title: Regulation of NOX-1 expression in beta cells: a positive feedback loop involving the Src-kinase signaling pathway.
abstract: NADPH oxidase-1 (NOX-1) is upregulated in beta cells in response to pro-inflammatory cytokines. Inhibition of NADPH oxidase activity blocked stimulated NOX-1 expression (p<0.05). Regulation of NOX-1 expression in beta cells followed modulation of cellular reactive oxygen species (ROS); pro-oxidants increased NOX-1 (p<0.001) and anti-oxidants decreased NOX-1 (p<0.05). Activation of Src-kinase followed ROS elevation. Inhibition of Src-kinase decreased NOX-1 expression (p<0.01). Beta cell dysfunction, measured by elevated MCP-1 expression, loss of glucose-sensitive insulin secretion or cell death, was induced by pro-inflammatory cytokine stimulation. Importantly, inhibition of Src-kinase or NOX-1 preserved beta cell function and survival. Collectively, these data indicate that expression of NOX-1 in beta cells is regulated in a feed-forward loop mediated by ROS and Src-kinase. Uncoupling of this feed-forward activation could provide new approaches to preserve and protect beta cells in diabetes.
authors: Strelitz Diabetes Center, Department of Internal Medicine, Eastern Virginia Medical School, Norfolk, VA 23501, USA.
authors: J R
authors: JR
authors: Weaver
authors: D A
authors: DA
authors: Taylor-Fishwick
mesh_terms: D017209:Apoptosis; D002460:Cell Line; D002470:Cell Survival; D025461:Feedback, Physiological; D005786:Gene Expression Regulation; D006801:Humans; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000201:enzymology*; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism*; D000074624:NADPH Oxidase 1; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; D009247:NADH, NADPH Oxidoreductases; D000074624:NADPH Oxidase 1; D019061:src-Family Kinases