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Overexpression of γ-glutamylcysteine synthetase suppresses tumor necrosis factor-induced apoptosis and activation of nuclear transcription factor-kappa B and activator protein-1

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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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Authors and Affiliations

  1. Department of Molecular Oncology, Cytokine Research Laboratory, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, Texas, USA

    Sunil K Manna & Bharat B Aggarwal

  2. Department of Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, Texas, USA

    M Tien Kuo

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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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