1. Academic Validation
  2. NR4A1 counteracts JNK activation incurred by ER stress or ROS in pancreatic β-cells for protection

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

  • J Cell Mol Med. 2020 Dec;24(24):14171-14183. doi: 10.1111/jcmm.16028.
Ze-Qing Pu 1 Dong Liu 1 Hanse Pablick Patherny Lobo Mouguegue 1 Cheng-Wen Jin 1 Esha Sadiq 1 Dan-Dan Qin 1 Tian-Fu Yu 1 Chen Zong 1 Ji-Cui Chen 2 Ru-Xing Zhao 3 Jing-Yu Lin 4 Jie Cheng 4 Xiao Yu 4 5 Xia Li 1 Yu-Chao Zhang 6 Yuan-Tao Liu 6 Qing-Bo Guan 7 Xiang-Dong Wang 1 5
Affiliations

Affiliations

  • 1 Department of Cell Biology, Shandong University School of Medicine, Jinan, China.
  • 2 Blood Transfusion Department, Qilu Hospital of Shandong University, Jinan, China.
  • 3 Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, China.
  • 4 Department of Physiology, Shandong University School of Medicine, Jinan, China.
  • 5 Key Laboratory of Protein Sciences for Chronic Degenerative Diseases in Universities of Shandong (Shandong University), Jinan, China.
  • 6 Department of Endocrinology, Qingdao Municipal Hospital, Qingdao, China.
  • 7 Department of Endocrinology, Shandong Provincial Hospital, Affiliated to Shandong University, Jinan, China.
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.

Keywords

ER stress; NR4A1 (Nur77); ROS; cbl-b; p-JNK; pancreatic β-cells.

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