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BAP1 inhibits the ER stress gene regulatory network and modulates metabolic stress response.

The endoplasmic reticulum (ER) is classically linked to metabolic homeostasis via the activation of unfolded protein response (UPR), which is instructed by multiple transcriptional regulatory cascades. BRCA1 associated protein 1 (BAP1) is a tumor suppressor with de-ubiquitinating enzyme activity and... Full description

Journal Title: Proceedings of the National Academy of Sciences of the United States of America March 21, 2017, Vol.114(12), pp.3192-3197
Main Author: Dai, Fangyan
Other Authors: Lee, Hyemin , Zhang, Yilei , Zhuang, Li , Yao, Hui , Xi, Yuanxin , Xiao, Zhen-Dong , You, M James , Li, Wei , Su, Xiaoping , Gan, Boyi
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: E-ISSN: 1091-6490 ; DOI: 10.1073/pnas.1619588114
Link: http://search.proquest.com/docview/1876499911/?pq-origsite=primo
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title: BAP1 inhibits the ER stress gene regulatory network and modulates metabolic stress response.
format: Article
creator:
  • Dai, Fangyan
  • Lee, Hyemin
  • Zhang, Yilei
  • Zhuang, Li
  • Yao, Hui
  • Xi, Yuanxin
  • Xiao, Zhen-Dong
  • You, M James
  • Li, Wei
  • Su, Xiaoping
  • Gan, Boyi
subjects:
  • Activating Transcription Factor 3–Genetics
  • Adenosine Triphosphate–Metabolism
  • Animals–Metabolism
  • Apoptosis–Metabolism
  • Endoplasmic Reticulum Stress–Genetics
  • Energy Metabolism–Genetics
  • Gene Expression Regulation–Metabolism
  • Gene Regulatory Networks–Pharmacology
  • Glucose–Genetics
  • Mice–Metabolism
  • Mice, Knockout–Metabolism
  • Reactive Oxygen Species–Metabolism
  • Signal Transduction–Metabolism
  • Stress, Physiological–Metabolism
  • Transcription Factor Chop–Metabolism
  • Tumor Suppressor Proteins–Metabolism
  • Tunicamycin–Metabolism
  • Ubiquitin Thiolesterase–Metabolism
  • Unfolded Protein Response–Metabolism
  • Activating Transcription Factor 3
  • Bap1 Protein, Mouse
  • Reactive Oxygen Species
  • Tumor Suppressor Proteins
  • Tunicamycin
  • Transcription Factor Chop
  • Adenosine Triphosphate
  • Ubiquitin Thiolesterase
  • Glucose
  • Bap1
  • Er Stress
  • Energy Stress
  • Glucose Starvation
  • Unfolded Protein Response
ispartof: Proceedings of the National Academy of Sciences of the United States of America, March 21, 2017, Vol.114(12), pp.3192-3197
description: The endoplasmic reticulum (ER) is classically linked to metabolic homeostasis via the activation of unfolded protein response (UPR), which is instructed by multiple transcriptional regulatory cascades. BRCA1 associated protein 1 (BAP1) is a tumor suppressor with de-ubiquitinating enzyme activity and has been implicated in chromatin regulation of gene expression. Here we show that BAP1 inhibits cell death induced by unresolved metabolic stress. This prosurvival role of BAP1 depends on its de-ubiquitinating activity and correlates with its ability to dampen the metabolic stress-induced UPR transcriptional network. BAP1 inhibits glucose deprivation-induced reactive oxygen species and ATP depletion, two cellular events contributing to the ER stress-induced cell death. In line with this, Bap1 KO mice are more sensitive to tunicamycin-induced renal damage. Mechanically, we show that BAP1 represses metabolic stress-induced UPR and cell death through activating transcription factor 3 (ATF3) and C/EBP homologous protein (CHOP), and reveal that BAP1 binds to ATF3 and CHOP promoters and inhibits their transcription. Taken together, our results establish a previously unappreciated role of BAP1 in modulating the cellular adaptability to metabolic stress and uncover a pivotal function of BAP1 in the regulation of the ER stress gene-regulatory network. Our study may also provide new conceptual framework for further understanding BAP1 function in cancer.
language: eng
source:
identifier: E-ISSN: 1091-6490 ; DOI: 10.1073/pnas.1619588114
fulltext: fulltext
issn:
  • 10916490
  • 1091-6490
url: Link


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titleBAP1 inhibits the ER stress gene regulatory network and modulates metabolic stress response.
creatorDai, Fangyan ; Lee, Hyemin ; Zhang, Yilei ; Zhuang, Li ; Yao, Hui ; Xi, Yuanxin ; Xiao, Zhen-Dong ; You, M James ; Li, Wei ; Su, Xiaoping ; Gan, Boyi
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identifierE-ISSN: 1091-6490 ; DOI: 10.1073/pnas.1619588114
subjectActivating Transcription Factor 3–Genetics ; Adenosine Triphosphate–Metabolism ; Animals–Metabolism ; Apoptosis–Metabolism ; Endoplasmic Reticulum Stress–Genetics ; Energy Metabolism–Genetics ; Gene Expression Regulation–Metabolism ; Gene Regulatory Networks–Pharmacology ; Glucose–Genetics ; Mice–Metabolism ; Mice, Knockout–Metabolism ; Reactive Oxygen Species–Metabolism ; Signal Transduction–Metabolism ; Stress, Physiological–Metabolism ; Transcription Factor Chop–Metabolism ; Tumor Suppressor Proteins–Metabolism ; Tunicamycin–Metabolism ; Ubiquitin Thiolesterase–Metabolism ; Unfolded Protein Response–Metabolism ; Activating Transcription Factor 3 ; Bap1 Protein, Mouse ; Reactive Oxygen Species ; Tumor Suppressor Proteins ; Tunicamycin ; Transcription Factor Chop ; Adenosine Triphosphate ; Ubiquitin Thiolesterase ; Glucose ; Bap1 ; Er Stress ; Energy Stress ; Glucose Starvation ; Unfolded Protein Response
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descriptionThe endoplasmic reticulum (ER) is classically linked to metabolic homeostasis via the activation of unfolded protein response (UPR), which is instructed by multiple transcriptional regulatory cascades. BRCA1 associated protein 1 (BAP1) is a tumor suppressor with de-ubiquitinating enzyme activity and has been implicated in chromatin regulation of gene expression. Here we show that BAP1 inhibits cell death induced by unresolved metabolic stress. This prosurvival role of BAP1 depends on its de-ubiquitinating activity and correlates with its ability to dampen the metabolic stress-induced UPR transcriptional network. BAP1 inhibits glucose deprivation-induced reactive oxygen species and ATP depletion, two cellular events contributing to the ER stress-induced cell death. In line with this, Bap1 KO mice are more sensitive to tunicamycin-induced renal damage. Mechanically, we show that BAP1 represses metabolic stress-induced UPR and cell death through activating transcription factor 3 (ATF3) and C/EBP homologous protein (CHOP), and reveal that BAP1 binds to ATF3 and CHOP promoters and inhibits their transcription. Taken together, our results establish a previously unappreciated role of BAP1 in modulating the cellular adaptability to metabolic stress and uncover a pivotal function of BAP1 in the regulation of the ER stress gene-regulatory network. Our study may also provide new conceptual framework for further understanding BAP1 function in cancer.
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