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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