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Nat Commun. 2016 Jun 20;7:11776. doi: 10.1038/ncomms11776.

Translation control during prolonged mTORC1 inhibition mediated by 4E-BP3.

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Department of Biochemistry and Goodman Cancer Research Centre, McGill University, Cancer Pavilion 1160 Pine Avenue West, Montreal, Quebec, Canada H3A 1A3.
Department of Biochemistry, Microbiology and Immunology, Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada K1H 8L1.
McGill University and Genome Quebec Innovation Centre, Department of Human Genetics, McGill University, Montreal, Quebec, Canada H3A 1A5.


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.

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