Interdependencies of Gene Expression and Function between Two Redox Enzymes and REG Family Proteins in Murine Pancreatic Islets and Human Pancreatic Cells.

Our laboratory previously revealed that regenerating islets-derived protein 2 (REG2) was diminished in pancreatic islets of glutathione peroxidase-1-overexpressing mice (). It remained unknown if there is an inverse relationship between the expression and function of all family genes and antioxidant enzymes in the pancreatic islets or human pancreatic cells. This research was to determine how altering the and superoxide dismutase-1 () genes alone or together (dKO) affected the expression of all seven murine genes in murine pancreatic islets. In Experiment 1, , their wild-type (WT), , dKO, and their WT (male, 8-wk old, = 4-6) were fed a Se-adequate diet and their islets were collected to assay the mRNA levels of family genes. In Experiment 2, islets from the six groups of mice were treated with phosphate-buffered saline (PBS), REG2, or REG2 mutant protein (1 µg/mL), and/or GPX mimic (ebselen, 50 µM) and SOD mimic (copper [II] diisopropyl salicylate, CuDIPS, 10 µM) for 48 h before the proliferation assay using bromodeoxyuridine (BrdU). In Experiment 3, human pancreatic cells (PANC1) were treated with REG2 (1 µg/mL) and assayed for gene expression, GPX1 and SOD1 activities, viability, and responses to Ca. Compared with the WT, knockouts of and/or up-regulated ( < 0.05) the mRNA levels of most of the murine Reg genes in islets whereas the overexpression down-regulated ( < 0.05) Reg mRNA levels. REG2, but not the REG2 mutant, inhibited islet proliferation in or -altered mice. Such inhibition was abolished by co-incubation the islets with ebselen and the islets with CuDIPS. Treating PANC1 cells with murine REG2 protein induced expression of its human orthologue and three other genes, but decreased SOD1 and GPX1 activities and cell viability. In conclusion, our results revealed an interdependence of REG family gene expression and/or function on intracellular GPX1 and SOD1 activities in murine islets and human pancreatic cells.