ArticleThe Biochemical journal1999
Overexpression of the regulatory subunit of gamma-glutamylcysteine synthetase in HeLa cells increases gamma-glutamylcysteine synthetase activity and confers drug resistance.
Article in The Biochemical journal, 1999. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 58 citations in OpenAlex.
- Upregulation of capacity for glutathione synthesis in response to amino acid deprivation: regulation of glutamate-cysteine ligase subunits.Amino acids · 2014Article
- Glutathione-dependent reductive stress triggers mitochondrial oxidation and cytotoxicity.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2012Article
- Manipulation of cellular GSH biosynthetic capacity via TAT-mediated protein transduction of wild-type or a dominant-negative mutant of glutamate cysteine ligase alters cell sensitivity to oxidant-induced cytotoxicity.Toxicology and applied pharmacology · 2010Article
- Overexpression of glutamate-cysteine ligase protects human COV434 granulosa tumour cells against oxidative and gamma-radiation-induced cell death.Mutagenesis · 2009Article
- Article
- Clock and ATF4 transcription system regulates drug resistance in human cancer cell lines.Oncogene · 2007Article
- Differential regulation of glutamate-cysteine ligase subunit expression and increased holoenzyme formation in response to cysteine deprivation.The Biochemical journal · 2006Article
- Article
- Kinetic characteristics of native gamma-glutamylcysteine ligase in the aging housefly, Musca domestica L.Biochemical and biophysical research communications · 2005Article
- Hammerhead ribozyme against gamma-glutamylcysteine synthetase attenuates resistance to ionizing radiation and cisplatin in human T98G glioblastoma cells.Japanese journal of cancer research : Gann · 2002Article
- Caspase-3-Dependent Cleavage of the Glutamate-L-Cysteine Ligase Catalytic Subunit during Apoptotic Cell Death.The American journal of pathology · 2002Article
- Hammerhead ribozyme against gamma-glutamylcysteine synthetase sensitizes human colonic cancer cells to cisplatin by down-regulating both the glutathione synthesis and the expression of multidrug resistance proteins.Cancer gene therapy · 2001Article
- Structure, function, and post-translational regulation of the catalytic and modifier subunits of glutamate cysteine ligase.Molecular aspects of medicineReview
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
gamma-Glutamylcysteine synthetase (GCS) is reported to catalyse the rate-limiting step in glutathione biosynthesis, and is a heterodimer composed of a catalytic subunit [heavy subunit (GCSh) of Mr 73000] and a regulatory subunit [light subunit (GCSl) of Mr 31000]. In the present study, we have demonstrated for the first time a potential role for GCSl in resistance towards doxorubicin and cadmium chloride. Addition of recombinant GCSl to HeLa cell extracts in vitro was found to result in an increase in GCS activity of between 2- and 3-fold. Transient transfections of COS-1 cells with the GCSl cDNA cause an increase in GCS activity of approx. 2-fold, and a small but significant (P=0.008) increase in glutathione levels from 126.9+/-4. 2 nmol/mg protein to 178.8+/-19.1 nmol/mg protein. We proceeded to make a HeLa cell line (LN73), which stably overexpresses GCSl. These cells overexpress GCSl approx. 20-fold above basal levels. LN73 was found to have a 2-fold increase in GCS activity (437.3+/-85.2 pmol/min per mg) relative to the control cell line, HL9 (213.4+/-71. 8 pmol/min per mg). In contrast with the transient transfections in COS-1 cells, stable overexpression of GCSl was found not to be associated with an increase in glutathione content. However, when the LN73 and HL9 cells were treated with the glutathione-depleting agent, diethylmaleate, the LN73 cells were found to have an enhanced ability to regenerate glutathione, compared with HL9 cells. The cell lines were treated with various anti-cancer drugs, and their cytotoxicity was examined. No obvious differences in toxicity were observed between the different cell lines following treatment with cisplatin and melphalan. The redox-cycling agent doxorubicin, however, was found to be more toxic (approx. 2-fold) to the HL9 cells than the LN73 cells. When the cells were treated with the carcinogenic transition-metal compound, cadmium chloride, LN73 cells were found to be approx. 3-fold more resistant than HL9 cells.
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9895302PMC1220010W2120413258What OpenQuestion holds
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