Cited by 1,574Cell death mechanisms and regulationMitochondrial Function and PathologyCancer-related Molecular Pathways

BCL-2 family proteins: changing partners in the dance towards death

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Kale, Justin, Osterlund, Elizabeth J, Andrews, David W·2018·Cell Death & Differentiation

Abstract

The BCL-2 family of proteins controls cell death primarily by direct binding interactions that regulate mitochondrial outer membrane permeabilization (MOMP) leading to the irreversible release of intermembrane space proteins, subsequent caspase activation and apoptosis. The affinities and relative abundance of the BCL-2 family proteins dictate the predominate interactions between anti-apoptotic and pro-apoptotic BCL-2 family proteins that regulate MOMP. We highlight the core mechanisms of BCL-2 family regulation of MOMP with an emphasis on how the interactions between the BCL-2 family proteins govern cell fate. We address the critical importance of both the concentration and affinities of BCL-2 family proteins and show how differences in either can greatly change the outcome. Further, we explain the importance of using full-length BCL-2 family proteins (versus truncated versions or peptides) to parse out the core mechanisms of MOMP regulation by the BCL-2 family. Finally, we discuss how post-translational modifications and differing intracellular localizations alter the mechanisms of apoptosis regulation by BCL-2 family proteins. Successful therapeutic intervention of MOMP regulation in human disease requires an understanding of the factors that mediate the major binding interactions between BCL-2 family proteins in cells.

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Authors
Kale, J., Osterlund, E. J., & Andrews, D. W.
Affiliations
  • Sunnybrook Hospital (CA)
  • University of Toronto (CA)
Corresponding author
Andrews, David W
Venue
Cell Death & Differentiation
Published
2017-11-17
Volume
25
Issue
1
Pages
65-80
ISSN
  • 1350-9047 (ISSN-L)
  • 1476-5403
OpenAlex
W2769631482
Cited by
1,574
References
120
Citations by year
2026: 123 · 2025: 189 · 2024: 225 · 2023: 231 · 2022: 242 · 2021: 228 · 2020: 155 · 2019: 123 · 2018: 52 · 2017: 3
FWCI
8.52
Type
journal article
Language
en
Open access
Locations
  • Cell Death and Differentiation (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
Funders
Canadian Institutes of Health Research ((FDN143312))
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
Keywords
Bcl-2 family proteins, mitochondrial outer membrane permeabilization, apoptosis, anti-apoptotic proteins, pro-apoptotic proteins, protein-protein interaction, binding affinity, protein concentration, post-translational modification, subcellular localization, caspase activation, cell fate regulation
MeSH terms
Cell Membrane Permeability, Protein Processing, Post-Translational, Apoptosis, Proto-Oncogene Proteins c-bcl-2, bcl-2 Homologous Antagonist-Killer Protein, Apoptosis Regulatory Proteins, bcl-2-Associated X Protein, Mitochondrial Membranes

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