H2O2-dependent Activation of GCLC-ARE4 Reporter Occurs by Mitogen-activated Protein Kinase Pathways without Oxidation of Cellular Glutathione or Thioredoxin-1

Go, Young‐Mi; Gipp, Jerry J.; Mulcahy, Ríona; Jones, Dean P.

doi:10.1074/jbc.m307547200

Cited by 95 publications

(58 citation statements)

References 47 publications

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“…We have confirmed similar findings after cellular insulin stimulation of insulin target cell types (X.W., B.J.G., unpublished observations). The biochemical evidence, therefore, also supports the notion of a discrete network of "redox circuitry" (51,59,155) with temporal and spatial influences that are likely to correspond to other regulatory aspects of the insulin action pathway (156).…”

Section: Potential Role Of G-proteins In Insulin-stimulated H 2 O 2 Amentioning

confidence: 55%

“…Relatively low levels of H 2 O 2 , generated in response to growth factor stimulation, occur in a concerted fashion with specific signaling targets in the cell, suggesting that it serves as a second messenger (44,51,57 Numerous studies have also recently emerged supporting the hypothesis that cellular oxidant signaling is mediated by discrete localized redox circuitry, which is distinct from the notion of a generalized "oxidative stress" effect (51). For example, overexpression of the Nox homolog Nox1 increases cellular ROS and specifically activates an oxidant-sensitive reporter gene via activation of c-Jun NH 2 -terminal kinase (JNK) and extracellular signal-related kinase 1/2 without affecting the overall redox state of glutathione and thioredoxin, the major thiol antioxidant substances in the cell (59). A novel regulatory paradigm: PTPs are thiol-dependent enzymes regulated by cellular ROS.…”

Section: Role Of Ptps In the Regulation Of Insulin Signalingmentioning

confidence: 99%

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Redox Paradox

2005

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Propelled by the identification of a small family of NADPH oxidase (Nox) enzyme homologs that produce superoxide in response to cellular stimulation with various growth factors, renewed interest has been generated in characterizing the signaling effects of reactive oxygen species (ROS) in relation to insulin action. Two key observations made >30 years ago-that oxidants can facilitate or mimic insulin action and that H 2 O 2 is generated in response to insulin stimulation of its target cells-have led to the hypothesis that ROS may serve as second messengers in the insulin action cascade. Specific molecular targets of insulin-induced ROS include enzymes whose signaling activity is modified via oxidative biochemical reactions, leading to enhanced insulin signal transduction. These positive responses to cellular ROS may seem "paradoxical" because chronic exposure to relatively high levels of ROS have also been associated with functional ␤-cell impairment and the chronic complications of diabetes. The best-characterized molecular targets of ROS are the protein-tyrosine phosphatases (PTPs) because these important signaling enzymes require a reduced form of a critical cysteine residue for catalytic activity. PTPs normally serve as negative regulators of insulin action via the dephosphorylation of the insulin receptor and its tyrosinephosphorylated cellular substrates. However, ROS can rapidly oxidize the catalytic cysteine of target PTPs, effectively blocking their enzyme activity and reversing their inhibitory effect on insulin signaling. Among the cloned Nox homologs, we have recently provided evidence that Nox4 may mediate the insulin-stimulated generation of cellular ROS and is coupled to insulin action via the oxidative inhibition of PTP1B, a PTP known to be a major regulator of the insulin signaling cascade. Further characterization of the molecular components of this novel signaling cascade, including the mechanism of ROS generated by insulin and the identification of various oxidation-sensitive signaling targets in insulin-sensitive cells, may provide a novel means of facilitating insulin action in states of insulin resistance.

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Section: Potential Role Of G-proteins In Insulin-stimulated H 2 O 2 Amentioning

confidence: 55%

Section: Role Of Ptps In the Regulation Of Insulin Signalingmentioning

confidence: 99%

Redox Paradox

2005

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“…A study of tumor necrosis factor (TNF)-␣-induced cell death showed that Trx-2 and GSH systems function in parallel and are nonredundant in mitochondria (205). In cells with increased Nox-1, H 2 O 2 -dependent signaling occurred without detectable oxidation of either cellular GSH/GSSG or Trx-1 (53). In contrast, epidermal growth factor (EGF) signaling oxidized cytoplasmic Trx-1 without detectable oxidation of GSH/GSSG (64).…”

Section: Gsh and Trxs As Common Control Nodes For Protein Thiol Redoxmentioning

confidence: 99%

Radical-free biology of oxidative stress

Jones¹

2008

American Journal of Physiology-Cell Physiology

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1,023

839

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Free radical-induced macromolecular damage has been studied extensively as a mechanism of oxidative stress, but large-scale intervention trials with free radical scavenging antioxidant supplements show little benefit in humans. The present review summarizes data supporting a complementary hypothesis for oxidative stress in disease that can occur without free radicals. This hypothesis, which is termed the "redox hypothesis," is that oxidative stress occurs as a consequence of disruption of thiol redox circuits, which normally function in cell signaling and physiological regulation. The redox states of thiol systems are sensitive to twoelectron oxidants and controlled by the thioredoxins (Trx), glutathione (GSH), and cysteine (Cys). Trx and GSH systems are maintained under stable, but nonequilibrium conditions, due to a continuous oxidation of cell thiols at a rate of about 0.5% of the total thiol pool per minute. Redox-sensitive thiols are critical for signal transduction (e.g., H-Ras, PTP-1B), transcription factor binding to DNA (e.g., Nrf-2, nuclear factor-B), receptor activation (e.g., ␣IIb␤3 integrin in platelet activation), and other processes. Nonradical oxidants, including peroxides, aldehydes, quinones, and epoxides, are generated enzymatically from both endogenous and exogenous precursors and do not require free radicals as intermediates to oxidize or modify these thiols. Because of the nonequilibrium conditions in the thiol pathways, aberrant generation of nonradical oxidants at rates comparable to normal oxidation may be sufficient to disrupt function. Considerable opportunity exists to elucidate specific thiol control pathways and develop interventional strategies to restore normal redox control and protect against oxidative stress in aging and age-related disease.thioredoxin; glutathione; cysteine; hydrogen peroxide; redox signaling; protein thiol ONE OF THE GREAT REDOX BIOLOGISTS of the past century, Howard S. Mason, professed that to advance science, a scientist must interpret observations at the limit of their meaning. The present review of the redox biology of thiol systems addresses the possibility that disruption of the function and homeostasis of thiol systems is the most central feature of oxidative stress that contributes to mechanisms of aging and age-related disease. I have termed this the "redox hypothesis" to facilitate distinction from free radical hypotheses.Many proteins contain redox-sensitive thiols, and reactions of thiol systems occur largely by nonradical two-electron transfers. Accumulating data show that central thiol-disulfide couples are maintained under nonequilibrium conditions in biological systems. This presents a condition wherein changes in abundance and distribution of redox catalysts and changes in rates of generation of relevant oxidants (e.g., peroxides) and precursors for NADPH supply can account for pathological effects of oxidative stress through altered functions of enzymes, receptors, transporters, transcription factors, and structural elements, without free ra...

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“…This concept is compatible with the observation that redox signaling can occur at ROS concentrations too low to alter whole cell redox state. 11 An alternative explanation could be that 5-HD interferes with the myocardial NADPH oxidase in a way that does not affect the leukocyte enzyme. In fact, little is known about the NADPH oxidase in rat cardiac myocytes.…”

mentioning

confidence: 99%

Triggering Mitochondrial Radical Release

Brandes

2005

Hypertension

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I schemic preconditioning describes a scenario in which brief intermittent periods of ischemia provide protection against subsequent ischemic injury. 1 A number of elements in the signal transduction cascade mediating ischemic preconditioning have been identified. The opening of mitochondrial K ATP channels is central for this process, as well as the subsequent release of reactive oxygen species (ROS) from mitochondria, and finally the activation of p38 mitogen-activated protein kinase (p38 MAP kinase). In addition to intermittent ischemia, several agonists, such as acetylcholine, phenylephrine, bradykinin, and opioids have been demonstrated to elicit (pharmacological) preconditioning 2 by a similar pathway.In this issue of Hypertension, Kimura et al extend this list of preconditioning agents by including angiotensin II. 3 In particular, they demonstrate that angiotensin II leads to the assembly of the NADPH oxidase in the rat myocardium and that inhibition of this assembly process using apocynin blocks angiotensin IImediated preconditioning. Moreover, the authors observed that inhibition of mitochondrial K ATP channels by 5-hydroxydecanoate (5-HD) blocked not only the preconditioning effect of angiotensin II but also prevented the angiotensin II-induced ROS formation from cardiac myocytes. 5-HD had no antioxidative properties and did not block the respiratory burst in leukocytes but prevented ROS formation of isolated mitochondrial preparations. Therefore, the authors conclude that the effects observed in response to angiotensin II in rat myocardium, such as lipid peroxidation, p38 MAP kinase activation, and preconditioning, are mediated by mitochondrial ROS (Figure).Given that the NADPH oxidase is considered a strong source of ROS, 4 the observations of this study are unexpected. Nevertheless, the data are compatible with the concept of ROStriggered ROS formation, which has been demonstrated in cardiac myocytes and pathophysiological vascular models. In cardiac myocytes, it was observed that ROS can induce mitochondrial depolarization and subsequent mitochondrial ROS generation through mitochondrial permeability transition. 5 It is assumed that K ATP channels are involved in the process of mitochondrial depolarization because the mitochondrial K ATP channel can be directly activated by superoxide anions 6 and because 5-HD, which blocks opening of the channel, prevented mitochondrial depolarization and ROS formation. Moreover, exogenously applied ROS can induce pharmacological preconditioning, and this effect was also blocked by 5-HD. 7 The concept of ROS-triggered ROS formation can be expanded further because exposure of vascular smooth muscle cells and fibroblasts to ROS has been shown to activate an NADPH oxidase, also facilitating ROS-triggered ROS release from this enzyme. 8 Finally, Landmesser et al demonstrated that activation of an NADPH oxidase in deoxycorticosterone acetate-and salt-induced hypertension leads to the release of ROS from endothelial NO synthase. 9 Therefore, it appears that several enzy...

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H2O2-dependent Activation of GCLC-ARE4 Reporter Occurs by Mitogen-activated Protein Kinase Pathways without Oxidation of Cellular Glutathione or Thioredoxin-1

Cited by 95 publications

References 47 publications

Redox Paradox

Redox Paradox

Radical-free biology of oxidative stress

Triggering Mitochondrial Radical Release

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