The nitric oxide-sensitive p21Ras–ERK pathway mediates S-nitrosoglutathione-induced apoptosis

p21Ras protein plays a critical role in cellular signaling that induces either cell cycle progression or apoptosis. Nitric oxide (NO) has been consistently reported to activate p21Ras through the redox sensitive cysteine residue (118). In this study, we demonstrated that the p21Ras–ERK pathway regul...

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Published in:Biochemical and biophysical research communications 2008-05, Vol.369 (4), p.1001-1006
Main Authors: Tsujita, Maristela, Batista, Wagner L., Ogata, Fernando T., Stern, Arnold, Monteiro, Hugo P., Arai, Roberto J.
Format: Article
Language:English
Subjects:
60 APPLIED LIFE SCIENCES
APOPTOSIS
CELL CYCLE
Cell Line
Cyclin-Dependent Kinase Inhibitor p21 - antagonists & inhibitors
Cyclin-Dependent Kinase Inhibitor p21 - metabolism
CYSTEINE
ERK
Flavonoids - pharmacology
Humans
INHIBITION
MACROPHAGES
Mitogen-Activated Protein Kinase 1 - antagonists & inhibitors
Mitogen-Activated Protein Kinase 1 - metabolism
Mitogen-Activated Protein Kinase 3 - antagonists & inhibitors
Mitogen-Activated Protein Kinase 3 - metabolism
MONOCYTES
MUTANTS
NITRIC OXIDE
Nitric Oxide - metabolism
Nitric Oxide Donors - pharmacology
p21Ras
PHOSPHOTRANSFERASES
Proto-Oncogene Proteins p21(ras) - metabolism
S-Nitrosoglutathione - pharmacology
SNOG
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Summary:p21Ras protein plays a critical role in cellular signaling that induces either cell cycle progression or apoptosis. Nitric oxide (NO) has been consistently reported to activate p21Ras through the redox sensitive cysteine residue (118). In this study, we demonstrated that the p21Ras–ERK pathway regulates THP-1 monocyte/macrophage apoptosis induced by S-nitrosoglutathione (SNOG). This was apparent from studies in THP-1 cells expressing NO-insensitive p21Ras (p21Ras C118S) where the pro-apoptotic action of SNOG was almost abrogated. Three major MAP kinase pathways (ERK, JNK, and p38) that are downstream to p21Ras were investigated. It was observed that only the activation of ERK1/2 MAP kinases by SNOG in THP-1 cells was attributable to p21Ras. The inhibition of the ERK pathway by PD98059 markedly attenuated apoptosis in SNOG-treated THP-1 cells, but had a marginal effect on SNOG-treated THP-1 cells expressing NO-insensitive p21Ras. The inhibition of the JNK and p38 pathways by selective inhibitors had no marked effects on the percentage of apoptosis. The induction of p21Waf1 expression by SNOG was observed in THP-1 cells harboring mutant and wild-type p21Ras, however in cells expressing mutant Ras, the expression of p21Waf1 was significantly attenuated. The treatment of THP-1 cells expressing wild-type p21Ras with PD98059 resulted in significant attenuation of p21Waf1 expression. These results indicate that the redox sensitive p21Ras–ERK pathway plays a critical role in sensing and delivering the pro-apoptotic signaling mediated by SNOG.
ISSN:0006-291X
1090-2104
DOI:10.1016/j.bbrc.2008.02.117