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. Epub 2020 Oct 30.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Endoplasmic Reticulum Stress*
  • Gene Expression Regulation
  • Hydrogen Peroxide / metabolism
  • Insulin-Secreting Cells / metabolism*
  • JNK Mitogen-Activated Protein Kinases / metabolism*
  • MAP Kinase Kinase 4 / metabolism
  • Mice
  • Mice, Knockout
  • Models, Biological
  • Nuclear Receptor Subfamily 4, Group A, Member 1 / genetics
  • Nuclear Receptor Subfamily 4, Group A, Member 1 / metabolism*
  • Phosphorylation
  • Promoter Regions, Genetic
  • Protein Binding
  • Reactive Oxygen Species / metabolism*
  • Ubiquitination


  • Nr4a1 protein, mouse
  • Nuclear Receptor Subfamily 4, Group A, Member 1
  • Reactive Oxygen Species
  • Hydrogen Peroxide
  • JNK Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 4