PMID- 26157144
OWN - NLM
STAT- MEDLINE
DCOM- 20151123
LR  - 20210306
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 290
IP  - 34
DP  - 2015 Aug 21
TI  - The Orphan Nuclear Receptor NR4A1 Protects Pancreatic beta-Cells from Endoplasmic 
      Reticulum (ER) Stress-mediated Apoptosis.
PG  - 20687-20699
LID - S0021-9258(20)42093-9 [pii]
LID - 10.1074/jbc.M115.654863 [doi]
AB  - The role of NR4A1 in apoptosis is controversial. Pancreatic beta-cells often face 
      endoplasmic reticulum (ER) stress under adverse conditions such as high free 
      fatty acid (FFA) concentrations and sustained hyperglycemia. Severe ER stress 
      results in beta-cell apoptosis. The aim of this study was to analyze the role of 
      NR4A1 in ER stress-mediated beta-cell apoptosis and to characterize the related 
      mechanisms. We confirmed that upon treatment with the ER stress inducers 
      thapsigargin (TG) or palmitic acid (PA), the mRNA and protein levels of NR4A1 
      rapidly increased in both MIN6 cells and mouse islets. NR4A1 overexpression in 
      MIN6 cells conferred resistance to cell loss induced by TG or PA, as assessed by 
      MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, and 
      TUNEL assays indicated that NR4A1 overexpression also protected against ER 
      stress-induced apoptosis. This conclusion was further confirmed by experiments 
      exploiting siRNA to knockdown NR4A1 expression in MIN6 cells or exploiting NR4A1 
      knock-out mice. NR4A1 overexpression in MIN6 cells reduced C/EBP homologous 
      protein (CHOP) expression and Caspase3 activation induced by TG or PA. NR4A1 
      overexpression in MIN6 cells or mouse islets resulted in Survivin up-regulation. 
      A critical regulatory element was identified in Survivin promoter (-1872 bp to 
      -1866 bp) with a putative NR4A1 binding site; ChIP assays demonstrated that NR4A1 
      physically associates with the Survivin promoter. In conclusion, NR4A1 protects 
      pancreatic beta-cells against ER stress-mediated apoptosis by up-regulating Survivin 
      expression and down-regulating CHOP expression, which we termed as "positive and 
      negative regulation."
CI  - (c) 2015 by The American Society for Biochemistry and Molecular Biology, Inc.
FAU - Yu, Cong
AU  - Yu C
AD  - The Department of Cell Biology, Shandong University School of Medicine, Jinan, 
      China, 250012.
FAU - Cui, Shang
AU  - Cui S
AD  - The Department of Cell Biology, Shandong University School of Medicine, Jinan, 
      China, 250012.
FAU - Zong, Chen
AU  - Zong C
AD  - The Department of Cell Biology, Shandong University School of Medicine, Jinan, 
      China, 250012.
FAU - Gao, Weina
AU  - Gao W
AD  - The Department of Cell Biology, Shandong University School of Medicine, Jinan, 
      China, 250012.
FAU - Xu, Tongfu
AU  - Xu T
AD  - The Department of Cell Biology, Shandong University School of Medicine, Jinan, 
      China, 250012.
FAU - Gao, Peng
AU  - Gao P
AD  - The Department of Cell Biology, Shandong University School of Medicine, Jinan, 
      China, 250012.
FAU - Chen, Jicui
AU  - Chen J
AD  - The Department of Cell Biology, Shandong University School of Medicine, Jinan, 
      China, 250012.
FAU - Qin, Dandan
AU  - Qin D
AD  - The Department of Cell Biology, Shandong University School of Medicine, Jinan, 
      China, 250012.
FAU - Guan, Qingbo
AU  - Guan Q
AD  - The Department of Endocrinology, Provincial Hospital affiliated to Shandong 
      University, Jinan, China, 250021.
FAU - Liu, Yuantao
AU  - Liu Y
AD  - Department of Endocrinology, Qingdao Municipal Hospital, Qingdao, China, 266071.
FAU - Fu, Yuchang
AU  - Fu Y
AD  - The Department of Nutrition Sciences, University of Alabama at Birmingham, 
      Alabama 35294.
FAU - Li, Xia
AU  - Li X
AD  - The Department of Cell Biology, Shandong University School of Medicine, Jinan, 
      China, 250012. Electronic address: lixia1666@sdu.edu.cn.
FAU - Wang, Xiangdong
AU  - Wang X
AD  - The Department of Cell Biology, Shandong University School of Medicine, Jinan, 
      China, 250012; Key Laboratory of Protein Sciences for Chronic Degenerative 
      Diseases in Universities of Shandong (Shandong University), Jinan, China 250012. 
      Electronic address: xdongw@sdu.edu.cn.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150708
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Birc5 protein, mouse)
RN  - 0 (Ddit3 protein, mouse)
RN  - 0 (Inhibitor of Apoptosis Proteins)
RN  - 0 (Nr4a1 protein, mouse)
RN  - 0 (Nuclear Receptor Subfamily 4, Group A, Member 1)
RN  - 0 (RNA, Messenger)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Repressor Proteins)
RN  - 0 (Survivin)
RN  - 147336-12-7 (Transcription Factor CHOP)
RN  - 2V16EO95H1 (Palmitic Acid)
RN  - 67526-95-8 (Thapsigargin)
RN  - EC 3.4.22.- (Casp3 protein, mouse)
RN  - EC 3.4.22.- (Caspase 3)
SB  - IM
MH  - Animals
MH  - Apoptosis/drug effects/*genetics
MH  - Base Sequence
MH  - Binding Sites
MH  - Caspase 3/genetics/metabolism
MH  - Endoplasmic Reticulum/drug effects/metabolism
MH  - Endoplasmic Reticulum Stress/drug effects/*genetics
MH  - Gene Expression Regulation
MH  - Inhibitor of Apoptosis Proteins/*genetics/metabolism
MH  - Insulin-Secreting Cells/cytology/drug effects/*metabolism
MH  - Mice
MH  - Mice, Knockout
MH  - Molecular Sequence Data
MH  - Nuclear Receptor Subfamily 4, Group A, Member 1/antagonists & 
      inhibitors/*genetics/metabolism
MH  - Palmitic Acid/pharmacology
MH  - Primary Cell Culture
MH  - Promoter Regions, Genetic
MH  - Protein Binding
MH  - RNA, Messenger/antagonists & inhibitors/*genetics/metabolism
MH  - RNA, Small Interfering/genetics/metabolism
MH  - Repressor Proteins/*genetics/metabolism
MH  - Signal Transduction
MH  - Survivin
MH  - Thapsigargin/pharmacology
MH  - Transcription Factor CHOP/*genetics/metabolism
PMC - PMC4543630
OTO - NOTNLM
OT  - NR4A1
OT  - apoptosis
OT  - beta cell (B-cell)
OT  - endoplasmic reticulum stress (ER stress)
OT  - pancreatic islet
OT  - survivin
EDAT- 2015/07/15 06:00
MHDA- 2015/12/15 06:00
PMCR- 2015/07/08
CRDT- 2015/07/10 06:00
PHST- 2015/03/26 00:00 [received]
PHST- 2015/07/10 06:00 [entrez]
PHST- 2015/07/15 06:00 [pubmed]
PHST- 2015/12/15 06:00 [medline]
PHST- 2015/07/08 00:00 [pmc-release]
AID - S0021-9258(20)42093-9 [pii]
AID - M115.654863 [pii]
AID - 10.1074/jbc.M115.654863 [doi]
PST - ppublish
SO  - J Biol Chem. 2015 Aug 21;290(34):20687-20699. doi: 10.1074/jbc.M115.654863. Epub 
      2015 Jul 8.