Nitric Oxide Induces Ataxia Telangiectasia Mutated ( ATM) Protein-dependent gamma H2AX Protein Formation in Pancreatic beta Cells

作者：Oleson Bryndon J; Broniowska Katarzyna A; Schreiber Katherine H; Tarakanova Vera L; Corbett John A^*

来源：JOURNAL OF BIOLOGICAL CHEMISTRY, 2014, 289(16): 11454-11464.

DOI：10.1074/jbc.M113.531228

• Apoptosis
• Cell
• Cytokine
• DNA Repair
• Nitric Oxide
• ATM
• H2AX

Background: The mechanisms that control cell fate following cytokine- and nitric oxide-induced damage remain unknown. Results: Cytokine-induced nitric oxide activates ATM and ATM-dependent caspase activation in cells. Conclusion: ATM regulates the induction of apoptosis in cytokine-treated cells. Significance: These studies define a role for DNA damage and ATM activation in nitric oxide-induced cell apoptosis. %26lt;br%26gt;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 cells. We show that cytokines stimulate H2AX phosphorylation (H2AX 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 H2AX 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 cells.

• 出版日期2014-4-18