How the Location of Superoxide Generation Influences the β-Cell Response to Nitric Oxide

Broniowska, Katarzyna A.; Oleson, Bryndon J.; McGraw, Jennifer; Naatz, Aaron; Mathews, Clayton E.; Corbett, John A.

doi:10.1074/jbc.m114.627869

Cited by 20 publications

(21 citation statements)

References 60 publications

(77 reference statements)

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“…In their report (1), the authors strengthen doubts that peroxynitrite is a main culprit for ␤-cell dysfunction and death in type 1 diabetes, confirming previous studies (2).…”

supporting

confidence: 79%

Is Nitric Oxide Really the Primary Mediator of Pancreatic β-Cell Death in Type 1 Diabetes?

Gurgul-Convey

Lenzen

2015

Journal of Biological Chemistry

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“…In their report (1), the authors strengthen doubts that peroxynitrite is a main culprit for ␤-cell dysfunction and death in type 1 diabetes, confirming previous studies (2).…”

supporting

confidence: 79%

Is Nitric Oxide Really the Primary Mediator of Pancreatic β-Cell Death in Type 1 Diabetes?

Gurgul-Convey

Lenzen

2015

Journal of Biological Chemistry

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“…Menadione stimulates DDR activation only at the concentration of 60 mmol/L ( Fig. 3C) (34). H 2 O 2 also stimulates DDR activation yet does not impair camptothecin-induced DDR activation at low concentrations ( Fig.…”

Section: Selectivity Of Reactive Oxygen and Nitrogen Species As Inhibmentioning

confidence: 80%

“…Reactive oxygen species (ROS) and nitrogen species (RNS) activate distinct signaling pathways in b-cells (34,35). For determination of whether other forms of ROS or RNS suppress DDR activation, INS 832/13 cells were treated for 1 h with camptothecin in the presence or absence of DPTA/NO, SIN-1 (peroxynitrite donor), menadione (superoxide generator), or H 2 O 2 ( Fig.…”

Section: Selectivity Of Reactive Oxygen and Nitrogen Species As Inhibmentioning

confidence: 99%

Role of Protein Phosphatase 1 and Inhibitor of Protein Phosphatase 1 in Nitric Oxide–Dependent Inhibition of the DNA Damage Response in Pancreatic β-Cells

et al. 2018

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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.

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“…We have shown that ␤ cells lack the ability to generate superoxide and therefore peroxynitrite in response to cytokines (35,49). When forced to generate peroxynitrite following treatment with the superoxide-generating redox cycler menadione and a chemical donor of nitric oxide, superoxide scavenges nitric oxide and protects ␤ cells from nitric oxide-mediated decreases in cellular ATP, oxidative metabolism, and the induction of nitric oxide-dependent gene expression (35,49). This protection from nitric oxide-mediated damage occurs under conditions where ␤ cells generate peroxynitrite to levels that are comparable to the levels generated by activated macrophages (35).…”

Section: Discussionmentioning

confidence: 99%

Nitric Oxide Suppresses β-Cell Apoptosis by Inhibiting the DNA Damage Response

Oleson

Broniowska

Naatz

et al. 2016

Molecular and Cellular Biology

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c Nitric oxide, produced in pancreatic ␤ cells in response to proinflammatory cytokines, plays a dual role in the regulation of ␤-cell fate. While nitric oxide induces cellular damage and impairs ␤-cell function, it also promotes ␤-cell survival through activation of protective pathways that promote ␤-cell recovery. In this study, we identify a novel mechanism in which nitric oxide prevents ␤-cell apoptosis by attenuating the DNA damage response (DDR). Nitric oxide suppresses activation of the DDR (as measured by ␥H2AX formation and the phosphorylation of KAP1 and p53) in response to multiple genotoxic agents, including camptothecin, H 2 O 2 , and nitric oxide itself, despite the presence of DNA damage. While camptothecin and H 2 O 2 both induce DDR activation, nitric oxide suppresses only camptothecin-induced apoptosis and not H 2 O 2 -induced necrosis. The ability of nitric oxide to suppress the DDR appears to be selective for pancreatic ␤ 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 ␤-cell death, these studies identify a novel role for nitric oxide as a protective molecule that promotes ␤-cell survival by suppressing DDR signaling and attenuating DNA damage-induced apoptosis.

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How the Location of Superoxide Generation Influences the β-Cell Response to Nitric Oxide

Cited by 20 publications

References 60 publications

Is Nitric Oxide Really the Primary Mediator of Pancreatic β-Cell Death in Type 1 Diabetes?

Is Nitric Oxide Really the Primary Mediator of Pancreatic β-Cell Death in Type 1 Diabetes?

Role of Protein Phosphatase 1 and Inhibitor of Protein Phosphatase 1 in Nitric Oxide–Dependent Inhibition of the DNA Damage Response in Pancreatic β-Cells

Nitric Oxide Suppresses β-Cell Apoptosis by Inhibiting the DNA Damage Response

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