋予癌症和器官纤维化中的上皮细胞疾病定义特性。先前的研究确定了转录和翻译水平上的EMT控制点，并表明翻译起始因子4 E（eIF 4 E）的激活参与了协调这两个水平控制的机制。我们发现，4 Ei-1是eIF 4 E-mRNA帽相互作用的特异性化学拮抗剂，可有效抑制肺上皮细胞中转化生长因子β 1（TGF-β1）介导的EMT。在用TGF-β1处理后，我们观察到Snail 1 mRNA快速募集到活跃翻译的多核糖体池中，伴随着EMT转录因子Snail 1在细胞核中的积累。4 Ei-1阻断核糖体向Snail 1转录物的募集，从而防止Snail 1蛋白在细胞核中的积累。我们的研究结果确立了上游翻译控制下游Snail 1介导的转录事件在TGF-β1诱导的EMT中的强制性作用，并为在癌症和器官纤维化的背景下，作为抑制病理性EMT的一种手段，间接调节eIF 4 E-cap相互作用的努力提供了概念证据。
The epithelial to mesenchymal transition (EMT) imparts disease-defining properties to epithelial cells in cancer and organ fibrosis. Prior studies identify EMT control points at the level of transcription and translation, and indicate that activation of translation initiation factor 4E (eIF4E) is involved in the mechanisms coordinating these two levels of control. Here we show that 4Ei-1, a specific chemical antagonist of the eIF4E-mRNA cap interaction, potently inhibits transforming growth factor beta 1 (TGF-β1) mediated EMT in lung epithelial cells. Upon treatment with TGF-β1, we observed a rapid recruitment of Snail1 mRNA into the actively translated polysome pool accompanied by accumulation of the EMT transcription factor Snail1 in the nucleus. 4Ei-1 blocks ribosome recruitment to the Snail1 transcript thereby preventing accumulation of the Snail1 protein in the nucleus. Our findings establish an obligatory role for upstream translational control of downstream Snail1-mediated transcriptional events in TGF-β1 induced EMT, and provide proof of concept for efforts to pharmacologically modulate the eIF4E-cap interaction as a means to inhibit pathological EMT in the setting of cancer and organ fibrosis.