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Nat Cell Biol. 2015 Oct;17(10):1270-81. doi: 10.1038/ncb3236. Epub 2015 Sep 7.

An interconnected hierarchical model of cell death regulation by the BCL-2 family.

Author information

1
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
2
Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA.
3
Department of Pharmacological Sciences, Stony Brook University, Stony Brook, New York 11794, USA.
4
Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
5
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
6
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
7
Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, Cornell University, New York, New York 10065, USA.

Abstract

Multidomain pro-apoptotic BAX and BAK, once activated, permeabilize mitochondria to trigger apoptosis, whereas anti-apoptotic BCL-2 members preserve mitochondrial integrity. The BH3-only molecules (BH3s) promote apoptosis by either activating BAX-BAK or inactivating anti-apoptotic members. Here, we present biochemical and genetic evidence that NOXA is a bona fide activator BH3. Using combinatorial gain-of-function and loss-of-function approaches in Bid(-/-)Bim(-/-)Puma(-/-)Noxa(-/-) and Bax(-/-)Bak(-/-) cells, we have constructed an interconnected hierarchical model that accommodates and explains how the intricate interplays between the BCL-2 members dictate cellular survival versus death. BID, BIM, PUMA and NOXA directly induce stepwise, bimodal activation of BAX-BAK. BCL-2, BCL-XL and MCL-1 inhibit both modes of BAX-BAK activation by sequestering activator BH3s and 'BH3-exposed' monomers of BAX-BAK, respectively. Furthermore, autoactivation of BAX and BAK can occur independently of activator BH3s through downregulation of BCL-2, BCL-XL and MCL-1. Our studies lay a foundation for targeting the BCL-2 family for treating diseases with dysregulated apoptosis.

PMID:
26344567
PMCID:
PMC4589531
DOI:
10.1038/ncb3236
[Indexed for MEDLINE]
Free PMC Article

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