The chemistry of cell signaling by reactive oxygen and nitrogen species and 4-hydroxynonenal - PubMed (original) (raw)

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The chemistry of cell signaling by reactive oxygen and nitrogen species and 4-hydroxynonenal

Henry Jay Forman et al. Arch Biochem Biophys. 2008.

Abstract

During the past several years, major advances have been made in understanding how reactive oxygen species (ROS) and nitrogen species (RNS) participate in signal transduction. Identification of the specific targets and the chemical reactions involved still remains to be resolved with many of the signaling pathways in which the involvement of reactive species has been determined. Our understanding is that ROS and RNS have second messenger roles. While cysteine residues in the thiolate (ionized) form found in several classes of signaling proteins can be specific targets for reaction with H(2)O(2) and RNS, better understanding of the chemistry, particularly kinetics, suggests that for many signaling events in which ROS and RNS participate, enzymatic catalysis is more likely to be involved than non-enzymatic reaction. Due to increased interest in how oxidation products, particularly lipid peroxidation products, also are involved with signaling, a review of signaling by 4-hydroxy-2-nonenal (HNE) is included. This article focuses on the chemistry of signaling by ROS, RNS, and HNE and will describe reactions with selected target proteins as representatives of the mechanisms rather attempt to comprehensively review the many signaling pathways in which the reactive species are involved.

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FIGURE 1

FIGURE 1

Model based on studies of the activation of JNK pathway upon generation of H2O2 in rat alveolar macrophages (30) and in human bronchial epithelial cells (HBE1) exposed to HNE (212). Several stimuli are able to induce the assembly of the membrane NADPH oxidase (NOX2) in macrphages resulting in the generation of extracellular superoxide that dismutes to H2O2. ASK1, in its inactive form, is bound to the reduced Trx. Oxidation of the bound Trx to the disulfide form by H2O2, which is catalyzed by a peroxiredoxin, causes dissociation of Trx from ASK1. ASK1 then can undergo dimerization and auto-phosphorylation that initiates the sequential phosphorylation of MKK4, JNK and cJun. Phospho- cJun, as part of the AP-1 transcription factor complex, can then bind to the TRE cis element resulting in the transcription of several genes. HNE generated from the peroxidation of ω-6 polyunsaturated fatty acids under physiologic or pathologic conditions, can react with SHP-1 leading to its inactivation and degradation. As a consequence, the inhibitory effect of SHP-1 on an unknown protein upstream of MKK4 (currently under investigation), is released allowing the signal to be transmitted along the same pathway as above.

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