The Orphan Nuclear Receptor NR4A1 Protects Pancreatic β-Cells from Endoplasmic Reticulum (ER) Stress-mediated Apoptosis.
Bottom Line: This conclusion was further confirmed by experiments exploiting siRNA to knockdown NR4A1 expression in MIN6 cells or exploiting NR4A1 knock-out mice.NR4A1 overexpression in MIN6 cells or mouse islets resulted in Survivin up-regulation.In conclusion, NR4A1 protects pancreatic β-cells against ER stress-mediated apoptosis by up-regulating Survivin expression and down-regulating CHOP expression, which we termed as "positive and negative regulation."
Affiliation: From the The Department of Cell Biology, Shandong University School of Medicine, Jinan, China, 250012.Show MeSH
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Mentions: To investigate whether ER stress-inducing reagents increase NR4A1 expression in mouse islets, we isolated islet cells from 16-week-old C57BL/6J mice. The isolated mice islets were treated with TG (0.5 μm) or PA (0.4 mm) for different time points. We found that TG and PA treatment induced a time-dependent rise in mRNA for sXBP1, Bip (immunoglobulin-binding protein) (data not shown), and CHOP (Fig. 2, A and C), which are markers for ER stress. As expected, TG or PA treatment also increased the NR4A1 mRNA level in a time-dependent manner in purified mouse islets (Fig. 2, B and D). TG- or PA-induced NR4A1 mRNA expression peaked at earlier time points than that of CHOP (Fig. 2, A–D). Olivier Briand (26) previously also showed that PA induces NR4A1 expression in mouse islet cells. To confirm if the increased NR4A1 expression induced by TG and PA in mouse islets occurred in β-cells, we did double immunofluorescence staining with specific antibodies against NR4A1 and Insulin. The images (Fig. 2E) showed that TG treatment increase NR4A1 expression (green), and it was mostly co-localized with insulin (red) in islets. These results confirmed that the two ER stress inducers truly induce NR4A1 expression in β-cells of mouse islets.
Affiliation: From the The Department of Cell Biology, Shandong University School of Medicine, Jinan, China, 250012.