Oncogene 1999,
PMID: 10439045
Manna, S K; Kuo, M T; Aggarwal, B B
Tumor necrosis factor (TNF) is a highly pleiotropic cytokine whose activity is at least partially regulated by the redox status of the cell. The cellular redox status is controlled primarily by glutathione, a major cellular antioxidant, whose synthesis is regulated by the rate-limiting enzyme gamma-glutamylcysteine synthetase (gamma-GCS). In the present report we investigated the effect of gamma-GCS overexpression on the TNF-induced activation of nuclear transcription factors NF-kappa B and AP-1, stress-activated protein kinase/c-Jun amino-terminal kinase (JNK) and apoptosis. Transfection of cells with gamma-GCS cDNA blocked TNF-induced NF-kappa B activation, cytoplasmic I kappa B alpha degradation, nuclear translocation of p65, and NF-kappa B-dependent gene transcription. gamma-GCS overexpression also completely suppressed NF-kappa B activation induced by phorbol ester and okadaic acid, whereas that induced by H2O2, ceramide, and lipopolysaccharide was minimally affected. gamma-GCS also abolished the activation of AP-1 induced by TNF and inhibited TNF-induced activation of JNK and mitogen-activated protein kinase kinase. TNF-mediated cytotoxicity and activation of caspase-3 were both abrogated in gamma-GCS-overexpressing cells. Overall, our results indicate that most of the pleiotropic actions of TNF are regulated by the glutathione-controlled redox status of the cell.
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Text Mining Data
activator protein-1 → tumor necrosis factor: "
Overexpression of gamma-glutamylcysteine synthetase suppresses
tumor necrosis factor induced apoptosis and activation of nuclear transcription factor-kappa B and
activator protein-1
"
activator protein-1 → gamma-glutamylcysteine synthetase: "
Overexpression of gamma-glutamylcysteine synthetase suppresses tumor necrosis factor induced apoptosis and activation of nuclear transcription factor-kappa B and activator protein-1
"
NF-kappa B → TNF: "
Transfection of cells with gamma-GCS cDNA blocked TNF induced NF-kappa B activation , cytoplasmic I kappa B alpha degradation, nuclear translocation of p65, and NF-kappa B-dependent gene transcription
"
NF-kappa B ⊣ gamma-GCS: "
gamma-GCS overexpression also completely suppressed NF-kappa B activation induced by phorbol ester and okadaic acid, whereas that induced by H2O2, ceramide, and lipopolysaccharide was minimally affected
"
AP-1 ⊣ TNF: "
gamma-GCS also abolished the activation of AP-1 induced by TNF and inhibited TNF induced activation of JNK and mitogen activated protein kinase kinase
"
AP-1 ⊣ mitogen activated protein kinase kinase: "
gamma-GCS also abolished the activation of AP-1 induced by TNF and inhibited TNF induced activation of JNK and mitogen activated protein kinase kinase
"
mitogen activated protein kinase kinase ⊣ gamma-GCS: "
gamma-GCS also abolished the activation of AP-1 induced by TNF and inhibited TNF induced activation of JNK and mitogen activated protein kinase kinase
"
mitogen activated protein kinase kinase → TNF: "
gamma-GCS also abolished the activation of AP-1 induced by TNF and inhibited TNF induced activation of JNK and mitogen activated protein kinase kinase
"
Manually curated Databases
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