NR4A1 counteracts JNK activation incurred by ER stress or ROS in pancreatic β‐cells for protection

Autor: Dong Liu, Yuantao Liu, Chen Zong, Tian‐fu Yu, Esha Sadiq, Jie Cheng, Ze‐qing Pu, Yuchao Zhang, Xiangdong Wang, Xiao Yu, Ruxing Zhao, Cheng‐wen Jin, Dandan Qin, Xia Li, Jicui Chen, Hanse Pablick Patherny Lobo Mouguegue, Jing-Yu Lin, Qingbo Guan
Rok vydání: 2020
Předmět:
0301 basic medicine
MAP Kinase Kinase 4
cbl‐b
Models
Biological
Cell Line
Mice
03 medical and health sciences
Transactivation
p‐JNK
0302 clinical medicine
Insulin-Secreting Cells
Gene expression
Nuclear Receptor Subfamily 4
Group A
Member 1
Animals
Phosphorylation
Promoter Regions
Genetic
pancreatic β‐cells
Mice
Knockout
chemistry.chemical_classification
Reactive oxygen species
biology
Kinase
Endoplasmic reticulum
JNK Mitogen-Activated Protein Kinases
Ubiquitination
ROS
Original Articles
Hydrogen Peroxide
Cell Biology
Endoplasmic Reticulum Stress
Cell biology
Ubiquitin ligase
030104 developmental biology
Gene Expression Regulation
chemistry
Apoptosis
030220 oncology & carcinogenesis
Unfolded protein response
biology.protein
Molecular Medicine
Original Article
ER stress
Reactive Oxygen Species
NR4A1 (Nur77)
Protein Binding
Zdroj: Journal of Cellular and Molecular Medicine
ISSN: 1582-4934
1582-1838
Popis: Sustained hyperglycaemia and hyperlipidaemia incur endoplasmic reticulum stress (ER stress) and reactive oxygen species (ROS) overproduction in pancreatic β‐cells. ER stress or ROS causes c‐Jun N‐terminal kinase (JNK) activation, and the activated JNK triggers apoptosis in different cells. Nuclear receptor subfamily 4 group A member 1 (NR4A1) is an inducible multi‐stress response factor. The aim of this study was to explore the role of NR4A1 in counteracting JNK activation induced by ER stress or ROS and the related mechanism. qPCR, Western blotting, dual‐luciferase reporter and ChIP assays were applied to detect gene expression or regulation by NR4A1. Immunofluorescence was used to detect a specific protein expression in β‐cells. Our data showed that NR4A1 reduced the phosphorylated JNK (p‐JNK) in MIN6 cells encountering ER stress or ROS and reduced MKK4 protein in a proteasome‐dependent manner. We found that NR4A1 increased the expression of cbl‐b (an E3 ligase); knocking down cbl‐b expression increased MKK4 and p‐JNK levels under ER stress or ROS conditions. We elucidated that NR4A1 enhanced the transactivation of cbl‐b promoter by physical association. We further confirmed that cbl‐b expression in β‐cells was reduced in NR4A1‐knockout mice compared with WT mice. NR4A1 down‐regulates JNK activation by ER stress or ROS in β‐cells via enhancing cbl‐b expression.
Databáze: OpenAIRE
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