title: Nitric oxide induces ataxia telangiectasia mutated (ATM) protein-dependent γH2AX protein formation in pancreatic β cells.
abstract: In this study, the effects of cytokines on the activation of the DNA double strand break repair factors histone H2AX (H2AX) and ataxia telangiectasia mutated (ATM) were examined in pancreatic β cells. We show that cytokines stimulate H2AX phosphorylation (γH2AX formation) in rat islets and insulinoma cells in a nitric oxide- and ATM-dependent manner. In contrast to the well documented role of ATM in DNA repair, ATM does not appear to participate in the repair of nitric oxide-induced DNA damage. Instead, nitric oxide-induced γH2AX formation correlates temporally with the onset of irreversible DNA damage and the induction of apoptosis. Furthermore, inhibition of ATM attenuates cytokine-induced caspase activation. These findings show that the formation of DNA double strand breaks correlates with ATM activation, irreversible DNA damage, and ATM-dependent induction of apoptosis in cytokine-treated β cells.
authors.affiliation: Department of Biochemistry and Medical College of Wisconsin, Milwaukee, Wisconsin 53226.
authors.forename: Bryndon J
authors.initials: BJ
authors.lastname: Oleson
authors.affiliation: Department of Biochemistry and Medical College of Wisconsin, Milwaukee, Wisconsin 53226.
authors.forename: Katarzyna A
authors.initials: KA
authors.lastname: Broniowska
authors.affiliation: Edward A. Doisy Department of Biochemistry and Molecular Biology, St. Louis University School of Medicine, St. Louis, Missouri 63104.
authors.forename: Katherine H
authors.initials: KH
authors.lastname: Schreiber
authors.affiliation: Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, Wisconsin 53226 and.
authors.forename: Vera L
authors.initials: VL
authors.lastname: Tarakanova
authors.affiliation: Department of Biochemistry and Medical College of Wisconsin, Milwaukee, Wisconsin 53226. Electronic address: jcorbett@mcw.edu.
authors.forename: John A
authors.initials: JA
authors.lastname: Corbett
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics / Q000378:metabolism*; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D004789:Enzyme Activation / Q000502:physiology; D006657:Histones; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D008297:Male; D009569:Nitric Oxide / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins; D010766:Phosphorylation / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D016207:Cytokines; D006657:Histones; D010750:Phosphoproteins; C577575:gamma-H2AX protein, rat; D009569:Nitric Oxide; D064007:Ataxia Telangiectasia Mutated Proteins; D020169:Caspases
keywords: ATM; Apoptosis; Cytokine; DNA Repair; H2AX; Nitric Oxide; β Cell