Mapping of the Glutamate-Cysteine Ligase Catalytic Subunit Gene (GLCLC) to Human Chromosome 6p12 and Mouse Chromosome 9D-E and of the Regulatory Subunit Gene (GLCLR) to Human Chromosome 1p21-p22 and Mouse Chromosome 3H1-3

Tsuchiya, Karen D.; Mulcahy, Ríona; Reid, Lynnda L.; Distèche, Christine M.; Kavanagh, Terrance J.

doi:10.1006/geno.1995.1293

Cited by 51 publications

(24 citation statements)

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“…GCL is composed of two subunits, a catalytic subunit (GCLC) and a modifier subunit (GCLM) (17,18). The 5Ј-untranslated region of GCLC mRNA (NM_001498) has been shown to contain a polymorphic guanine-adenine-guanine (GAG) trinucleotide repeat (TNR) just upstream of the translation start codon (19).…”

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confidence: 99%

Variants in the Glutamate-Cysteine-Ligase Gene Are Associated with Cystic Fibrosis Lung Disease

McKone

Shao

Frangolias

et al. 2006

Am J Respir Crit Care Med

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Background: Chronic progressive lung disease is the most serious complication of cystic fibrosis (CF). Glutathione plays an important role in the protection of the CF lung against oxidant-induced lung injury. Objectives: We hypothesized that a polymorphism in a novel candidate gene that regulates glutathione synthesis might influence CF lung disease. Methods: In a cross-sectional study, subjects were recruited from CF clinics in Seattle and multiple centers in Canada. We tested for an association between CF lung disease and a functional polymorphism in the glutamate-cysteine ligase catalytic subunit (GCLC) gene. Multiple linear regression was used to test for association between polymorphisms of GCLC and severity of CF lung disease while adjusting for age, Pseudomonas aeruginosa infection, and cystic fibrosis transmembrane conductance regulator (CFTR) genotype. Analysis was repeated for patients with CF stratified by CFTR genotype. Measurements and Main Results

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confidence: 99%

Variants in the Glutamate-Cysteine-Ligase Gene Are Associated with Cystic Fibrosis Lung Disease

McKone

Shao

Frangolias

et al. 2006

Am J Respir Crit Care Med

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“…Catalytic activity resides entirely with the heavy subunit, but it has recently been demonstrated that the kinetic properties of the heavy subunit can be profoundly influenced by association with the light, or regulatory, subunit and the redox state of a single disulfide linkage between the two subunits (19,20). The heavy and light subunits are encoded for by two distinct genes located on chromosomes 1 and 6, respectively (21)(22)(23). The cDNAs for each subunit of human GCS has been cloned and sequenced (24,25), as has the 5Ј-flanking sequence of the heavy subunit gene (26).…”

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confidence: 99%

Constitutive and β-Naphthoflavone-induced Expression of the Human γ-Glutamylcysteine Synthetase Heavy Subunit Gene Is Regulated by a Distal Antioxidant Response Element/TRE Sequence

Mulcahy¹,

Wartman²,

Bailey

et al. 1997

Journal of Biological Chemistry

423

366

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Glutathione (GSH) is an abundant cellular non-protein sulfhydryl that functions as an important protectant against reactive oxygen species and electrophiles, is involved in the detoxification of xenobiotics, and contributes to the maintenance of cellular redox balance. The rate-limiting enzyme in the de novo synthesis of glutathione is ␥-glutamylcysteine synthetase (GCS), a heterodimer consisting of heavy and light subunits expressing catalytic and regulatory functions, respectively. Exposure of HepG2 cells to ␤-naphthoflavone (␤-NF) resulted in a time-and dose-dependent increase in the steady-state mRNA levels for both subunits. In order to identify sequences mediating the constitutive and induced expression of the heavy subunit gene, a series of deletion mutants created from the 5 -flanking region (؊3802 to ؉465) were cloned into a luciferase reporter vector (pGL3-Basic) and transfected into HepG2 cells. Constitutive expression was maximally directed by sequences between ؊202 and ؉22 as well as by elements between ؊3802 to ؊2752. Glutathione (L-␥-glutamyl-L-cysteinyl-glycine, GSH), 1 a nonprotein sulfhydryl compound present in millimolar concentrations in virtually all cells, serves a myriad of cellular functions and plays a prominent role as an intracellular protectant (1, 2). GSH is an effective oxygen radical scavenger and serves as a critical co-factor in peroxide detoxification via a reaction catalyzed by glutathione peroxidase. Furthermore, conjugation with GSH is an integral step in the detoxification and elimination of diverse classes of toxic chemical compounds. The formation of hydrophilic glutathionyl conjugates is catalyzed by glutathione S-transferases, a family of isozymes that mediate the conjugation reaction in a substrate-dependent fashion (3). Long the object of interest from a toxicology perspective, the protective properties of GSH have assumed even further significance since GSH not only plays a critical role in protection of normal cells, but it has recently been implicated in protection of neoplastic cells from a number of chemotherapeutic agents that exert their cytotoxic effects via generation of reactive oxygen species or production of electrophilic intermediates (4, 5). The augmentation of GSH and GSH-related detoxification systems has also engendered considerable interest as a possible approach for the chemoprevention of cancer. Many chemical chemopreventive agents have been shown to exert an effect on GSH homeostasis or on other elements of GSH detoxification pathways (6 -8).Exposure of cells to a number of xenobiotic agents has been demonstrated to result in an increase in the total intracellular GSH content. In several cases (9 -16) where it has been examined, the increase in GSH has been attributed to an

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“…14 The rate-limiting enzyme in GSH synthesis is glutamatecysteine ligase (GCL), a heterodimeric enzyme composed of a catalytic subunit GCLC and a modifier subunit GCLM, which are encoded by separate genes. 15,16 The promoters of both GCL subunit genes contain consensus antioxidant response elements (AREs) [17][18][19] that play essential roles in regulating the cellular responses to oxidative stress 20 and mediate induction of both GCL subunits in several different cell types. 17,[21][22][23] The increase in GSH synthesis after treatment with oxLDL occurs via an increase in GCL activity and protein and increases in the expression of both subunits of GCL.…”

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Induction of Glutathione Synthesis in Macrophages by Oxidized Low-Density Lipoproteins Is Mediated by Consensus Antioxidant Response Elements

Bea

Hudson

Chait

et al. 2003

Circulation Research

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101

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Abstract-The uptake of oxidized low-density lipoproteins (oxLDL) by macrophages leading to conversion into foam cells is a seminal event in atherogenesis. Excessive accumulation of oxLDL can cause oxidative stress in foam cells leading to cell death and the progression and destabilization of atherosclerotic lesions. Oxidative stress induces a protective compensatory increase in the synthesis of the endogenous antioxidant glutathione (GSH). Glutamate-cysteine ligase (GCL) is the rate-limiting enzyme in GSH synthesis and is composed of a catalytic subunit (GCLC) and a modifier subunit (GCLM), which are products of separate genes. Treatment of RAW 264.7 mouse macrophages and mouse peritoneal macrophages with oxLDL (30 g/mL) induces increased expression of both Gclc and Gclm in vitro. The increase in mRNA occurs in part via increased transcription as demonstrated with luciferase reporter constructs. The promoters for both GCLC and GCLM contain consensus antioxidant response elements (AREs). Electrophoretic mobility shift assays revealed induction of nuclear factor binding to these AREs after treatment of RAW 264.7 cells and mouse peritoneal macrophages with oxLDL. Nuclear factor binding to the AREs is diminished by a single base pair substitution in the core sequence. Site-directed mutagenesis of the AREs within the Gclc and Gclm promoters resulted in a decrease of oxLDL-induced luciferase activity. Supershift analyses revealed that oxLDL stimulates binding of the transcription factors Nrf1, Nrf2, and c-jun to the AREs. These data suggest that AREs play a direct role in mediating the induction of GSH synthesis by oxLDL and in protecting macrophages against oxidized lipid-induced oxidative stress.

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Mapping of the Glutamate-Cysteine Ligase Catalytic Subunit Gene (GLCLC) to Human Chromosome 6p12 and Mouse Chromosome 9D-E and of the Regulatory Subunit Gene (GLCLR) to Human Chromosome 1p21-p22 and Mouse Chromosome 3H1-3

Cited by 51 publications

References 0 publications

Variants in the Glutamate-Cysteine-Ligase Gene Are Associated with Cystic Fibrosis Lung Disease

Variants in the Glutamate-Cysteine-Ligase Gene Are Associated with Cystic Fibrosis Lung Disease

Constitutive and β-Naphthoflavone-induced Expression of the Human γ-Glutamylcysteine Synthetase Heavy Subunit Gene Is Regulated by a Distal Antioxidant Response Element/TRE Sequence

Induction of Glutathione Synthesis in Macrophages by Oxidized Low-Density Lipoproteins Is Mediated by Consensus Antioxidant Response Elements

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