Differential susceptibilities of serine/threonine phosphatases to oxidative and nitrosative stress

Sommer, Debbie; Coleman, Stacy; Swanson, Stanley A.; Stemmer, Paul M.

doi:10.1016/s0003-9861(02)00242-4

Cited by 103 publications

(72 citation statements)

References 45 publications

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“…4B). This result is consistent with previous studies, in which PP2A was found to be resistant to oxidants (2,30). In addition, NaHS did not affect H 2 O 2 -induced translocation of PKC bII from cytosol to particulate membrane (Fig.…”

Section: H 2 S Alleviates H 2 O 2 -Induced Mitochondrial Ros Productisupporting

confidence: 93%

Sulfhydration of p66Shc at Cysteine59 Mediates the Antioxidant Effect of Hydrogen Sulfide

Xie

Shi²,

Xie³

et al. 2014

Antioxidants & Redox Signaling

113

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Aims: Mitochondrion is considered as the major source of intracellular reactive oxygen species (ROS). H 2 S has been reported to be an antioxidant, but its mechanism remains largely elusive. P66Shc is an upstream activator of mitochondrial redox signaling. The aim of this study was to explore whether the antioxidant effect of H 2 S is mediated by p66Shc. Results: Application of exogenous H 2 S with its donor, NaHS, or overexpression of its generating enzyme, cystathionine b-synthase, induced sulfhydration of p66Shc, but inhibited its phosphorylation caused by H 2 O 2 /D-galactose in SH-SY5Y cells or in the mice cortex. H 2 S also decreased mitochondrial ROS production and protected neuronal cells against stress-induced senescence. PKC bII and PP2A are the two key proteins to regulate p66Shc phosphorylation. Although H 2 S failed to affect the activities of these two proteins, it disrupted their association. Cysteine-59 resides in proximity to serine-36, the phosphorylation site of p66Shc. The C59S mutant attenuated the above-described biological function of H 2 S. Innovation: We revealed a novel mechanism for the antioxidant effect of H 2 S and its role in oxidative stress-related diseases. Conclusion: H 2 S inhibits mitochondrial ROS production via the sulfhydration of Cys-59 residue, which in turn, prevents the phosphorylation of p66Shc. Antioxid. Redox Signal. 21, 2531-2542.

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Section: H 2 S Alleviates H 2 O 2 -Induced Mitochondrial Ros Productisupporting

confidence: 93%

Sulfhydration of p66Shc at Cysteine59 Mediates the Antioxidant Effect of Hydrogen Sulfide

Xie

Shi²,

Xie³

et al. 2014

Antioxidants & Redox Signaling

113

View full text Add to dashboard Cite

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“…These data show that in macrophages, hyperoxia permits cell survival, in part, via sustained activation of ERK, resulting in down-regulation of BimEL. This information complements prior studies (43,45), which have found that oxidant stimuli inhibit the activity of a variety of phosphatases, including those with the potential to regulate ERK activity.…”

Section: Discussionsupporting

confidence: 84%

Macrophages Survive Hyperoxia via Prolonged ERK Activation Due to Phosphatase Down-regulation

Nyunoya

Monick

Powers

et al. 2005

Journal of Biological Chemistry

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Macrophages exposed to hyperoxia in the lung continue to survive for prolonged periods. We previously reported (Nyunoya, T., Powers, L. S., Yarovinsky, T. O., Butler, N. S., Monick, M. M., and Hunninghake, G. W. (2003) J. Biol. Chem. 278, 36099 -36106) that hyperoxia induces cell cycle arrest and sustained extracellular signal-related kinase (ERK) activity in macrophages. In this study, we determined the mechanisms of hyperoxiainduced ERK activation and how ERK activity plays a pro-survival role in hyperoxia-exposed cells. Inhibition of ERK activity decreased survival of hyperoxia-exposed macrophages. This was due, at least in part, to down-regulation of the pro-apoptotic Bcl-2 family member, BimEL. In determining the mechanism of ERK activation by hyperoxia, we found that ERK activation was not associated with hyperoxia-induced activation of the upstream ERK kinase mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2. When we examined the ability of whole cell lysates from hyperoxia-exposed cells to dephosphorylate purified phosphorylated ERK, we found decreased ERK-directed phosphatase activity. Two particular ERK-directed phosphatases (protein phosphatase 2A and MAPK phosphatase-3) demonstrated decreased activity in hyperoxia-exposed cells. Moreover, whole cell lysates from normoxia-exposed cells depleted of PP2A or MAPK phosphatase-3 were also less able to dephosphorylate ERK. These data demonstrate that, in hyperoxia-exposed macrophages, sustained activation of ERK due to phosphatase down-regulation permits macrophage survival via effects on the balance between pro-and antiapoptotic Bcl-2 family proteins.

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“…Changes in calcium concentration may also lead to cell death via calpain-dependent cleavage of calcineurin (Kim et al, 2002). Lasting elevations in intracellular calcium concentration activate the calciumdependant phosphatase calcineurin, which activates the transcription factor NFAT (nuclear factor of activated T-lymphocytes) and initiates apoptosis (see Morioka et al, 1999;Huang et al, 2001;Li et al, 2002;Sommer et al, 2002;Feske et al, 2003;Christians et al, 2004;Gooch et al, 2004;Kalivendi et al, 2005;Rivera and Maxwell, 2005). Additional detail on calpainand calcineurin-mediated mechanisms of cell death in the inner ear are provided first; we then review the role of Bcl-2 anti-apoptotic proteins, caspase inhibitors, and stress-activated kinases in the inner ear.…”

Section: Calcium Homeostasis Overviewmentioning

confidence: 99%

Mechanisms of noise-induced hearing loss indicate multiple methods of prevention

et al. 2007

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Recent research has shown the essential role of reduced blood flow and free radical formation in the cochlea in noise-induced hearing loss (NIHL). The amount, distribution, and time course of free radical formation have been defined, including a clinically significant late formation 7-10 days following noise exposure, and one mechanism underlying noise-induced reduction in cochlear blood flow has finally been identified. These new insights have led to the formulation of new hypotheses regarding the molecular mechanisms of NIHL; and, from these, we have identified interventions that prevent NIHL, even with treatment onset delayed up to 3 days post-noise. It is essential to now assess the additive effects of agents intervening at different points in the cell death pathway to optimize treatment efficacy. Finding safe and effective interventions that attenuate NIHL will provide a compelling scientific rationale to justify human trials to eliminate this single major cause of acquired hearing loss.

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Differential susceptibilities of serine/threonine phosphatases to oxidative and nitrosative stress

Cited by 103 publications

References 45 publications

Sulfhydration of p66Shc at Cysteine59 Mediates the Antioxidant Effect of Hydrogen Sulfide

Sulfhydration of p66Shc at Cysteine59 Mediates the Antioxidant Effect of Hydrogen Sulfide

Macrophages Survive Hyperoxia via Prolonged ERK Activation Due to Phosphatase Down-regulation

Mechanisms of noise-induced hearing loss indicate multiple methods of prevention

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