Translation control during prolonged mTORC1 inhibition mediated by 4E-BP3.
Translation control during prolonged mTORC1 inhibition mediated by 4E-BP3.
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DOI：
10.1038/ncomms11776
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发表时间：
2016-06-20
影响因子：
16.6
通讯作者：
Sonenberg N
中科院分区：
文献类型：
--
作者：
Tsukumo Y;Alain T;Fonseca BD;Nadon R;Sonenberg N
靶向mTORC1是一种非常有前途的癌症治疗策略。MTORC1活性的抑制会导致eIF4E结合蛋白(4E-BP1-3)的快速去磷酸化，从而抑制mRNA的翻译。然而，在长期使用mTOR抑制剂的过程中，不同的4e-bps如何影响翻译尚不清楚。在这里，我们表明，在体外和体内长期抑制mTORC1的过程中，4E-BP3的表达被转录诱导，而4E-BP1或4E-BP2的表达不被诱导。从机制上讲，我们的数据表明4E-BP3的表达是由转录因子TFE3通过EIF4EBP3基因启动子中的顺式调控元件控制的。CRISPR/Cas9介导的EIF4EBP3基因在人癌细胞中的破坏减轻了mTOR抑制剂长期治疗对翻译和增殖的抑制。我们的研究结果表明，4E-BP3是mTORC1的一个重要效应者，也是一个强有力的预测肿瘤mTOR靶向药物长期治疗疗效的生物标志物。EIF4E结合蛋白(4E-Bps)是通过mTOR的帽依赖翻译的关键抑制因子，mTOR是癌症中经常过度激活的途径。在这里，作者证明了4E-BP3特异性地介导了帽依赖的翻译抑制和长期的药理学mTOR抑制的抗增殖作用。
Targeting mTORC1 is a highly promising strategy in cancer therapy. Suppression of mTORC1 activity leads to rapid dephosphorylation of eIF4E-binding proteins (4E-BP1–3) and subsequent inhibition of mRNA translation. However, how the different 4E-BPs affect translation during prolonged use of mTOR inhibitors is not known. Here we show that the expression of 4E-BP3, but not that of 4E-BP1 or 4E-BP2, is transcriptionally induced during prolonged mTORC1 inhibition in vitro and in vivo. Mechanistically, our data reveal that 4E-BP3 expression is controlled by the transcription factor TFE3 through a cis-regulatory element in the EIF4EBP3 gene promoter. CRISPR/Cas9-mediated EIF4EBP3 gene disruption in human cancer cells mitigated the inhibition of translation and proliferation caused by prolonged treatment with mTOR inhibitors. Our findings show that 4E-BP3 is an important effector of mTORC1 and a robust predictive biomarker of therapeutic response to prolonged treatment with mTOR-targeting drugs in cancer. The eIF4E-binding proteins (4E-BPs) are critical repressors of cap-dependent translation via mTOR, a pathway frequently hyperactivated in cancer. Here the authors show that 4E-BP3 specifically mediates the cap-dependent translation repression and antiproliferative effects of prolonged pharmacological mTOR inhibition.