title: Nitric Oxide Suppresses β-Cell Apoptosis by Inhibiting the DNA Damage Response.
abstract: Nitric oxide, produced in pancreatic β cells in response to proinflammatory cytokines, plays a dual role in the regulation of β-cell fate. While nitric oxide induces cellular damage and impairs β-cell function, it also promotes β-cell survival through activation of protective pathways that promote β-cell recovery. In this study, we identify a novel mechanism in which nitric oxide prevents β-cell apoptosis by attenuating the DNA damage response (DDR). Nitric oxide suppresses activation of the DDR (as measured by γH2AX formation and the phosphorylation of KAP1 and p53) in response to multiple genotoxic agents, including camptothecin, H2O2, and nitric oxide itself, despite the presence of DNA damage. While camptothecin and H2O2 both induce DDR activation, nitric oxide suppresses only camptothecin-induced apoptosis and not H2O2-induced necrosis. The ability of nitric oxide to suppress the DDR appears to be selective for pancreatic β cells, as nitric oxide fails to inhibit DDR signaling in macrophages, hepatocytes, and fibroblasts, three additional cell types examined. While originally described as the damaging agent responsible for cytokine-induced β-cell death, these studies identify a novel role for nitric oxide as a protective molecule that promotes β-cell survival by suppressing DDR signaling and attenuating DNA damage-induced apoptosis.
authors.affiliation: Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
authors.forename: Bryndon J
authors.initials: BJ
authors.lastname: Oleson
authors.affiliation: Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
authors.forename: Katarzyna A
authors.initials: KA
authors.lastname: Broniowska
authors.affiliation: Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
authors.forename: Aaron
authors.initials: A
authors.lastname: Naatz
authors.affiliation: Department of Biophysics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
authors.forename: Neil
authors.initials: N
authors.lastname: Hogg
authors.affiliation: Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
authors.forename: Vera L
authors.initials: VL
authors.lastname: Tarakanova
authors.affiliation: Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, USA jcorbett@mcw.edu.
authors.forename: John A
authors.initials: JA
authors.lastname: Corbett
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002166:Camptothecin / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival; D004249:DNA Damage / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects*; D056945:Hep G2 Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects*; D008297:Male; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism*; D009928:Organ Specificity; D010766:Phosphorylation / Q000187:drug effects; D000067996:RAW 264.7 Cells; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D009569:Nitric Oxide; D006861:Hydrogen Peroxide; D002166:Camptothecin