TY - JOUR
T1 - An interconnected hierarchical model of cell death regulation by the BCL-2 family
AU - Chen, Hui Chen
AU - Kanai, Masayuki
AU - Inoue-Yamauchi, Akane
AU - Tu, Ho Chou
AU - Huang, Yafen
AU - Ren, Decheng
AU - Kim, Hyungjin
AU - Takeda, Shugaku
AU - Reyna, Denis E.
AU - Chan, Po M.
AU - Ganesan, Yogesh Tengarai
AU - Liao, Chung Ping
AU - Gavathiotis, Evripidis
AU - Hsieh, James J.
AU - Cheng, Emily H.
N1 - Funding Information:
We apologize to all of the investigators whose research could not be appropriately cited owing to space limitation. We thank H.-F. Chen and S. Han for technical assistance. This work was supported by grants to E.H.C. from the NIH (R01CA125562) and the American Cancer Society (118518-RSG-10-030-01-CCG), and to E.G. from the NIH (R01CA178394) This work was also supported by the NIH P30CA008748.
Publisher Copyright:
© 2015 Macmillan Publishers Limited.
PY - 2015/10/3
Y1 - 2015/10/3
N2 - 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.
AB - 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.
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U2 - 10.1038/ncb3236
DO - 10.1038/ncb3236
M3 - Article
C2 - 26344567
AN - SCOPUS:84942991698
SN - 1465-7392
VL - 17
SP - 1270
EP - 1281
JO - Nature Cell Biology
JF - Nature Cell Biology
IS - 10
ER -