Reactive Oxygen Species and Signal Transduction

Abstract

SummaryIncreasing evidence suggests a role for intracellular reactive oxygen species (ROS) as mediators of normal and pathological signal transduction pathways. In particular, a growing list of recent reports have demonstrated a rapid and signi cant increases in intracellular ROS following growth factor or cytokine stimulation. These ROS appear essential for a host of downstream signaling events. Biochemical characterization of this ligand-activated ROS production has revealed important information regarding the molecular composition of the cellular oxidases and the regulation of their activity by small GTPases. Work is proceeding on identifying strategies to identify how ROS might speci cally regulate signaling pathways by altering the activity of direct target molecules. This review will focus on the progress in the rapid emerging area of oxidant or redox-dependent signal transduction and speculate how these insights might alter our view and treatment of diseases thought to be caused by oxidative stress. It has been well known that bacteria respond to changes in the concentration of either superoxide anion or hydrogen peroxide with a precise signaling pathway and a corresponding discrete set of induced gene expression (1). The pattern of gene expression differs depending on whether the bacteria is exposed to either superoxide anions or hydrogen peroxide. This speci city suggests that the response to ROS is not a generalized stress response but instead has evolved to allow bacteria to be able to sense, and respond accordingly, to subtly different oxidant species. Although the ability of bacteria to sense and respond to changes in intracellular ROS has been appreciated for some time, the realization that eukaryotic cells might have similar abilities has only recently been advanced. Over the last 5 years, a growing number of reports have suggested that mammalian cells can rapidly respond to ligand stimulation with a change in intracellular ROS. For many of these reports, investigators have used uorescent dyes to measure the level of intracellular ROS in living cells. These dyes, dichloro uorescein diacetate (DCFDA) being the most common, are readily available and their ease of use has spurred interest in the eld. Many of these compounds are non uorescent moieties that, when oxidized by ROS form uorescent compounds, can be imaged by standard uorescent or confocal microscopy. Although the use of compounds such as DCFDA is widespread, it is important to note that the speci city of these compounds for their intended ROS species (in the case of DCFDA, hydrogen peroxide) is not well established. In addition, at present it is impossible to determine absolute levels of ROS from the uorescent intensity and, as such, these measurements represent a qualitative, (not quantitative) assessment of ligand-activated ROS production.With these caveats in mind, the last few years have seen a growing number of reports demonstrating that ROS production represents a common aspect of multiple signaling pathways. Included among these lig...

Hydrogen peroxide generated at the level of mitochondria in response to peroxynitrite promotes U937 cell death via inhibition of the cytoprotective signalling mediated by cytosolic phospholipase A2

“…(ii) H 2 O 2 may interfere with cytoprotective signalling events counteracting the lethal response evoked by peroxynitrite. This scenario would instead be consistent with the notion that reactive species can specifically regulate cell signalling 19,20 and with the emerging hypothesis that necrosis might not always be an obligatory response to a stochastic process of cell damage. 21 Our previous findings 22 that peroxynitrite promotes an early activation of the cytosolic phospholipase A 2 isoform (cPLA 2 ), and that the ensuing release of arachidonic acid (AA) plays an important cytoprotective role, offer important clues in this direction.…”

Reactive oxygen species (ROS) control the expression of Bcl‐2 family proteins by regulating their phosphorylation and ubiquitination

“…[37][38][39] An appropriate amount of ROS, usually a small amount, activates phosphokinases and increases the intracellular Ca 2+ level. 40,41) However, a large amount induces hyperoxidation of DNA, proteins, and lipids, which results in cell impairment.…”

Mitochondrial Protein Targets of Thiol-Reactive Electrophiles

“…The characteristics of protein damage associated with apoptosis have been explored only to a limited extent. Cysteine thiols are thought to be particularly important targets for pro-apoptotic damage, as these nucleophilic residues are easily modified by oxidants and electrophiles and are critical in regulating certain aspects of cellular signaling (8)(9)(10). Protein covalent binding can trigger apoptosis, at least in part through modification of critical cellular protein thiols (11)(12)(13)(14).…”