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NR4A1 enhances MKP7 expression to diminish JNK activation induced by ROS or ER-stress in pancreatic β cells for

Ze-Qing Pu1, Tian-Fu Yu1, Dong Liu1

  • 1Department of Cell Biology, Shandong University School of Medicine, Jinan, China.

Cell Death Discovery
|June 5, 2021
PubMed

Insights

Nuclear Receptor NR4A1 protects pancreatic beta cells from damage by reducing stress-induced JNK phosphorylation via enhancing MKP7 expression, offering a potential strategy for diabetes prevention.

Area of Science:

  • Cell Biology
  • Endocrinology
  • Molecular Biology

Background:

  • Hyperglycemia and hyperlipidemia induce reactive oxygen species (ROS) and endoplasmic reticulum (ER) stress in pancreatic beta cells.
  • ROS and ER stress can damage beta cells, leading to apoptosis and potentially contributing to diabetes.
  • Previous research indicated that NR4A1 overexpression reduces JNK activation in beta cells by modulating cbl-b expression.

Purpose of the Study:

  • To investigate the underlying mechanisms by which NR4A1 influences JNK activation in pancreatic beta cells under stress conditions.
  • To explore the role of MKP7 (a phosphatase for phospho-JNK) in the context of NR4A1 expression and its impact on beta cell function.

Main Methods:

  • Utilized NR4A1 knockout (KO) mice and MIN6 pancreatic beta cell lines.
  • Assessed mRNA and protein levels of MKP7.
  • Overexpressed and knocked down MKP7 to evaluate its effect on JNK phosphorylation (p-JNK) following treatment with thapsigargin (TG) or hydrogen peroxide (H2O2).
  • Analyzed NR4A1's interaction with the MKP7 promoter using luciferase assays.

Main Results:

  • NR4A1 KO mice exhibited reduced MKP7 mRNA and protein levels in pancreatic beta cells compared to wild-type mice.
  • Overexpression of NR4A1 in MIN6 cells led to increased MKP7 expression.
  • Knocking down MKP7 enhanced p-JNK levels in beta cells treated with TG or H2O2.
  • NR4A1 physically associated with the MKP7 promoter, enhancing its transactivation.

Conclusions:

  • NR4A1 attenuates JNK phosphorylation induced by ER stress or ROS, at least partially, by upregulating MKP7 expression.
  • This mechanism may protect pancreatic beta cells from apoptosis under adverse conditions.
  • The findings provide a potential therapeutic target for diabetes prevention.

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