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

Author

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  • Yoshinori Tsukumo

    (McGill University)

  • Tommy Alain

    (Microbiology and Immunology, Children’s Hospital of Eastern Ontario Research Institute, University of Ottawa)

  • Bruno D. Fonseca

    (Microbiology and Immunology, Children’s Hospital of Eastern Ontario Research Institute, University of Ottawa)

  • Robert Nadon

    (McGill University and Genome Quebec Innovation Centre, McGill University)

  • Nahum Sonenberg

    (McGill University)

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.

Suggested Citation

  • Yoshinori Tsukumo & Tommy Alain & Bruno D. Fonseca & Robert Nadon & Nahum Sonenberg, 2016. "Translation control during prolonged mTORC1 inhibition mediated by 4E-BP3," Nature Communications, Nature, vol. 7(1), pages 1-13, September.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms11776
    DOI: 10.1038/ncomms11776
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    Cited by:

    1. Valentina Gandin & Brian P. English & Melanie Freeman & Louis-Philippe Leroux & Stephan Preibisch & Deepika Walpita & Maritza Jaramillo & Robert H. Singer, 2022. "Cap-dependent translation initiation monitored in living cells," Nature Communications, Nature, vol. 13(1), pages 1-15, December.

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