Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer therapeutics
Open accessAbstract
The "BH3-only" proteins of the BCL-2 family require "multidomain" proapoptotic members BAX and BAK to release cytochrome c from mitochondria and kill cells. We find short peptides representing the alpha-helical BH3 domains of BID or BIM are capable of inducing oligomerization of BAK and BAX to release cytochrome c. Another subset characterized by the BH3 peptides from BAD and BIK cannot directly activate BAX, BAK but instead binds antiapoptotic BCL-2, resulting in the displacement of BID-like BH3 domains that initiate mitochondrial dysfunction. Transduced BAD-like and BID-like BH3 peptides also displayed synergy in killing leukemic cells. These data support a two-class model for BH3 domains: BID-like domains that "activate" BAX, BAK and BAD-like domains that "sensitize" by occupying the pocket of antiapoptotic members.
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Upon induction of apoptosis, BAX retrotranslocation ceases as the mitochondrial pools of BAX and BAK undergo direct or indirect activation by pro-apoptotic BH3-only proteins.
“Upon induction of apoptosis, BAX retrotranslocation ceases as the mitochondrial pools of BAX and BAK undergo direct or indirect activation (see below) by pro-apoptotic BH3-only proteins [48, 56–59].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [58]
These BH3-only proteins (sensitizers or inactivators) bind to anti-apoptotic BCL2 family members and hence limit their availability to sequester BAX, BAK, or BH3-only activators.
“These BH3-only proteins, which are sometimes referred to as “sensitizers” or “inactivators” bind to anti-apoptotic BCL2 family members and hence limit their availability to sequester BAX, BAK, or BH3-only activators [58, 93].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [58]
Some BH3-only proteins including BAD, BMF, or HRK promote MOMP in the absence of a physical interaction with BAX or BAK.
“Importantly, some BH3-only proteins including BCL2 associated agonist of cell death (BAD), Bcl2 modifying factor (BMF), or harakiri, BCL2 interacting protein (HRK) promote MOMP in the absence of a physical interaction with BAX or BAK.”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [58]
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- Authors
- Letai, A., Bassik, M. C., Walensky, L. D., Sorcinelli, M. D., Weiler, S., & Korsmeyer, S. J.
- Affiliations
- Howard Hughes Medical Institute (US)
- Corresponding author
- Korsmeyer, Stanley J.
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2002-09
- Volume
- 2
- Issue
- 3
- Pages
- 183-192
- ISSN
- 1535-6108 (ISSN-L)
- OpenAlex
- W1976720365
- Cited by
- 1,677
- References
- 40
- Citations by year
- 2026: 24 · 2025: 31 · 2024: 36 · 2023: 53 · 2022: 39 · 2021: 50 · 2020: 47 · 2019: 60 · 2018: 47 · 2017: 62 · 2016: 60 · 2015: 62 · 2014: 70 · 2013: 87 · 2012: 93
- FWCI
- 26.49
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 3972 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (CA 92625)
- American Society of Hematology
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- BH3-only proteins, Bcl-2 family proteins, Bax, Bak, Bid, building information modeling, Bad, BIK, BH3 peptides, mitochondrial apoptosis, cytochrome c release, cancer therapeutics, peptide oligomerization
- MeSH terms
- Bcl-2-Like Protein 11, Animals, Carrier Proteins, Cytochrome c Group, Humans, Membrane Proteins, Mitochondria, Proto-Oncogene Proteins, Transduction, Genetic, Apoptosis, Protein Structure, Tertiary, Jurkat Cells, Proto-Oncogene Proteins c-bcl-2, bcl-2 Homologous Antagonist-Killer Protein, Apoptosis Regulatory Proteins, BH3 Interacting Domain Death Agonist Protein, bcl-2-Associated X Protein, Mice
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