Abstract
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 γ-glutamylcysteine synthetase (γ-GCS). In the present report we investigated the effect of γ-GCS overexpression on the TNF-induced activation of nuclear transcription factors NF-κB and AP-1, stress-activated protein kinase/c-Jun amino-terminal kinase (JNK) and apoptosis. Transfection of cells with γ-GCS cDNA blocked TNF-induced NF-κB activation, cytoplasmic IκBα degradation, nuclear translocation of p65, and NF-κB-dependent gene transcription. γ-GCS overexpression also completely suppressed NF-κB activation induced by phorbol ester and okadaic acid, whereas that induced by H2O2, ceramide, and lipopolysaccharide was minimally affected. γ-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 γ-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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Abbreviations
- TNF:
-
tumor necrosis factor
- NF-κB:
-
nuclear transcription factor-κB
- IκB:
-
inhibitory subunit of NF-κB
- EMSA:
-
electrophoretic mobility shift assay
- GCS:
-
glutamylcysteine synthetase
- ROI:
-
reactive oxygen intermediate
- DTT:
-
dithiothreitol
- FBS:
-
fetal bovine serum
- CAT:
-
chloramphenicol acetyl transferase
- MTT:
-
3-(4,5-dihydro-6-(4-(3,4-dimethoxybenzoyl)-1-piperazinyl)-2(1H)-quinolinine
- PARP:
-
poly (ADP ribose) polymerase
- PMA:
-
phorbol 12-myristate 13 acetate
- CD:
-
cytoplasmic domain
- BSO:
-
buthionine-L-sulfoximine
- PDTC:
-
pyrrolidine dithiocarbamate
- NAC:
-
N-acetylcysteine
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Acknowledgements
This research was supported by a grant from The Clayton Foundation for Research and from National Institute of Health (CA 72404-01 to MT Kuo). This is a CRL contribution number 213.
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Manna, S., Kuo, M. & Aggarwal, B. Overexpression of γ-glutamylcysteine synthetase suppresses tumor necrosis factor-induced apoptosis and activation of nuclear transcription factor-kappa B and activator protein-1. Oncogene 18, 4371–4382 (1999). https://doi.org/10.1038/sj.onc.1202811
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DOI: https://doi.org/10.1038/sj.onc.1202811
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