Posttranscriptional Regulation ofMRP/GS-XPump and γ-Glutamylcysteine Synthetase Expression by 1-(4-Amino-2-methyl-5-pyrimidinyl) methyl-3- (2-chloroethyl)-3-nitrosourea and by Cycloheximide in Human Glioma Cells

Gomi, Akira; Masuzawa, Toshio; Ishikawa, Toshihisa; Kuo, M. Tien

doi:10.1006/bbrc.1997.7423

Cited by 43 publications

(38 citation statements)

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“…41 Moreover, we previously reported a posttranscriptional regulation mechanism of ␥-GCSh. 42 These observations, collectively, suggest a complex regulation mechanism for the activation of ␥-GCSh under oxidative stress. In this regard, it is of importance to elucidate the activation mechanisms underlying ␥-GCSh upexpression during colorectal carcinogenesis.…”

Section: Discussionmentioning

confidence: 94%

Expression of heavy subunit of γ‐glutamylcysteine synthetase (γ‐GCSh) in human colorectal carcinoma

Tatebe

Unate

Sinicrope

et al. 2001

Intl Journal of Cancer

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Gamma-glutamylcysteine synthetase (␥-GCS) is a heterodimer consisting of heavy (␥-GCSh) and light (␥-GCSl) subunits. ␥-GCS catalyzes the rate-limiting de novo biosynthesis of glutathione (GSH), an abundant physiological antioxidant that plays important roles for regulating oxidative stress. Expression of ␥-GCSh and ␥-GCSl are sensitive to oxidative stress. To investigate whether expression of ␥-GCS is correlated with tumor progression, we used immunohistochemical approaches to examine 16 human colorectal adenomas and resected 57 carcinomas from untreated patients. In adjacent normal colorectal epithelium, levels of ␥-GCSh expression were low. Strong cytoplasmic staining for ␥-GCSh was detected in 3 (18.8%) adenoma and 48 (84.2%) carcinomas. The frequency of ␥-GCSh expression in carcinoma was significantly higher than in adenoma (p<0.0001). We used RNase protation assay and Western blot to determine levels of ␥-GCSh mRNA and protein from 10 pairs of matched carcinomas with adjacent normal controls. Elevated expression of both ␥-GCSh mRNA and protein were found in 6 cases, suggesting that transcriptional and/or posttranscriptional regulation play an important role in the upregulation of ␥-GCS during colorectal carcinogenesis. We also examined the expression of another redox-regulated gene, multidrug resistance protein 1 (MRP1). Strong staining for MRP1 was detected in 1 (6.3%) adenoma and 40 (70.2%) carcinomas. The frequency of MRP1 expression in carcinoma was significantly higher than in adenoma ( p<0.0001). Nuclear p53 expression was detected in 30 (52.6%) of carcinomas. There is a significant correlation between ␥-GCSh and MRP1 expression (p‫)310.0؍‬ but not between ␥-GCSh and p53. Since ␥-GCS is a sensor of oxidative stress, these results are consistent with the notion that oxidative stress is associated with colorectal tumor progression. © 2002 Wiley-Liss, Inc. Key words: ␥-GCSh; MRP1; colorectal neoplasmGlutathione (GSH) plays an important role in regulating intracellular redox conditions. Biosynthesis of GSH involves 2 enzymatic reactions: the first reaction involves the synthesis of glutamylcysteine through ␥-peptide bond formation between glutamate and cysteine and is catalyzed by the rate-limiting enzyme gamma-glutamylcysteine synthetase. 1 The second reaction is catalyzed by GSH synthetase, which conjugates glycine to glutamylcysteine. The mammalian ␥-GCS holoenzyme is a heterodimer that consists of a 73 kDa heavy subunit (␥-GCSh) and a 28 kDa light subunit (␥-GCSl). [2][3][4][5] The steady-state levels of ␥-GCSh and ␥-GCSl mRNA are increased in cultured cells exposed to prooxidants (␤-naphthoflavone, menadione, tert-butylhydorquinone and pyrrolidine dithiocarbamate, 6,7 ), antitumor agents (cisplatin, 8 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3 nitrosourea 9 ), cytokines (interleukin 1␤ 10 ), etc. These cytotoxic agents are known to generate reactive oxygen species (ROS) and exert various degrees of oxidative stress to the cells. In all cases, induction of ␥-GCS is accompanied by the...

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Section: Discussionmentioning

confidence: 94%

Expression of heavy subunit of γ‐glutamylcysteine synthetase (γ‐GCSh) in human colorectal carcinoma

Tatebe

Unate

Sinicrope

et al. 2001

Intl Journal of Cancer

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“…Regulation of GSH and c-GCS has also been described at the post-transcriptional and pretranslational levels in rat liver in vivo and in other cells [105,106]. Various inflammatory agents such as cyclic adenosine monophosphate (cAMP) and intracellular calcium, which are released during inflammation, may inhibit GSH synthesis at the translational level (table 3) [107].…”

Section: At Post-transcriptional and Translational Levelsmentioning

confidence: 99%

Oxidative stress and regulation of glutathione in lung inflammation

Rahman¹,

MacNee²

2000

Eur Respir J

802

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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“…Gomi et al 21 have reported that MRP1 and -GCS are concomitantly induced by an antitumor nitrosourea. Similarly, Yamane et al 22 have reported that oxidative stress upregulates the expression of these two genes.…”

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confidence: 99%

Hammerhead ribozyme against γ-glutamylcysteine synthetase sensitizes human colonic cancer cells to cisplatin by down-regulating both the glutathione synthesis and the expression of multidrug resistance proteins

et al. 2001

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Multidrug resistance in cancer cells is often associated with an elevation in the concentration of glutathione ( GSH ) and the expression of -glutamylcysteine synthetase ( -GCS ), a rate -limiting enzyme for GSH. We constructed a hammerhead ribozyme against a -GCS heavy subunit ( -GCSh ) mRNA transcript and transfected it to human colonic cancer cells ( HCT8DDP ) resistant to cisplatin ( CDDP ). The effect of the ribozyme transfection on the drug resistance of cancer cells was studied.

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Posttranscriptional Regulation ofMRP/GS-XPump and γ-Glutamylcysteine Synthetase Expression by 1-(4-Amino-2-methyl-5-pyrimidinyl) methyl-3- (2-chloroethyl)-3-nitrosourea and by Cycloheximide in Human Glioma Cells

Cited by 43 publications

References 0 publications

Expression of heavy subunit of γ‐glutamylcysteine synthetase (γ‐GCSh) in human colorectal carcinoma

Expression of heavy subunit of γ‐glutamylcysteine synthetase (γ‐GCSh) in human colorectal carcinoma

Oxidative stress and regulation of glutathione in lung inflammation

Hammerhead ribozyme against γ-glutamylcysteine synthetase sensitizes human colonic cancer cells to cisplatin by down-regulating both the glutathione synthesis and the expression of multidrug resistance proteins

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