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Mito-priming as a method to engineer Bcl-2 addiction

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  • Jonathan Lopez

    (Cancer Research UK Beatson Institute
    Institute of Cancer Sciences, University of Glasgow, Garscube Estate
    Present address: University of Lyon, Cancer Research Centre of Lyon, U1052 INSERM, UMS 3453 CNRS, Lyon I University, Léon Bérard Centre, Lyon, France.)

  • Margaux Bessou

    (Cancer Research UK Beatson Institute
    Institute of Cancer Sciences, University of Glasgow, Garscube Estate
    Present address: University of Lyon, Cancer Research Centre of Lyon, U1052 INSERM, UMS 3453 CNRS, Lyon I University, Léon Bérard Centre, Lyon, France.)

  • Joel S. Riley

    (Cancer Research UK Beatson Institute
    Institute of Cancer Sciences, University of Glasgow, Garscube Estate)

  • Evangelos Giampazolias

    (Cancer Research UK Beatson Institute
    Institute of Cancer Sciences, University of Glasgow, Garscube Estate)

  • Franziska Todt

    (Institute for Biochemistry and Molecular Biology, ZBMZ, Faculty of Medicine, University of Freiburg)

  • Tony Rochegüe

    (Cancer Research UK Beatson Institute
    Institute of Cancer Sciences, University of Glasgow, Garscube Estate
    Present address: École Supérieure de Biologie-Biochimie-Biotechnologies, Université catholique de Lyon, Lyon, France.)

  • Andrew Oberst

    (University of Washington)

  • Douglas R. Green

    (St Jude Children’s Research Hospital)

  • Frank Edlich

    (Institute for Biochemistry and Molecular Biology, ZBMZ, Faculty of Medicine, University of Freiburg
    BIOSS, Centre for Biological Signaling Studies, University of Freiburg)

  • Gabriel Ichim

    (Cancer Research UK Beatson Institute
    Institute of Cancer Sciences, University of Glasgow, Garscube Estate)

  • Stephen W. G. Tait

    (Cancer Research UK Beatson Institute
    Institute of Cancer Sciences, University of Glasgow, Garscube Estate)

Abstract

Most apoptotic stimuli require mitochondrial outer membrane permeabilization (MOMP) in order to execute cell death. As such, MOMP is subject to tight control by Bcl-2 family proteins. We have developed a powerful new technique to investigate Bcl-2-mediated regulation of MOMP. This method, called mito-priming, uses co-expression of pro- and anti-apoptotic Bcl-2 proteins to engineer Bcl-2 addiction. On addition of Bcl-2 targeting BH3 mimetics, mito-primed cells undergo apoptosis in a rapid and synchronous manner. Using this method we have comprehensively surveyed the efficacy of BH3 mimetic compounds, identifying potent and specific MCL-1 inhibitors. Furthermore, by combining different pro- and anti-apoptotic Bcl-2 pairings together with CRISPR/Cas9-based genome editing, we find that tBID and PUMA can preferentially kill in a BAK-dependent manner. In summary, mito-priming represents a facile and robust means to trigger mitochondrial apoptosis.

Suggested Citation

  • Jonathan Lopez & Margaux Bessou & Joel S. Riley & Evangelos Giampazolias & Franziska Todt & Tony Rochegüe & Andrew Oberst & Douglas R. Green & Frank Edlich & Gabriel Ichim & Stephen W. G. Tait, 2016. "Mito-priming as a method to engineer Bcl-2 addiction," Nature Communications, Nature, vol. 7(1), pages 1-11, April.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms10538
    DOI: 10.1038/ncomms10538
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    Cited by:

    1. Florian J. Bock & Egor Sedov & Elle Koren & Anna L. Koessinger & Catherine Cloix & Désirée Zerbst & Dimitris Athineos & Jayanthi Anand & Kirsteen J. Campbell & Karen Blyth & Yaron Fuchs & Stephen W. G, 2021. "Apoptotic stress-induced FGF signalling promotes non-cell autonomous resistance to cell death," Nature Communications, Nature, vol. 12(1), pages 1-14, December.

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