Transcriptional Regulation of γ-Glutamylcysteine Synthetase-Heavy Subunit by Oxidants in Human Alveolar Epithelial Cells

Rahman, Irfan; Bel, Agnes; Mulier, Brigitte; Lawson, Mark F.; Harrison, David J.; MacNee, William; Smith, Christopher A.

doi:10.1006/bbrc.1996.1888

Cited by 140 publications

(90 citation statements)

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“…Indeed, previous studies have shown that AP-1 binding sites control the expression of ␥-GCS-HS in response to diverse stimuli. [25][26][27][28][29][30] In line with this, recent studies in HL-60 cells have shown that bSMase activates JNK/SAPK, 46 which in turn triggers the activation of AP-1, resulting in the induction of genes with AP-1 binding sites.…”

Section: Discussionmentioning

confidence: 64%

“…The former catalyzes the rate-limiting step in de novo GSH synthesis, and has been shown to be up-regulated in multiple cell types in response to a diverse array of stimuli. [25][26][27][28][29][30] Recent studies in a human acute lymphoblastic cell line have indicated that NSMase is inhibited by GSH, whereas GSH depletion did not affect the activity of the acid pHoptimum ASMase, suggesting that cellular GSH selectively controls the activation of NSMase. 31 However, because the regulation of cellular GSH by either NSMase or ASMase has not been previously reported, we have examined the regulation of GSH and induction of oxidative stress in cultured rat hepatocytes incubated with exogenous SMases, including the commonly used Mg 2ϩ -dependent, neutral pH optimun bacterial SMase from Bacillus cereus (bSMase).…”

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confidence: 99%

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Human placenta sphingomyelinase, an exogenous acidic pH-optimum sphingomyelinase, induces oxidative stress, glutathione depletion, and apoptosis in rat hepatocytes

et al. 2000

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Ceramide has been identified as a putative lipid messenger that mediates diverse cellular processes including cell death. Since glutathione (GSH) depletion is known to sensitize cells to many cytotoxic agents and as a result of the reported regulation of neutral sphyngomyelinase (NSMase) by GSH, the present study compared the role of individual SMases in the induction of oxidative stress, regulation of cellular GSH, and apoptosis of rat hepatocytes. Exposure of cultured rat hepatocytes to exogenous Bacillus cereus sphingomyelinase (bSMase), a neutral SMase, or human placenta sphingomyelinase (hSMase), an acidic SMase (ASMase), generated similar ceramide levels in a dose-dependent manner. However, whereas bSMase increased hepatocellular GSH levels, hSMase depleted GSH stores, an effect that was prevented by monensin and mannose 6-phosphate (M-6-P), suggesting that exogenous hSMase enters hepatocytes by endocytosis and is delivered to an endosomal/lysosomal acidic compartment. Interestingly, despite the differential effect of either SMases on cell GSH levels, both bSMase and hSMase increased ␥-glutamylcysteine synthetase heavy-subunit chain (␥-GCS-HS) mRNA levels. Consistent with these findings on GSH regulation, hSMase, but not bSMase, generated reactive oxygen species (ROS), being accompanied by mitochondrial depolarization, suggesting that hSMase targeted mitochondria, leading to oxidative stress. Accordingly, hepatocytes displayed a selective sensitivity to hSMase in contrast to bSMase exposure, and depletion of GSH stores enhanced susceptibility to hSMase as a result of potentiation of ROS formation and caspase 3 activation. Thus, these findings reveal the ability of ASMase to induce oxidative stress as a result of the targeting of mitochondria, and that GSH depletion sensitizes hepatocytes to the ASMase-induced apoptosis. (HEPATOLOGY 2000;32:56-65.)

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Section: Discussionmentioning

confidence: 64%

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confidence: 99%

Human placenta sphingomyelinase, an exogenous acidic pH-optimum sphingomyelinase, induces oxidative stress, glutathione depletion, and apoptosis in rat hepatocytes

et al. 2000

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“…Some reports describe exposure to ROS and nitrogen species as raising the GSH content by increasing the GSH synthesis rate (40,41). GSH depletion can result in short-term increases in both GCL activity and GSH synthesis.…”

Section: Gsh Synthesismentioning

confidence: 99%

Regulation of Neuronal Glutathione Synthesis

2008

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Abstract. The brain is among the major organs generating large amounts of reactive oxygen species and is especially susceptible to oxidative stress. Glutathione (GSH) plays critical roles as an antioxidant, enzyme cofactor, cysteine storage form, the major redox buffer, and a neuromodulator in the central nervous system. GSH deficiency has been implicated in neurodegenerative diseases. GSH is a tripeptide comprised of glutamate, cysteine, and glycine. Cysteine is the rate-limiting substrate for GSH synthesis within neurons. Most neuronal cysteine uptake is mediated by sodium-dependent excitatory amino acid transporter (EAAT) systems, known as excitatory amino acid carrier 1 (EAAC1). Previous studies demonstrated EAAT is vulnerable to oxidative stress, leading to impaired function. A recent study found EAAC1-deficient mice to have decreased brain GSH levels and increased susceptibility to oxidative stress. The function of EAAC1 is also regulated by glutamate transporter associated protein 3-18. This review focuses on the mechanisms underlying GSH synthesis, especially those related to neuronal cysteine transport via EAAC1, as well as on the importance of GSH functions against oxidative stress.

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“…This is concomitant with increased expression of messenger ribonucleic acid (mRNA) for the c-GCS gene [30, 70,72]. Epithelial cells also take up glutathione by a redox-dependent mechanism [137].…”

Section: Effects Of Oxidantsmentioning

confidence: 99%

Oxidative stress and regulation of glutathione in lung inflammation

Rahman¹,

MacNee²

2000

Eur Respir J

808

555

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Inflammatory lung diseases are characterized by chronic inflammation and oxidant/antioxidant imbalance, a major cause of cell damage. The development of an oxidant/antioxidant imbalance in lung inflammation may activate redox‐sensitive transcription factors such as nuclear factor‐κB, and activator protein‐1 (AP‐1), which regulate the genes for pro‐inflammatory mediators and protective antioxidant genes. Glutathione (GSH), a ubiquitous tripeptide thiol, is a vital intra‐ and extracellular protective antioxidant against oxidative/nitrosative stresses, which plays a key role in the control of pro‐inflammatory processes in the lungs. Recent findings have suggested that GSH is important in immune modulation, remodelling of the extracellular matrix, apoptosis and mitochondrial respiration. The rate‐limiting enzyme in GSH synthesis is γ‐glutamylcysteine synthetase (γ‐GCS). The human γ‐GCS heavy and light subunits are regulated by AP‐1 and antioxidant response elements and are modulated by oxidants, phenolic antioxidants, growth factors, and inflammatory and anti‐inflammatory agents in lung cells. Alterations in alveolar and lung GSH metabolism are widely recognized as a central feature of many inflammatory lung diseases such as idiopathic pulmonary fibrosis, acute respiratory distress syndrome, cystic fibrosis and asthma. The imbalance and/or genetic variation in antioxidant γ‐GCS and pro‐inflammatory versus antioxidant genes in response to oxidative stress and inflammation in some individuals may render them more susceptible to lung inflammation. Knowledge of the mechanisms of GSH regulation and balance between the release and expression of pro‐ and anti‐inflammatory mediators could lead to the development of novel therapies based on the pharmacological manipulation of the production as well as gene transfer of this important antioxidant in lung inflammation and injury. This review describes the redox control and involvement of nuclear factor‐κB and activator protein‐1 in the regulation of cellular glutathione and γ‐glutamylcysteine synthetase under conditions of oxidative stress and inflammation, the role of glutathione in oxidant‐mediated susceptibility/tolerance, γ‐glutamylcysteine synthetase genetic susceptibility and the potential therapeutic role of glutathione and its precursors in protecting against lung oxidant stress, inflammation and injury.

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Transcriptional Regulation of γ-Glutamylcysteine Synthetase-Heavy Subunit by Oxidants in Human Alveolar Epithelial Cells

Cited by 140 publications

References 0 publications

Human placenta sphingomyelinase, an exogenous acidic pH-optimum sphingomyelinase, induces oxidative stress, glutathione depletion, and apoptosis in rat hepatocytes

Human placenta sphingomyelinase, an exogenous acidic pH-optimum sphingomyelinase, induces oxidative stress, glutathione depletion, and apoptosis in rat hepatocytes

Regulation of Neuronal Glutathione Synthesis

Oxidative stress and regulation of glutathione in lung inflammation

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