Eukaryotic Translation Initiation Factor 4E Is a Feed-Forward Translational Coactivator of Transforming Growth Factor β Early Protransforming Events in Breast Epithelial Cells
Eukaryotic Translation Initiation Factor 4E Is a Feed-Forward Translational Coactivator of Transforming Growth Factor β Early Protransforming Events in Breast Epithelial Cells
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DOI：
10.1128/mcb.00324-15
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发表时间：
2015-08-01
影响因子：
5.3
通讯作者：
Schneidera, Robert J.
中科院分区：
文献类型：
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作者：
Decarlo, Lindsey;Mestel, Celine;Schneidera, Robert J.
真核翻译起始因子4E （eIF4E）在乳腺癌早期过度表达，与疾病进展和生存率降低相关。关于eIF4E在人类癌症中的作用，还有很多有待了解的地方。我们使用永生化的人乳腺上皮细胞确定，eIF4E表达升高激活转化生长因子β (tgf - β)途径，促进细胞侵袭，细胞极性丧失，细胞存活增加，以及早期肿瘤的其他特征。eIF4E的过表达可促进整合素b1 mRNA的选择性翻译，从而驱动tgf - β受体信号复合物的翻译控制组装，该复合物包含α 3 β 1整合素、β -连环蛋白、tgf - β受体I、E-cadherin和磷酸化的Smad2/3。这种受体复合物使非恶性乳腺上皮细胞对典型的亚刺激水平激活的tgf - β急性敏感。tgf - β可以促进细胞分化或侵袭转化。作为tgf - β的翻译共激活因子，eIF4E通过降低激活tgf - β刺激的设定值，赋予选择性mRNA翻译，将非恶性细胞重编程为侵袭性表型。eIF4E的过表达可能是tgf - β活性的有益促进因子。
Eukaryotic translation initiation factor 4E (eIF4E) is overexpressed early in breast cancers in association with disease progression and reduced survival. Much remains to be understood regarding the role of eIF4E in human cancer. We determined, using immortalized human breast epithelial cells, that elevated expression of eIF4E translationally activates the transforming growth factor beta (TGF-beta) pathway, promoting cell invasion, a loss of cell polarity, increased cell survival, and other hallmarks of early neoplasia. Overexpression of eIF4E is shown to facilitate the selective translation of integrin b 1 mRNA, which drives the translationally controlled assembly of a TGF-beta receptor signaling complex containing alpha 3 beta 1 integrins, beta-catenin, TGF-beta receptor I, E-cadherin, and phosphorylated Smad2/3. This receptor complex acutely sensitizes nonmalignant breast epithelial cells to activation by typically substimulatory levels of activated TGF-beta. TGF-beta can promote cellular differentiation or invasion and transformation. As a translational coactivator of TGF-beta, eIF4E confers selective mRNA translation, reprogramming nonmalignant cells to an invasive phenotype by reducing the set point for stimulation by activated TGF-beta. Overexpression of eIF4E may be a proinvasive facilitator of TGF-beta activity.