Proximal 5′-Flanking Sequence of the Human γ-Glutamylcysteine Synthetase Heavy Subunit Gene Is Involved in Cisplatin-Induced Transcriptional Up-regulation in a Lung Cancer Cell Line SBC-3

Tomonari, Akira; Nishio, Kazuto; Kurokawa, Hirokazu; Fukumoto, Hisao; Fukuoka, Kazuya; Iwamoto, Yasuo; Usuda, J; Suzuki, Toshihiro; Itakura, Mitsuo; Saijo, Nagahiro

doi:10.1006/bbrc.1997.7020

Cited by 11 publications

(10 citation statements)

References 18 publications

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“…They also showed that expression of the γ‐GCS‐HS gene increased in cisplatin‐resistant human ovarian cells. Similarly, Tomonari and colleagues [14]showed that an AP‐1 regulatory site present in the proximal 5′‐flanking sequence of the human γ‐GCS‐HS was involved in cisplatin‐induced transcriptional up‐regulation in a SBC‐3 cancer cell line. These results are supported by the recent demonstration of the participation of AP‐1 in the regulation of glutathione metabolism in human hepatoma (HepG2) cells [15].…”

Section: Discussionmentioning

confidence: 95%

Characterisation of γ‐glutamylcysteine synthethase‐heavy subunit promoter: a critical role for AP‐1

et al. 1998

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The 5P-flanking region of human Q Q-glutamylcysteine synthetase-heavy subunit (Q Q-GCS-HS) was characterised by creating a series of chloramphenicol acetyl transferase (CAT) reporter deletion constructs. Analysis of various deleted CAT constructs revealed that a putative AP-1 consensus sequence is required to direct the constitutive and oxidant-mediated promoter activity. Gel mobility shift and mutation analysis of the sequence (3269 to 3263 bp), showed binding of AP-1 is involved in the oxidant-mediated regulation of Q Q-GCS-HS promoter activity.z 1998 Federation of European Biochemical Societies.

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Section: Discussionmentioning

confidence: 95%

Characterisation of γ‐glutamylcysteine synthethase‐heavy subunit promoter: a critical role for AP‐1

et al. 1998

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“…In the latter work, AP‐1 binding was highly associated with cisplatin resistance and increased GCS‐HS expression, whereas AP‐2 and NF‐κB binding activities were not (84). Using a cisplatin‐resistant lung cancer cell line SBC‐3, Tomonari et al described the 5′‐flanking sequence from −192 to +91 (especially −108 to −28 and +34 to +91 bp) to be involved in cisplatin‐induced transcriptional up‐regulation of GCS‐HS (80). These regions contain two AP‐2 sites, an Sp1 site and a GCF binding site, but no AP‐1 site (80).…”

Section: Synthesis Of Hepatic Gshmentioning

confidence: 99%

Regulation of hepatic glutathione synthesis: current concepts and controversies

1999

FASEB j.

757

596

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Glutathione (GSH) is an important intracellular peptide with multiple functions ranging from antioxidant defense to modulation of cell proliferation. GSH is synthesized in the cytosol of all mammalian cells in a tightly regulated manner. The major determinants of GSH synthesis are the availability of cysteine, the sulfur amino acid precursor, and the activity of the rate-limiting enzyme, gamma-glutamylcysteine synthetase (GCS). In the liver, major factors that determine the availability of cysteine are diet, membrane transport activities of the three sulfur amino acids cysteine, cystine and methionine, and the conversion of methionine to cysteine via the trans-sulfuration pathway. Many conditions alter GSH level via changes in GCS activity and GCS gene expression. These include oxidative stress, activators of Phase II detoxifying enzymes, antioxidants, drug-resistant tumor cell lines, hormones, cell proliferation, and diabetes mellitus. Since the molecular cloning of GCS, much has been learned about the regulation of this enzyme. Both transcriptional and post-transcriptional mechanisms modulate the activity of this critical cellular enzyme.--Lu, S. C. Regulation of hepatic glutathione synthesis: current concepts and controversies.

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“…The heavy subunit possesses all of the catalytic activity (12). However, ␥-GCS-HS promoter has been shown to contain a large number of potential consensus elements for transcriptional proteins such as activator protein (AP)-1 and NF-B sites, an antioxidantresponsive element and an AP-2 site, and metal response elements (MREs) (5,48). Earlier studies demonstrated that TNF-␣ plays a regulatory role in gene transcription (1,2,11,19,23,35,36), and some TNF-␣-regulated genes contain lens epithelium-derived growth factor (LEDGF) regulatory elements, heat shock element (HSE; nGAAn) and stress response element (STRE; A/TGGGGA/T) (6,8,16,38,43).…”

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confidence: 99%

Regulation of heavy subunit chain of γ-glutamylcysteine synthetase by tumor necrosis factor-α in lens epithelial cells: role of LEDGF/p75

Takamura

Fatma

Kubo

et al. 2006

American Journal of Physiology-Cell Physiology

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TNF-alpha induces oxidative stress by generating reactive oxygen species (ROS). This molecule elevates the expression of gamma-glutamylcysteine synthetase heavy subunit (gamma-GCS-HS). Lens epithelium-derived growth factor (LEDGF)/p75, a transcriptional protein, is inducible by oxidative stress and protects cells from various stresses by upregulating stress-responsive genes. This paper presents evidence that TNF-alpha elevates the expression of LEDGF and that LEDGF is one of the transactivators of gamma-GCS-HS gene. An analysis of the gamma-GCS-HS promoter sequence (-819 to +518 nt) revealed the presence of putative sites for LEDGF binding. Gel mobility assay confirmed the binding of LEDGF to the heat shock element (nGAAn) and the stress response element (A/TGGGGA/T) present in gamma-GCS-HS promoter. Transactivation experiments showed activation of gamma-GCS-HS promoter in cells overexpressing LEDGF or treated with a sublethal dose of TNF-alpha (20 ng/ml). Downregulation of gamma-GCS-HS promoter activity in cells transfected with LEDGF small interfering RNA validated the finding. Notably, cells treated with TNF-alpha (20 ng/ml) for 24 h had an increased abundance of LEDGF and gamma-GCS-HS mRNA and protein. In contrast, cells treated with TNF-alpha for longer periods or with higher concentrations of TNF-alpha showed reduced expression of LEDGF and gamma-GCS-HS and increased cellular death with higher ROS levels. Cells overexpressing LEDGF revealed elevated GSH levels (10-15%), a condition that may potentially eliminate the insult to cells induced by TNF-alpha. Thus TNF-alpha regulation of LEDGF may be physiologically important, as elevated expression of LEDGF increases the expression of endogenous gamma-GCS-HS gene, the catalytic subunit of the regulating enzyme in GSH biosynthesis that may constitute a protective mechanism in limiting oxidative stress induced by inflammatory cytokines.

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Proximal 5′-Flanking Sequence of the Human γ-Glutamylcysteine Synthetase Heavy Subunit Gene Is Involved in Cisplatin-Induced Transcriptional Up-regulation in a Lung Cancer Cell Line SBC-3

Cited by 11 publications

References 18 publications

Characterisation of γ‐glutamylcysteine synthethase‐heavy subunit promoter: a critical role for AP‐1

Characterisation of γ‐glutamylcysteine synthethase‐heavy subunit promoter: a critical role for AP‐1

Regulation of hepatic glutathione synthesis: current concepts and controversies

Regulation of heavy subunit chain of γ-glutamylcysteine synthetase by tumor necrosis factor-α in lens epithelial cells: role of LEDGF/p75

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