Phosphorylation of eIF4E promotes EMT and metastasis via translational control of SNAIL and MMP-3.
Phosphorylation of eIF4E promotes EMT and metastasis via translational control of SNAIL and MMP-3.
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DOI：
10.1038/onc.2014.146
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发表时间：
2015-04-16
期刊：
影响因子：
8
通讯作者：
Sonenberg N
中科院分区：
文献类型：
--
作者：
Robichaud N;del Rincon SV;Huor B;Alain T;Petruccelli LA;Hearnden J;Goncalves C;Grotegut S;Spruck CH;Furic L;Larsson O;Muller WJ;Miller WH;Sonenberg N
癌症从原发性肿瘤到侵袭性和转移性阶段的进展占癌症死亡的绝大多数。因此，了解促进转移的分子事件在临床上至关重要。翻译控制是肿瘤发生的一个重要因素。mRNA帽结合蛋白eIF 4 E是一种在癌症发生和发展中起重要作用的癌蛋白。eIF 4 E必须被磷酸化以促进肿瘤发展。然而，eIF 4 E磷酸化在转移中的作用尚不清楚。在这里，我们表明，小鼠eIF 4 E不能被磷酸化是耐肺转移的乳腺肿瘤模型，从这些小鼠中分离的细胞表现出受损的侵袭。我们还证明，TGFβ诱导eIF 4 E磷酸化，以促进Snail和Mmp-3 mRNA的翻译，并诱导上皮向间充质转化（EMT）。此外，我们描述了一种新的模型，其中TGFβ诱导的EMT需要通过非经典TGFβ信号传导分支的翻译激活，该分支通过eIF 4 E磷酸化起作用。
The progression of cancers from primary tumors to invasive and metastatic stages accounts for the overwhelming majority of cancer deaths. Understanding the molecular events which promote metastasis is thus critical in the clinic. Translational control is emerging as an important factor in tumorigenesis. The mRNA cap-binding protein eIF4E is an oncoprotein that plays an important role in cancer initiation and progression. eIF4E must be phosphorylated to promote tumor development. However, the role of eIF4E phosphorylation in metastasis is not known. Here, we show that mice in which eIF4E cannot be phosphorylated are resistant to lung metastases in a mammary tumor model, and that cells isolated from these mice exhibit impaired invasion. We also demonstrate that TGFβ induces eIF4E phosphorylation to promote translation of Snail and Mmp-3 mRNAs, and the induction of epithelial-to-mesenchymal transition (EMT). Furthermore, we describe a new model wherein EMT induced by TGFβ requires translational activation via the non-canonical TGFβ signaling branch acting through eIF4E phosphorylation.