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


Authors: Chen, H. C.; Kanai, M.; Inoue-Yamauchi, A.; Tu, H. C.; Huang, Y.; Ren, D.; Kim, H.; Takeda, S.; Reyna, D. E.; Chan, P. M.; Ganesan, Y. T.; Liao, C. P.; Gavathiotis, E.; Hsieh, J. J.; Cheng, E. H.
Article Title: An interconnected hierarchical model of cell death regulation by the BCL-2 family
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-X L 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-X L and MCL-1. Our studies lay a foundation for targeting the BCL-2 family for treating diseases with dysregulated apoptosis. © 2015 Macmillan Publishers Limited.
Keywords: controlled study; nonhuman; molecular genetics; protein function; animal cell; mouse; animal tissue; cell death; cell survival; protein bcl 2; biological model; embryo; protein protein interaction; protein targeting; animal experiment; bim protein; protein bcl xl; regulatory mechanism; protein mcl 1; down regulation; protein family; bid gene; puma protein; protein defect; protein bax; protein bid; protein bak; bh3 protein; bax gene; biochemical analysis; protein noxa; male; female; priority journal; article; bak gene; bim gene; noxa gene; puma gene
Journal Title: Nature Cell Biology
Volume: 17
Issue: 10
ISSN: 1465-7392
Publisher: Nature Publishing Group  
Date Published: 2015-10-01
Start Page: 1270
End Page: 1281
Language: English
DOI: 10.1038/ncb3236
PROVIDER: scopus
PMCID: PMC4589531
PUBMED: 26344567
DOI/URL:
Notes: Export Date: 2 November 2015 -- Source: Scopus
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MSK Authors
  1. Ho Chou Tu
    3 Tu
  2. Yafen Huang
    2 Huang
  3. Shugaku Takeda
    16 Takeda
  4. James J Hsieh
    114 Hsieh
  5. Emily H Cheng
    56 Cheng
  6. Po M Chan
    2 Chan
  7. Masayuki Kanai
    2 Kanai
  8. Hui-Chen   Chen
    6 Chen
  9. Chung-Ping   Liao
    1 Liao