NR4A1 counteracts JNK activation incurred by ER stress or ROS in pancreatic β‐cells for protection. Issue 24 (30th October 2020)

• Record Type: Journal Article
• Authors: Pu, Ze‐qing; Liu, Dong; Lobo Mouguegue, Hanse Pablick Patherny; Jin, Cheng‐wen; Sadiq, Esha; Qin, Dan‐dan; Yu, Tian‐fu; Zong, Chen; Chen, Ji‐cui; Zhao, Ru‐xing; Lin, Jing‐Yu; Cheng, Jie; Yu, Xiao; Li, Xia; Zhang, Yu‐chao; Liu, Yuan‐tao; Guan, Qing‐bo; Wang, Xiang‐dong
• Is Part Of: Journal of cellular and molecular medicine. Volume 24:Issue 24(2020)
• Page Start: 14171
• Page End: 14183
• Publication Date: 2020-10-30
• Subjects: cbl‐b -- ER stress -- NR4A1 (Nur77) -- pancreatic β‐cells -- p‐JNK -- ROS; Cytology; Medicine; Molecular Biology; Cytologie -- Périodiques; Médecine -- Périodiques; Biologie moléculaire -- Périodiques; Cytology -- Periodicals; Medicine -- Periodicals; Molecular biology -- Periodicals; 611.01805
• DOI: 10.1111/jcmm.16028
• Languages: English
• ISSNs: 1582-1838

Abstract

Abstract: 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.