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Bax/Bak activation in the absence of Bid, Bim, Puma, and p53
How BH3-only proteins activate Bax/Bak, the two gateway proteins of the mitochondria-dependent apoptotic pathway, remains incompletely understood. Although all pro-apoptotic BH3-only proteins are known to bind/neutralize the anti-apoptotic Bcl-2 proteins, the three most potent ones, Bid (tBid), Bim,...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5143395/ https://www.ncbi.nlm.nih.gov/pubmed/27310874 http://dx.doi.org/10.1038/cddis.2016.167 |
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author | Zhang, J Huang, K O'Neill, K L Pang, X Luo, X |
author_facet | Zhang, J Huang, K O'Neill, K L Pang, X Luo, X |
author_sort | Zhang, J |
collection | PubMed |
description | How BH3-only proteins activate Bax/Bak, the two gateway proteins of the mitochondria-dependent apoptotic pathway, remains incompletely understood. Although all pro-apoptotic BH3-only proteins are known to bind/neutralize the anti-apoptotic Bcl-2 proteins, the three most potent ones, Bid (tBid), Bim, and Puma, possess an additional activity of directly activating Bax/Bak in vitro. This latter activity has been proposed to be responsible for triggering Bax/Bak activation following apoptotic stimulation. To test this hypothesis, we generated Bid(−/)(−)Bim(−/)(−)Puma(−/)(−) (TKO), TKO/Bax(−/)(−)/Bak(−/)(−) (PentaKO), and PentaKO/Mcl-1(−/−) (HexaKO) HCT116 cells through gene editing. Surprisingly, although the TKO cells were resistant to several apoptotic stimuli, robust apoptosis was induced upon the simultaneous inactivation of Bcl-xL and Mcl-1, two anti-apoptotic Bcl-2 proteins known to suppress Bax/Bak activation and activity. Importantly, such apoptotic activity was completely abolished in the PentaKO cells. In addition, ABT-737, a BH3 mimetic that inhibits Bcl-xL/Bcl-w/Bcl-2, induced Bax activation in HexaKO cells reconstituted with endogenous level of GFP-Bax. Further, by generating TKO/p53(−/−) (QKO) cells, we demonstrated that p53, a tumor suppressor postulated to directly activate Bax, is not required for Bid/Bim/Puma-independent Bax/Bak activation. Together, these results strongly suggest that the direct activation activities of Bid (tBid), Bim, Puma, and p53 are not essential for activating Bax/Bak once the anti-apoptotic Bcl-2 proteins are neutralized. |
format | Online Article Text |
id | pubmed-5143395 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-51433952016-12-23 Bax/Bak activation in the absence of Bid, Bim, Puma, and p53 Zhang, J Huang, K O'Neill, K L Pang, X Luo, X Cell Death Dis Original Article How BH3-only proteins activate Bax/Bak, the two gateway proteins of the mitochondria-dependent apoptotic pathway, remains incompletely understood. Although all pro-apoptotic BH3-only proteins are known to bind/neutralize the anti-apoptotic Bcl-2 proteins, the three most potent ones, Bid (tBid), Bim, and Puma, possess an additional activity of directly activating Bax/Bak in vitro. This latter activity has been proposed to be responsible for triggering Bax/Bak activation following apoptotic stimulation. To test this hypothesis, we generated Bid(−/)(−)Bim(−/)(−)Puma(−/)(−) (TKO), TKO/Bax(−/)(−)/Bak(−/)(−) (PentaKO), and PentaKO/Mcl-1(−/−) (HexaKO) HCT116 cells through gene editing. Surprisingly, although the TKO cells were resistant to several apoptotic stimuli, robust apoptosis was induced upon the simultaneous inactivation of Bcl-xL and Mcl-1, two anti-apoptotic Bcl-2 proteins known to suppress Bax/Bak activation and activity. Importantly, such apoptotic activity was completely abolished in the PentaKO cells. In addition, ABT-737, a BH3 mimetic that inhibits Bcl-xL/Bcl-w/Bcl-2, induced Bax activation in HexaKO cells reconstituted with endogenous level of GFP-Bax. Further, by generating TKO/p53(−/−) (QKO) cells, we demonstrated that p53, a tumor suppressor postulated to directly activate Bax, is not required for Bid/Bim/Puma-independent Bax/Bak activation. Together, these results strongly suggest that the direct activation activities of Bid (tBid), Bim, Puma, and p53 are not essential for activating Bax/Bak once the anti-apoptotic Bcl-2 proteins are neutralized. Nature Publishing Group 2016-06 2016-06-16 /pmc/articles/PMC5143395/ /pubmed/27310874 http://dx.doi.org/10.1038/cddis.2016.167 Text en Copyright © 2016 Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Original Article Zhang, J Huang, K O'Neill, K L Pang, X Luo, X Bax/Bak activation in the absence of Bid, Bim, Puma, and p53 |
title | Bax/Bak activation in the absence of Bid, Bim, Puma, and p53 |
title_full | Bax/Bak activation in the absence of Bid, Bim, Puma, and p53 |
title_fullStr | Bax/Bak activation in the absence of Bid, Bim, Puma, and p53 |
title_full_unstemmed | Bax/Bak activation in the absence of Bid, Bim, Puma, and p53 |
title_short | Bax/Bak activation in the absence of Bid, Bim, Puma, and p53 |
title_sort | bax/bak activation in the absence of bid, bim, puma, and p53 |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5143395/ https://www.ncbi.nlm.nih.gov/pubmed/27310874 http://dx.doi.org/10.1038/cddis.2016.167 |
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