Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI.
Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI
Diabetes. 2018 May;67(5):898-910. doi: 10.2337/db17-1062. Epub 2018 Feb 14.
Nitric oxide is produced at micromolar levels by pancreatic β-cells during exposure to proinflammatory cytokines. While classically viewed as damaging, nitric oxide also activates pathways that promote β-cell survival. We have shown that nitric oxide, in a cell type-selective manner, inhibits the DNA damage response (DDR) and, in doing so, protects β-cells from DNA damage-induced apoptosis. This study explores potential mechanisms by which nitric oxide inhibits DDR signaling. We show that inhibition of DDR signaling (measured by γH2AX formation and the phosphorylation of KAP1) is selective for nitric oxide, as other forms of reactive oxygen/nitrogen species do not impair DDR signaling. The kinetics and broad range of DDR substrates that are inhibited suggest that protein phosphatase activation may be one mechanism by which nitric oxide attenuates DDR signaling in β-cells. While protein phosphatase 1 (PP1) is a primary regulator of DDR signaling and an inhibitor of PP1 (IPP1) is selectively expressed only in β-cells, disruption of either IPP1 or PP1 does not modify the inhibitory actions of nitric oxide on DDR signaling in β-cells. These findings support a PP1-independent mechanism by which nitric oxide selectively impairs DDR signaling and protects β-cells from DNA damage-induced apoptosis.
一氧化氮在受到促炎细胞因子作用时，由胰腺β细胞以微摩尔水平生成。虽然一氧化氮通常被认为具有破坏性，但它也能激活促进β细胞存活的途径。我们已经表明，一氧化氮以细胞类型选择性的方式抑制 DNA 损伤反应（DDR），从而保护β细胞免受 DNA 损伤诱导的细胞凋亡。本研究探讨了一氧化氮抑制 DDR 信号转导的潜在机制。我们发现，DDR 信号转导的抑制（通过 γH2AX 形成和 KAP1 的磷酸化来衡量）是一氧化氮特有的，因为其他形式的活性氧/氮物种不会损害 DDR 信号转导。抑制的 DDR 信号转导的动力学和广泛的 DDR 底物表明，蛋白磷酸酶的激活可能是一氧化氮减弱β细胞 DDR 信号转导的一种机制。虽然蛋白磷酸酶 1（PP1）是 DDR 信号转导的主要调节剂，而仅在β细胞中选择性表达的抑制剂（IPP1），但破坏 IPP1 或 PP1 都不会改变一氧化氮对β细胞 DDR 信号转导的抑制作用。这些发现支持了一种 PP1 非依赖性机制，即一氧化氮选择性地损害 DDR 信号转导并保护β细胞免受 DNA 损伤诱导的细胞凋亡。
