Regulation of gamma-glutamylcysteine synthetase subunit gene expression: insights into transcriptional control of antioxidant defenses
- PMID: 10741850
- DOI: 10.1080/10715760000300291
Regulation of gamma-glutamylcysteine synthetase subunit gene expression: insights into transcriptional control of antioxidant defenses
Abstract
Gamma-glutamylcysteine synthetase (GCS; also referred to as glutamate-cysteine ligase, GLCL) catalyzes the rate-limiting reaction in glutathione (GSH) biosynthesis. The GCS holoenzyme is composed of a catalytic and regulatory subunit, each encoded by a unique gene. In addition to some conditions which specifically upregulate the catalytic subunit gene, expression of both genes is increased in response to many Phase II enzyme inducers including oxidants, heavy metals, phenolic antioxidants and GSH-conjugating agents. Electrophile Response Elements (EpREs), located in 5'-flanking sequences of both the GCSh and GCSl subunit genes, are hypothesized to at least partially mediate gene induction following xenobiotic exposure. Recent experiments indicate that the bZip transcription factor Nrf2 participates in EpRE-mediated GCS subunit gene activation in combination with other bZip proteins. An AP-1-like binding sequence and an NF-kappaB site have also been implicated in regulation of the catalytic subunit gene following exposure to certain pro-oxidants. Potential signaling mechanisms mediating GCS gene induction by the diverse families of Phase II enzyme inducers include thiol modification of critical regulatory sensor protein(s) and the generation of the reactive oxygen species. This review summarizes recent progress in defining the molecular mechanisms operative in transcriptional control of the genes encoding the two GCS subunits, identifying areas of agreement and controversy. The mechanisms involved in GCS regulation might also be relevant to the transcriptional control of other components of the antioxidant defense battery.
Similar articles
-
An electrophile responsive element (EpRE) regulates beta-naphthoflavone induction of the human gamma-glutamylcysteine synthetase regulatory subunit gene. Constitutive expression is mediated by an adjacent AP-1 site.J Biol Chem. 1998 Jun 12;273(24):14683-9. doi: 10.1074/jbc.273.24.14683. J Biol Chem. 1998. PMID: 9614065
-
Up-regulation of the human gamma-glutamylcysteine synthetase regulatory subunit gene involves binding of Nrf-2 to an electrophile responsive element.Biochem Biophys Res Commun. 1999 Aug 11;261(3):661-8. doi: 10.1006/bbrc.1999.1109. Biochem Biophys Res Commun. 1999. PMID: 10441483
-
Tumor necrosis factor increases hepatocellular glutathione by transcriptional regulation of the heavy subunit chain of gamma-glutamylcysteine synthetase.J Biol Chem. 1997 Nov 28;272(48):30371-9. doi: 10.1074/jbc.272.48.30371. J Biol Chem. 1997. PMID: 9374527
-
Oxidative stress and regulation of glutathione in lung inflammation.Eur Respir J. 2000 Sep;16(3):534-54. doi: 10.1034/j.1399-3003.2000.016003534.x. Eur Respir J. 2000. PMID: 11028671 Review.
-
Regulation of redox glutathione levels and gene transcription in lung inflammation: therapeutic approaches.Free Radic Biol Med. 2000 May 1;28(9):1405-20. doi: 10.1016/s0891-5849(00)00215-x. Free Radic Biol Med. 2000. PMID: 10924859 Review.
Cited by
-
Biological Functions and Potential Therapeutic Significance of O-GlcNAcylation in Hepatic Cellular Stress and Liver Diseases.Cells. 2024 May 9;13(10):805. doi: 10.3390/cells13100805. Cells. 2024. PMID: 38786029 Free PMC article. Review.
-
The Impact of Genetic Polymorphisms in Glutamate-Cysteine Ligase, a Key Enzyme of Glutathione Biosynthesis, on Ischemic Stroke Risk and Brain Infarct Size.Life (Basel). 2022 Apr 18;12(4):602. doi: 10.3390/life12040602. Life (Basel). 2022. PMID: 35455093 Free PMC article.
-
Extensive Thiol Profiling for Assessment of Intracellular Redox Status in Cultured Cells by HPLC-MS/MS.Antioxidants (Basel). 2021 Dec 23;11(1):24. doi: 10.3390/antiox11010024. Antioxidants (Basel). 2021. PMID: 35052528 Free PMC article.
-
Contribution of the Nrf2 Pathway on Oxidative Damage and Mitochondrial Failure in Parkinson and Alzheimer's Disease.Antioxidants (Basel). 2021 Jul 2;10(7):1069. doi: 10.3390/antiox10071069. Antioxidants (Basel). 2021. PMID: 34356302 Free PMC article. Review.
-
Severe pantothenic acid deficiency induces alterations in the intestinal mucosal proteome of starter Pekin ducks.BMC Genomics. 2021 Jun 30;22(1):491. doi: 10.1186/s12864-021-07820-x. BMC Genomics. 2021. PMID: 34193047 Free PMC article.
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Medical