Peroxynitrite Targets the Epidermal Growth Factor Receptor, Raf-1, and MEK Independently to Activate MAPK

Zhang, Ping; Wang, Yi-Zhe; Kagan, Elliott; Bonner, James C.

doi:10.1074/jbc.m910425199

Cited by 118 publications

(109 citation statements)

References 38 publications

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“…To investigate the effect of ONOO Ϫ on ERK activation, we incubated the cultured hippocampal neurons with 0, 0.1, 0.5, or 1.0 mM SIN-1 with or without UA for 24 h. As shown in Fiugre 6 D, 1.0 mM SIN-1 significantly increased pERK level (pERK1/ ERK1: F (4,10) ϭ 14.92, p ϭ 0.001; pERK2/ERK2: F (4,10) ϭ 12.12, p ϭ 0.005), indicating ERK activation by ONOO Ϫ , which is consistent with previous reports (Zhang et al, 2000;Csibi et al, 2010). UA abolished the effect of 1.0 mM SIN-1 on ERK activation.…”

supporting

confidence: 81%

“…Our data show that glucocorticoids promote ERK phosphorylation via upregulating nNOS expression, and that ONOO Ϫ caused a substantial ERK activation. In fact, both NO-cGMP signaling pathway and ONOO Ϫ are implicated in ERK activation (Zhang et al, 2000;Rangaswami et al, 2009). In this study, the glucocorticoidmediated ERK activation led to hippocampal GR downregulation.…”

Section: Discussionmentioning

confidence: 66%

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Hippocampal Neuronal Nitric Oxide Synthase Mediates the Stress-Related Depressive Behaviors of Glucocorticoids by Downregulating Glucocorticoid Receptor

Zhou¹,

Zhu²,

Chen³

et al. 2011

J. Neurosci.

134

130

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The molecular mechanisms underlying the behavioral effects of glucocorticoids are poorly understood. We report here that hippocampal neuronal nitric oxide synthase (nNOS) is a crucial mediator. Chronic mild stress and glucocorticoids exposures caused hippocampal nNOS overexpression via activating mineralocorticoid receptor. In turn, hippocampal nNOS-derived nitric oxide (NO) significantly downregulated local glucocorticoid receptor expression through both soluble guanylate cyclase (sGC)/cGMP and peroxynitrite (ONOO Ϫ )/extracellular signal-regulated kinase signal pathways, and therefore elevated hypothalamic corticotrophin-releasing factor, a peptide that governs the hypothalamic-pituitary-adrenal axis. More importantly, nNOS deletion or intrahippocampal nNOS inhibition and NO-cGMP signaling blockade (using NO scavenger or sGC inhibitor) prevented the corticosterone-induced behavioral modifications, suggesting that hippocampal nNOS is necessary for the role of glucocorticoids in mediating depressive behaviors. In addition, directly delivering ONOO Ϫ donor into hippocampus caused depressive-like behaviors. Our findings reveal a role of hippocampal nNOS in regulating the behavioral effects of glucocorticoids.

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supporting

confidence: 81%

Section: Discussionmentioning

confidence: 66%

Hippocampal Neuronal Nitric Oxide Synthase Mediates the Stress-Related Depressive Behaviors of Glucocorticoids by Downregulating Glucocorticoid Receptor

Zhou¹,

Zhu²,

Chen³

et al. 2011

J. Neurosci.

134

130

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“…ERK activation by these environmental agents generally causes cell death (apoptosis) rather than normal cell growth and differentiation. For example, H 2 O 2 causes a cytotoxic response of mammalian connective tissue cells via the EGF receptor pathway leading to ERK activation, and a metabolic inhibitor of the ERK pathway (PD98059) blocked this cytotoxic response (23,30). We also observed that pretreatment of XTC-2 cells with PD98059 reduced the cytotoxic response of these cells to either H 2 O 2 or LPS ( Figure 6).…”

Section: Discussionmentioning

confidence: 99%

“…Rapid activation of ERK-2 by oxidative stress. We next evaluated whether oxidative stress would activate ERK-2 in XTC-2 cells, as has been reported in mammalian cell culture systems (23) Delayed activation of ERK-2 by LPS. We then investigated whether ERK-2 in XTC-2 cells was a target for endotoxinmediated cell stress.…”

Section: Phospho-erk/erk Ratiomentioning

confidence: 99%

Mitogen-activated protein kinase activation by oxidative and bacterial stress in an amphibian cell culture model.

Carter

Tabor

Bonner

et al. 2002

Environ Health Perspect

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The decline of many amphibian species could be caused by their susceptibility to environmental pollutants that cause cellular stress and cell death. A variety of intracellular signal transduction pathways are activated by environmental stress factors, which result in cell death. Mitogen-activated protein kinases are intracellular signaling molecules that include the extracellular signal-regulated kinases (ERK-1 and ERK-2). We used cultured (italic)Xenopus(/italic) tadpole cells (XTC-2 cells) to investigate the activation of ERK by oxidative or bacterial stress, two environmental factors that could contribute to pollution in aquatic systems. We exposed XTC-2 cell monolayers to hydrogen peroxide or bacterial lipopolysaccharide and measured ERK activation by Western blotting using antibodies raised against phosphorylated ERK-1 and ERK-2. Only ERK-2 was detected in XTC-2 cells. Both hydrogen peroxide and lipopolysaccharide caused ERK-2 phosphorylation in a time- and concentration-dependent manner. Hydrogen peroxide caused a 20- to 30-fold increase in ERK-2 activation that peaked 30 min after treatment, and lipopolysaccharide induced a 5- to 10-fold increase in ERK-2 activation that peaked 60 min after treatment. PD98059, an inhibitor of the ERK pathway, reduced the cytotoxic response of XTC-2 cells to hydrogen peroxide or lipopolysaccharide. These data suggest that ERK-2 is an intracellular target of oxidative and bacterial stress in amphibians that mediates, at least in part, the cytotoxic response to hydrogen peroxide or lipopolysaccharide. Moreover, the (italic)Xenopus(/italic) (XTC-2) cell culture system could serve as a useful model to identify agents that might threaten amphibian populations and human health.

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“…In particular, peroxynitrite was recently shown to upregulate src tyrosine kinases (25) as well as the phosphoinositide 3-kinase Akt pathway (26). A large number of studies investigated the effects of peroxynitrite on mitogen-activated protein kinases (27)(28)(29)(30), a family of serine/threonine kinases that regulate an array of cellular activities. It was found that the three major subfamilies, extracellular signalregulated kinases, p38 mitogen-activated protein kinases, and c-Jun NH 2 -terminal kinases, are activated by peroxynitrite.…”

Section: Cell Signaling Induced By Peroxynitritementioning

confidence: 99%

Cell signaling and cytotoxicity by peroxynitrite.

Cantoni

Palomba

Guidarelli

et al. 2002

Environ Health Perspect

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Reactive nitrogen species are now considered to play an important role in various pathologies. Although the pathological significance of these molecules, peroxynitrite in particular, has long been attributed to their abilities to react with any component of the cells, including lipids, proteins, and DNA, a paradigm shift has recently been occurring whereby reactive nitrogen species are appreciated as signaling molecules. The question therefore arises as to whether nitrosative stress is indeed the result of a random (stochastic) process of cell damage, as it has traditionally been viewed, or rather is a consequence of the specific activation of a cascade of signaling events. The above considerations have provided the bases for the research work performed in our laboratory, and the results obtained are illustrated in the present article. In particular, our results indicate that some effects of peroxynitrite are not directly mediated by the oxidant; rather, it appears that peroxynitrite triggers a signaling pathway that finally leads to cytotoxicity.

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Peroxynitrite Targets the Epidermal Growth Factor Receptor, Raf-1, and MEK Independently to Activate MAPK

Abstract: Activation of ERK-1 and -2 by

Cited by 118 publications

References 38 publications

Hippocampal Neuronal Nitric Oxide Synthase Mediates the Stress-Related Depressive Behaviors of Glucocorticoids by Downregulating Glucocorticoid Receptor

Hippocampal Neuronal Nitric Oxide Synthase Mediates the Stress-Related Depressive Behaviors of Glucocorticoids by Downregulating Glucocorticoid Receptor

Mitogen-activated protein kinase activation by oxidative and bacterial stress in an amphibian cell culture model.

Cell signaling and cytotoxicity by peroxynitrite.

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