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Medientyp:
E-Artikel
Titel:
Mito-priming as a method to engineer Bcl-2 addiction
Beteiligte:
Lopez, Jonathan;
Bessou, Margaux;
Riley, Joel S.;
Giampazolias, Evangelos;
Todt, Franziska;
Rochegüe, Tony;
Oberst, Andrew;
Green, Douglas R.;
Edlich, Frank;
Ichim, Gabriel;
Tait, Stephen W. G.
Erschienen:
Springer Science and Business Media LLC, 2016
Erschienen in:
Nature Communications, 7 (2016) 1
Sprache:
Englisch
DOI:
10.1038/ncomms10538
ISSN:
2041-1723
Entstehung:
Anmerkungen:
Beschreibung:
AbstractMost 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.