Nitric Oxide Inhibition of ERK1/2 Activity in Cells Expressing Neuronal Nitric-oxide Synthase

Raines, Kimberly W.; Cao, Guan-Liang; Porsuphatana, Supatra; Tsai, Pei Shan; Rosen, Gerald M.; Shapiro, Paul

doi:10.1074/jbc.m304813200

Cited by 32 publications

(29 citation statements)

References 63 publications

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“…Inhibition of ERK activation by S-nitrosylation of H-Ras has been reported in human embryonic kidney 293 cells transfected with nNOS (31), whereas in T lymphocytes and neurons S-nitrosylation is associated with activation of this pathway (12,32). In this regard, parallels can be drawn between the mechanisms of action of NO in neurons and those described here in T cells.…”

Section: Discussionsupporting

confidence: 54%

Endothelial nitric oxide synthase regulates N-Ras activation on the Golgi complex of antigen-stimulated T cells

Ibiza

Pérez-Rodríguez

Ortega

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Ras/ERK signaling plays an important role in T cell activation and development. We recently reported that endothelial nitric oxide synthase (eNOS)-derived NO regulates T cell receptor (TCR)-dependent ERK activation by a cGMP-independent mechanism. Here, we explore the mechanisms through which eNOS exerts this regulation. We have found that eNOS-derived NO positively regulates Ras/ERK activation in T cells stimulated with antigen on antigenpresenting cells (APCs). Intracellular activation of N-, H-, and K-Ras was monitored with fluorescent probes in T cells stably transfected with eNOS-GFP or its G2A point mutant, which is defective in activity and cellular localization. Using this system, we demonstrate that eNOS selectively activates N-Ras but not K-Ras on the Golgi complex of T cells engaged with APC, even though Ras isoforms are activated in response to NO from donors. We further show that activation of N-Ras involves eNOS-dependent S-nitrosylation on Cys 118 , suggesting that upon TCR engagement, eNOS-derived NO directly activates N-Ras on the Golgi. Moreover, wild-type but not C118S N-Ras increased TCR-dependent apoptosis, suggesting that S-nitrosylation of Cys 118 contributes to activation-induced T cell death. Our data define a signaling mechanism for the regulation of the Ras/ERK pathway based on the eNOS-dependent differential activation of N-Ras and K-Ras at specific cell compartments. S-nitrosylation ͉ eNOS ͉ apoptosis

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Section: Discussionsupporting

confidence: 54%

Endothelial nitric oxide synthase regulates N-Ras activation on the Golgi complex of antigen-stimulated T cells

Ibiza

Pérez-Rodríguez

Ortega

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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“…NO is a signaling molecule, neurotransmitter, and immune effector. 5,32,34) As shown by the ELISA data, NO production was significantly inhibited by 1 mg/ml NS (Fig. 1).…”

Section: Fig 2 Dose-dependent Inhibitory Effects Of Nelumbinis Semementioning

confidence: 91%

“…Activation of the MAPK pathway often occurs in response to growth factor stimulation of receptor tyrosine kinases, which are coupled to the activation of Ras G-proteins through Src homology 2 domain-containing proteins, such as Shc and Grb2, and quinine nucleotide exchange factors such as SOS. 32,33) In this study, we detected the down-regulation of Fgfr3, Fgf12, Rasal2, Nfkb2, Nfatc2, Mapk1, Map2k5, and Map3k7 in NStreated BV-2 microglial cells ( Table 1, Figs. 6B-E).…”

Section: Fig 2 Dose-dependent Inhibitory Effects Of Nelumbinis Semementioning

confidence: 96%

The Genome-Wide Expression Profile of Nelumbinis semen on Lipopolysaccharide-Stimulated BV-2 Microglial Cells

Sohn

Chung

et al. 2009

Biological & Pharmaceutical Bulletin

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This study was conducted to evaluate the protective mechanisms of Nelumbinis semen (NS) on lipopolysaccharide (LPS)-induced activation of BV-2 microglial cells. The anti-inflammatory effects of NS were determined by analyzing nitric oxide production and proinflammatory cytokines using enzyme-linked immunosorbent assay. The mechanism was evaluated in BV-2 cells with or without NS treated with LPS for various lengths of time using oligonucleotide microarray and real time reverse transcription-polymerase chain reaction. The oligonucleotide microarray analysis revealed that mitogen activated protein kinase (MAPK) signaling pathway-related genes such as Fgfr3, Fgf12, Rasal2, Nfkb2, Map2k5, Mapk1, Map3k7, and NFatc2 were down-regulated in LPS activated BV-2 cells by pretreatment with NS. In addition, significant decreases in Nos1ap gene expression were observed with NS pretreatment. Cluster linked pathway analysis using the Kyoto Encyclopedia of Genes and Genomes database revealed that the effects of NS were closely associated with the regulation of mitochondria functions. These results suggested that NS can affect the MAPK signaling pathway and mitochondrial functions in BV-2 cells activated with LPS.

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“…In this study, we found that, in breast cancer cells, low NO stress increases monomeric cytosolic forms of PKR whereas active forms of PKR was up-regulated by high NO stress. To further assess the mechanism by which NO induced up-regulation of PKR, we examined the possible involvement of p-ERK1/2 and pAkt, which have been implicated to be responsive to NO and other stimuli (32)(33)(34). We have reported in MDA-MB-231 cells that, with NO treatment, there was decline in cyclin D1 levels, retinoblastoma was hypophosphorylated, and cells underwent cytostasis (16).…”

Section: Resultsmentioning

confidence: 99%

Increased Susceptibility of Breast Cancer Cells to Stress Mediated Inhibition of Protein Synthesis

Pervin

Tran²,

Zekavati³

et al. 2008

Cancer Research

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Protein synthesis is a tightly controlled process, and its deregulation plays an important role in tumorigenesis. Protein synthesis remains poorly understood with very few well-identified validated targets for therapeutic purposes. In this study, we use nitric oxide (NO), which suppresses protein synthesis by inactivating eukaryotic initiation factor 2-A (eIF2-A), to examine the mechanism by which low and high oxidative stress inhibits protein synthesis. In breast cancer cells, low NO stress induced heme-regulated inhibitor (HRI) activation, which facilitated gradual decline in short half-life proteins. High NO stress induced HRI and protein kinase R (PKR) activation, leading to a sharp decline in protein synthesis as accessed by a decline in short and long half-life proteins and dramatic morphologic changes. In contrast, human mammary epithelial (HME) and Ras transfected untransformed HME (MCF-10A1 neo N) cells were less susceptible to NO-induced inhibition of protein synthesis and cytostasis. Our results suggest that NO-induced cytostasis in breast cancer cells was due to PKR activation and increased phosphorylation of eIF2-A, whereas the reduced susceptibility of normal mammary epithelial cells to NO could be due to the inaccessibility of PKR, which is bound to inhibitor p58.

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Nitric Oxide Inhibition of ERK1/2 Activity in Cells Expressing Neuronal Nitric-oxide Synthase

Cited by 32 publications

References 63 publications

Endothelial nitric oxide synthase regulates N-Ras activation on the Golgi complex of antigen-stimulated T cells

Endothelial nitric oxide synthase regulates N-Ras activation on the Golgi complex of antigen-stimulated T cells

The Genome-Wide Expression Profile of Nelumbinis semen on Lipopolysaccharide-Stimulated BV-2 Microglial Cells

Increased Susceptibility of Breast Cancer Cells to Stress Mediated Inhibition of Protein Synthesis

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