Inactivation of the mTORC1-Eukaryotic Translation Initiation Factor 4E Pathway Alters Stress Granule Formation
Inactivation of the mTORC1-Eukaryotic Translation Initiation Factor 4E Pathway Alters Stress Granule Formation
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DOI：
10.1128/mcb.01517-12
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发表时间：
2013-06-01
影响因子：
5.3
通讯作者：
Mazroui, Rachid
中科院分区：
文献类型：
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作者：
Fournier, Marie-Josee;Coudert, Laetitia;Mazroui, Rachid
应激颗粒(SG)是在胁迫条件下形成的细胞质多聚体RNA小体，可抑制帽依赖的翻译。SG含有翻译起始因子、RNA结合蛋白和信号分子。已知SG可抑制细胞凋亡途径，从而促进肿瘤细胞的化疗和放射耐药。然而，应激颗粒的形成是否涉及致癌信号通路目前尚不清楚。在这里，我们报告了mTORC1-真核翻译起始因子4E(EIF4E)途径在SG形成中的一个新的作用，eIF4E是致癌因子帽子依赖的翻译起始的关键调节因子。MTORC1通过4E-BP1的磷酸化特异性地驱动eIF4E介导的SG的形成，这是已知的抑制依赖mTORC1的eIF4E-eIF4GI相互作用形成的关键因素。通过用mTOR的特异性抑制剂pp242使mTOR失活，或者通过耗尽eIF4E或eIF4GI来干扰SG的形成，阻断了SG相关的抗凋亡p21途径。最后，pp242在体外使癌细胞对死亡敏感，并在体内抑制化疗耐药肿瘤的生长。因此，这项工作突出了致癌mTORC1-eIF4E途径的一个新作用，即促进抗凋亡SG的形成。
Stress granules (SG) are cytoplasmic multimeric RNA bodies that form under stress conditions known to inhibit cap-dependent translation. SG contain translation initiation factors, RNA binding proteins, and signaling molecules. SG are known to inhibit apoptotic pathways, thus contributing to chemo-and radioresistance in tumor cells. However, whether stress granule formation involves oncogenic signaling pathways is currently unknown. Here, we report a novel role of the mTORC1-eukaryotic translation initiation factor 4E (eIF4E) pathway, a key regulator of cap-dependent translation initiation of oncogenic factors, in SG formation. mTORC1 specifically drives the eIF4E-mediated formation of SG through the phosphorylation of 4E-BP1, a key factor known to inhibit formation of the mTORC1-dependent eIF4E-eIF4GI interactions. Disrupting formation of SG by inactivation of mTOR with its specific inhibitor pp242 or by depletion of eIF4E or eIF4GI blocks the SG-associated antiapoptotic p21 pathway. Finally, pp242 sensitizes cancer cells to death in vitro and inhibits the growth of chemoresistant tumors in vivo. This work therefore highlights a novel role of the oncogenic mTORC1-eIF4E pathway, namely, the promotion of formation of antiapoptotic SG.