| First Author | Yun JW | Year | 2019 |
| Journal | Free Radic Biol Med | Volume | 134 |
| Pages | 385-393 | PubMed ID | 30703484 |
| Mgi Jnum | J:329172 | Mgi Id | MGI:7341750 |
| Doi | 10.1016/j.freeradbiomed.2019.01.024 | Citation | Yun JW, et al. (2019) Glutathione peroxidase-1 inhibits transcription of regenerating islet-derived protein-2 in pancreatic islets. Free Radic Biol Med 134:385-393 |
| abstractText | Our group previously demonstrated that overexpression of selenium-dependent glutathione peroxidase-1 (GPX1) in mice (OE) led to escalated glucose-stimulated insulin secretion and hyperinsulinemia. Because we found a strong correlation of this phenotype with a diminished expression of regenerating islet-derived protein 2 (REG2) in the OE pancreatic islets, the present study was to reveal underlying mechanisms for that down-regulation of REG2 by GPX1 as a major scavenger of reactive oxygen species. We first treated the OE and wild-type (WT) mice and their islets with ROS-generating diquat, streptozotocin, and H2O2 and ROS-scavenging ebselen and N-acetylcysteine (NAC). Their effects on pancreatic and islet REG2 protein and(or) secretion were opposite (P<0.05). Thereafter, we identified 13 transcriptional factors with putative binding sites in the Reg2 proximate promoter, and found that only activator protein-1 (AP-1) and albumin D box-binding protein (DBP) mRNA and protein levels were affected (elevated) (P<0.05) by the GPX1 overproduction in the OE pancreatic islets compared with the WT islets. Contrary to that of Reg2 expression, their mRNA abundances in the cultured islets were elevated (P<0.05) by ebselen and NAC, but decreased (P<0.05) by H2O2. Both AP-1 and DBP could bind to the Reg2 promoter at the location of -168 to 0 base pair (bp) in the OE islets. Deleting the AP-1 (-143/-137 and -60/-57 bp) and(or) DBP (-35/-29 bp) binding domains in the Reg2 promoter attenuated and(or) abolished the inhibition of Reg2 promoter activation by ebselen as the GPX1 mimic in betaTC-3cells. In conclusion, the down-regulation of Reg2 expression in the GPX1-overproducing pancreatic islets was mediated by a transcriptional inhibition of the gene through two ROS responsive transcription factors AP-1 and DBP. Our findings reveal GPX1 as a novel regulator of Reg2 expression, and linking these two previously-unrelated proteins will have broad biomedical implications. |
