Nitric Oxide Suppresses β-Cell Apoptosis by Inhibiting the DNA Damage Response. Mol Cell Biol 2016 Aug 01;36(15):2067-77
Date
05/18/2016Pubmed ID
27185882Pubmed Central ID
PMC4946431DOI
10.1128/MCB.00262-16Scopus ID
2-s2.0-85000890117 (requires institutional sign-in at Scopus site) 40 CitationsAbstract
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.
Author List
Oleson BJ, Broniowska KA, Naatz A, Hogg N, Tarakanova VL, Corbett JAAuthors
John A. Corbett PhD Chair, Professor in the Biochemistry department at Medical College of WisconsinNeil Hogg PhD Associate Dean, Professor in the Biophysics department at Medical College of Wisconsin
Vera Tarakanova PhD Professor in the Microbiology and Immunology department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsApoptosis
Camptothecin
Cell Line
Cell Survival
DNA Damage
DNA Repair
Hep G2 Cells
Humans
Hydrogen Peroxide
Insulin-Secreting Cells
Male
Mice
Nitric Oxide
Organ Specificity
Phosphorylation
RAW 264.7 Cells
Rats
Rats, Sprague-Dawley
Signal Transduction
