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Inactivation of prosurvival Bcl-2 proteins activates Bax/Bak through the outer mitochondrial membrane
- Source :
- Genes & Development. 30:973-988
- Publication Year :
- 2016
- Publisher :
- Cold Spring Harbor Laboratory, 2016.
-
Abstract
- The mechanism of Bax/Bak activation remains a central question in mitochondria-dependent apoptotic signaling. While it is established that all proapoptotic Bcl-2 homology 3 (BH3)-only proteins bind and neutralize the anti-apoptotic Bcl-2 family proteins, how this neutralization leads to Bax/Bak activation has been actively debated. Here, genome editing was used to generate cells deficient for all eight proapoptotic BH3-only proteins (OctaKO) and those that lack the entire Bcl-2 family (Bcl-2 allKO). Although the OctaKO cells were resistant to most apoptotic stimuli tested, they underwent Bax/Bak-dependent and p53/Rb-independent apoptosis efficiently when both Bcl-xL and Mcl-1, two anti-apoptotic Bcl-2 proteins, were inactivated or eliminated. Strikingly, when expressed in the Bcl-2 allKO cells, both Bax and Bak spontaneously associated with the outer mitochondrial membrane (OMM) through their respective helix 9, and this association triggered their homo-oligomerization/activation. Together, these results strongly suggest that the OMM, not BH3-only proteins or p53/Rb, is the long-sought-after direct activator of Bax/Bak following BH3-only-mediated neutralization of anti-apoptotic Bcl-2 proteins.
- Subjects :
- 0301 basic medicine
Apoptosis
Biology
Mitochondrial apoptosis-induced channel
Cell Line
Mice
03 medical and health sciences
Bcl-2-associated X protein
Genetics
Animals
Humans
Gene silencing
Gene Silencing
bcl-2-Associated X Protein
Regulation of gene expression
Activator (genetics)
HCT116 Cells
Molecular biology
Cell biology
bcl-2 Homologous Antagonist-Killer Protein
030104 developmental biology
Gene Expression Regulation
Proto-Oncogene Proteins c-bcl-2
Cell culture
Mitochondrial Membranes
biology.protein
Myeloid Cell Leukemia Sequence 1 Protein
biological phenomena, cell phenomena, and immunity
Bcl-2 Homologous Antagonist-Killer Protein
Research Paper
HeLa Cells
Developmental Biology
Subjects
Details
- ISSN :
- 15495477 and 08909369
- Volume :
- 30
- Database :
- OpenAIRE
- Journal :
- Genes & Development
- Accession number :
- edsair.doi.dedup.....c99c7f6e9d283d346b06f694b3f34123