Mito-priming as a method of engineered Bcl-2 addiction

Lopez, J. et al. (2016) Mito-priming as a method of engineered Bcl-2 addiction. Nature Communications, 7, 10538. (doi:10.1038/ncomms10538) (PMID:26833356) (PMCID:PMC4740867)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Rochegue, Mr Tony and Ichim, Dr Gabriel and Riley, Dr Joel and Tait, Professor Stephen
Authors: Lopez, J., Bessou, M., Riley, J. S., Giampazolias, E., Todt, F., Rochegüe, T., Oberst, A., Green, D. R., Edlich, F., Ichim, G., and Tait, S. W.G.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Nature Communications
Publisher:Nature Publishing Group
ISSN:2041-1723
ISSN (Online):2041-1723
Copyright Holders:Copyright © 2016 Lopez, J. et al
Publisher Policy:Reproduced under a Creative Commons License
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
690911Apoptosis as an oncogenic process: understanding and exploiting its dark-sideStephen TaitCancer Research UK (CAN-RES-UK)C40872/A20145RI CANCER SCIENCES
607521A new approach to understanding mitochondrial functions in cell death, autophagy and beyondStephen TaitBiotechnology and Biological Sciences Research Council (BBSRC)BB/K008374/1RI CANCER SCIENCES