PMID- 24638142
OWN - NLM
STAT- MEDLINE
DCOM- 20150106
LR  - 20211021
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 9
IP  - 3
DP  - 2014
TI  - Elevation of NR4A3 expression and its possible role in modulating insulin 
      expression in the pancreatic beta cell.
PG  - e91462
LID - 10.1371/journal.pone.0091462 [doi]
LID - e91462
AB  - BACKGROUND: NR4A3/NOR-1 is a member of the NR4A orphan nuclear receptor 
      subfamily, which contains early response genes that sense and respond to a 
      variety of stimuli in the cellular environment. The role of NR4A3 in insulin 
      expression in pancreatic beta cells remains unknown. METHODS: Dynamic changes in 
      NR4A3 were examined in a pancreatic beta-cell line, MIN6, treated with 
      thapsigargin (TG), palmitate (PA), tunicamycin (TM), and dithiothreitol (DTT), 
      chemicals that produce cell stress and even apoptosis. We exploited virus 
      infection techniques to induce expression of NR4A3 or three deletion mutants, and 
      determined expression of insulin and insulin regulatory genes in MIN6 cells. 
      RESULTS: TG and PA, two endoplasmic reticulum (ER) stress inducers, were able to 
      induce unfolded protein response (UPR) activation and elevation of NR4A3 
      expression in MIN6 cells, whereas TM and DTT, two other ER stress inducers, were 
      able to induce UPR activation but not NR4A3 elevation. MIN6 cells over-expressing 
      NR4A3 protein after adenoviral infection exhibited reduced transcription of the 
      insulin genes Ins1 and Ins2, and reduced insulin protein secretion, which were 
      negatively correlated with NR4A3 expression levels. Functional analysis of 
      different deletion mutants of NR4A3 showed that deleting the activation domain 
      AF1 or the DNA-binding domain abolished the down-regulation of insulin 
      transcription by NR4A3 in MIN6 cells, indicating that this down-regulative role 
      was closely related to the NR4A3 trans-activation activity. Over-expression of 
      NR4A3 in MIN6 cells resulted in reduced mRNA transcription of the insulin 
      positive-regulation genes, Pdx1 and NeuroD1. CONCLUSION: Some ER stress inducers, 
      such as TG or PA, are able to elevate NR4A3 expression in MIN6 cells, while 
      others, such as TM or DTT, are not. Over-expression of NR4A3 in MIN6 cells 
      results in down-regulation of insulin gene transcription and insulin secretion. 
      NR4A3 reduces insulin gene expression by modulating the expression of Pdx1 and 
      NeuroD1.
FAU - Gao, Weina
AU  - Gao W
AD  - Department of Cell Biology, Shandong University School of Medicine, Jinan, China; 
      School of Medical Technology and Engineering, Henan University of Science and 
      Technology, Luoyang, China.
FAU - Fu, Yuchang
AU  - Fu Y
AD  - Department of Nutrition Sciences, University of Alabama at Birmingham, 
      Birmingham, Alabama, United States of America.
FAU - Yu, Cong
AU  - Yu C
AD  - Department of Cell Biology, Shandong University School of Medicine, Jinan, China.
FAU - Wang, Shunke
AU  - Wang S
AD  - Department of Cell Biology, Shandong University School of Medicine, Jinan, China.
FAU - Zhang, Yuchao
AU  - Zhang Y
AD  - Department of Cell Biology, Shandong University School of Medicine, Jinan, China.
FAU - Zong, Chen
AU  - Zong C
AD  - Department of Cell Biology, Shandong University School of Medicine, Jinan, China.
FAU - Xu, Tongfu
AU  - Xu T
AD  - Department of Cell Biology, Shandong University School of Medicine, Jinan, China.
FAU - Liu, Yong
AU  - Liu Y
AD  - The Institute for Nutritional Sciences, Chinese Academy of Science, Shanghai, 
      China.
FAU - Li, Xia
AU  - Li X
AD  - Department of Cell Biology, Shandong University School of Medicine, Jinan, China.
FAU - Wang, Xiangdong
AU  - Wang X
AD  - Department of Cell Biology, Shandong University School of Medicine, Jinan, China; 
      Key Laboratory of Protein Sciences for Chronic Degenerative Diseases in 
      Universities of Shandong (Shandong University), Jinan, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140317
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Insulin)
RN  - 0 (Nerve Tissue Proteins)
RN  - 0 (Nr4a3 protein, mouse)
RN  - 0 (Palmitates)
RN  - 0 (Receptors, Steroid)
RN  - 0 (Receptors, Thyroid Hormone)
RN  - 11089-65-9 (Tunicamycin)
RN  - 67526-95-8 (Thapsigargin)
SB  - IM
MH  - Animals
MH  - Cell Line
MH  - DNA-Binding Proteins/chemistry/*genetics/metabolism
MH  - *Gene Expression Regulation/drug effects
MH  - Insulin/*genetics/metabolism
MH  - Insulin-Secreting Cells/drug effects/*metabolism
MH  - Mice
MH  - Nerve Tissue Proteins/chemistry/*genetics/metabolism
MH  - Palmitates/pharmacology
MH  - Protein Interaction Domains and Motifs
MH  - Receptors, Steroid/chemistry/*genetics/metabolism
MH  - Receptors, Thyroid Hormone/chemistry/*genetics/metabolism
MH  - Thapsigargin/pharmacology
MH  - Transcription, Genetic
MH  - Tunicamycin/pharmacology
MH  - Unfolded Protein Response/drug effects
PMC - PMC3956668
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2014/03/19 06:00
MHDA- 2015/01/07 06:00
PMCR- 2014/03/17
CRDT- 2014/03/19 06:00
PHST- 2013/11/27 00:00 [received]
PHST- 2014/02/11 00:00 [accepted]
PHST- 2014/03/19 06:00 [entrez]
PHST- 2014/03/19 06:00 [pubmed]
PHST- 2015/01/07 06:00 [medline]
PHST- 2014/03/17 00:00 [pmc-release]
AID - PONE-D-13-45723 [pii]
AID - 10.1371/journal.pone.0091462 [doi]
PST - epublish
SO  - PLoS One. 2014 Mar 17;9(3):e91462. doi: 10.1371/journal.pone.0091462. eCollection 
      2014.