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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.

Author information

1
Department of Biochemistry and Goodman Cancer Research Centre, McGill University, Cancer Pavilion 1160 Pine Avenue West, Montreal, Quebec, Canada H3A 1A3.
2
Department of Biochemistry, Microbiology and Immunology, Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada K1H 8L1.
3
McGill University and Genome Quebec Innovation Centre, Department of Human Genetics, McGill University, Montreal, Quebec, Canada H3A 1A5.

Abstract

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.

PMID:
27319316
PMCID:
PMC4915159
DOI:
10.1038/ncomms11776
[Indexed for MEDLINE]
Free PMC Article

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