BAX and BAK1 are dispensable for ABT-737- induced dissociation of the BCL2-BECN1 complex and autophagy

Jose Manuel Bravo San Pedro; Yongjie Wei; Valentina Sica; Maria Chiara Maiuri; Zhongju Zou; Guido Kroemer; Beth Levine

doi:10.1080/15548627.2015.1017191

BAX and BAK1 are dispensable for ABT-737- induced dissociation of the BCL2-BECN1 complex and autophagy

Jose Manuel Bravo San Pedro, Yongjie Wei, Valentina Sica, Maria Chiara Maiuri, Zhongju Zou, Guido Kroemer, Beth Levine

Research output: Contribution to journal › Article › peer-review

79 Scopus citations

Abstract

Disruption of the complex of BECN1 with BCL2 or BCL2L1/BCL-X_L is an essential switch that turns on cellular autophagy in response to environmental stress or treatment with BH3 peptidomimetics. Recently, it has been proposed that BCL2 and BCL2L1/BCL-X_L may inhibit autophagy indirectly through a mechanism dependent on the proapoptotic BCL2 family members, BAX and BAK1. Here we report that the BH3 mimetic, ABT-737, induces autophagy in parallel with disruption of BCL2-BECN1 binding in 2 different apoptosis-deficient cell types lacking BAX and BAK1, namely in mouse embryonic fibroblasts cells and in human colon cancer HCT116 cells. We conclude that the BH3 mimetic ABT- 737 induces autophagy through a BAX and BAK1-independent mechanism that likely involves disruption of BECN1 binding to antiapoptotic BCL2 family members.

Original language	English (US)
Pages (from-to)	452-459
Number of pages	8
Journal	Autophagy
Volume	11
Issue number	3
DOIs	https://doi.org/10.1080/15548627.2015.1017191
State	Published - Jan 1 2015

Keywords

ABT-737
Apoptosis
Autophagy
BAK1
BAX
BCL2
BECN1 (Beclin 1)

ASJC Scopus subject areas

Molecular Biology
Cell Biology

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10.1080/15548627.2015.1017191

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title = "BAX and BAK1 are dispensable for ABT-737- induced dissociation of the BCL2-BECN1 complex and autophagy",

abstract = "Disruption of the complex of BECN1 with BCL2 or BCL2L1/BCL-XL is an essential switch that turns on cellular autophagy in response to environmental stress or treatment with BH3 peptidomimetics. Recently, it has been proposed that BCL2 and BCL2L1/BCL-XL may inhibit autophagy indirectly through a mechanism dependent on the proapoptotic BCL2 family members, BAX and BAK1. Here we report that the BH3 mimetic, ABT-737, induces autophagy in parallel with disruption of BCL2-BECN1 binding in 2 different apoptosis-deficient cell types lacking BAX and BAK1, namely in mouse embryonic fibroblasts cells and in human colon cancer HCT116 cells. We conclude that the BH3 mimetic ABT- 737 induces autophagy through a BAX and BAK1-independent mechanism that likely involves disruption of BECN1 binding to antiapoptotic BCL2 family members.",

keywords = "ABT-737, Apoptosis, Autophagy, BAK1, BAX, BCL2, BECN1 (Beclin 1)",

author = "Pedro, {Jose Manuel Bravo San} and Yongjie Wei and Valentina Sica and Maiuri, {Maria Chiara} and Zhongju Zou and Guido Kroemer and Beth Levine",

note = "Publisher Copyright: {\textcopyright} 2015, Jose Manuel Bravo-San Pedro, Yongjie Wei, Valentina Sica, Maria Chiara Maiuri, Zhongju Zou, Guido Kroemer, and Beth Levine.",

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AU - Pedro, Jose Manuel Bravo San

AU - Wei, Yongjie

AU - Sica, Valentina

AU - Maiuri, Maria Chiara

AU - Zou, Zhongju

AU - Kroemer, Guido

AU - Levine, Beth

PY - 2015/1/1

Y1 - 2015/1/1

N2 - Disruption of the complex of BECN1 with BCL2 or BCL2L1/BCL-XL is an essential switch that turns on cellular autophagy in response to environmental stress or treatment with BH3 peptidomimetics. Recently, it has been proposed that BCL2 and BCL2L1/BCL-XL may inhibit autophagy indirectly through a mechanism dependent on the proapoptotic BCL2 family members, BAX and BAK1. Here we report that the BH3 mimetic, ABT-737, induces autophagy in parallel with disruption of BCL2-BECN1 binding in 2 different apoptosis-deficient cell types lacking BAX and BAK1, namely in mouse embryonic fibroblasts cells and in human colon cancer HCT116 cells. We conclude that the BH3 mimetic ABT- 737 induces autophagy through a BAX and BAK1-independent mechanism that likely involves disruption of BECN1 binding to antiapoptotic BCL2 family members.

AB - Disruption of the complex of BECN1 with BCL2 or BCL2L1/BCL-XL is an essential switch that turns on cellular autophagy in response to environmental stress or treatment with BH3 peptidomimetics. Recently, it has been proposed that BCL2 and BCL2L1/BCL-XL may inhibit autophagy indirectly through a mechanism dependent on the proapoptotic BCL2 family members, BAX and BAK1. Here we report that the BH3 mimetic, ABT-737, induces autophagy in parallel with disruption of BCL2-BECN1 binding in 2 different apoptosis-deficient cell types lacking BAX and BAK1, namely in mouse embryonic fibroblasts cells and in human colon cancer HCT116 cells. We conclude that the BH3 mimetic ABT- 737 induces autophagy through a BAX and BAK1-independent mechanism that likely involves disruption of BECN1 binding to antiapoptotic BCL2 family members.

KW - ABT-737

KW - Apoptosis

KW - Autophagy

KW - BAK1

KW - BAX

KW - BCL2

KW - BECN1 (Beclin 1)

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BAX and BAK1 are dispensable for ABT-737- induced dissociation of the BCL2-BECN1 complex and autophagy

Abstract

Keywords

ASJC Scopus subject areas

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