title: JunB Inhibits ER Stress and Apoptosis in Pancreatic Beta Cells.
abstract: Cytokines contribute to pancreatic beta-cell apoptosis in type 1 diabetes (T1D) by modulation of beta-cell gene expression networks. The transcription factor Activator Protein-1 (AP-1) is a key regulator of inflammation and apoptosis. We presently evaluated the function of the AP-1 subunit JunB in cytokine-mediated beta-cell dysfunction and death. The cytokines IL-1beta+IFN-gamma induced an early and transitory upregulation of JunB by NF-kappaB activation. Knockdown of JunB by RNA interference increased cytokine-mediated expression of inducible nitric oxide synthase (iNOS) and endoplasmic reticulum (ER) stress markers, leading to increased apoptosis in an insulin-producing cell line (INS-1E) and in purified rat primary beta-cells. JunB knockdown beta-cells and junB(-/-) fibroblasts were also more sensitive to the chemical ER stressor cyclopiazonic acid (CPA). Conversely, adenoviral-mediated overexpression of JunB diminished iNOS and ER markers expression and protected beta-cells from cytokine-induced cell death. These findings demonstrate a novel and unexpected role for JunB as a regulator of defense mechanisms against cytokine- and ER stress-mediated apoptosis.
authors: Laboratory of Experimental Medicine, Université Libre de Bruxelles (ULB), Brussels, Belgium.
authors: Esteban N
authors: EN
authors: Gurzov
authors: Fernanda
authors: F
authors: Ortis
authors: Latifa
authors: L
authors: Bakiri
authors: Erwin F
authors: EF
authors: Wagner
authors: Decio L
authors: DL
authors: Eizirik
mesh_terms: D016475:3T3 Cells; D000256:Adenoviridae; D000818:Animals; D017209:Apoptosis; D016923:Cell Death; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000502:physiology*; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D017353:Gene Deletion; D005822:Genetic Vectors; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000502:physiology*; D051379:Mice; D009569:Nitric Oxide / Q000502:physiology; D016755:Proto-Oncogene Proteins c-jun / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D016755:Proto-Oncogene Proteins c-jun; D009569:Nitric Oxide