Nrf2-regulated glutathione recycling independent of biosynthesis is critical for cell survival during oxidative stress
- PMID: 19028565
- PMCID: PMC2634824
- DOI: 10.1016/j.freeradbiomed.2008.10.040
Nrf2-regulated glutathione recycling independent of biosynthesis is critical for cell survival during oxidative stress
Abstract
Nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) is the primary transcription factor protecting cells from oxidative stress by regulating cytoprotective genes, including the antioxidant glutathione (GSH) pathway. GSH maintains cellular redox status and affects redox signaling, cell proliferation, and death. GSH homeostasis is regulated by de novo synthesis as well as GSH redox state; previous studies have demonstrated that Nrf2 regulates GSH homeostasis by affecting de novo synthesis. We report that Nrf2 modulates the GSH redox state by regulating glutathione reductase (GSR). In response to oxidants, lungs and embryonic fibroblasts (MEFs) from Nrf2-deficient (Nrf2(-/-)) mice showed lower levels of GSR mRNA, protein, and enzyme activity relative to wild type (Nrf2(+/+)). Nrf2(-/-) MEFs exhibited greater accumulation of glutathione disulfide and cytotoxicity compared to Nrf2(+/+) MEFs in response to t-butylhydroquinone, which was rescued by restoring GSR. Microinjection of glutathione disulfide induced greater apoptosis in Nrf2(-/-) MEFs compared to Nrf2(+/+) MEFs. In silico promoter analysis of the GSR gene revealed three putative antioxidant-response elements (ARE1, -44; ARE2, -813; ARE3, -1041). Reporter analysis, site-directed mutagenesis, and chromatin immunoprecipitation assays demonstrated binding of Nrf2 to two AREs distal to the transcription start site. Overall, Nrf2 is critical for maintaining the GSH redox state via transcriptional regulation of GSR and protecting cells against oxidative stress.
Figures
![Fig. 1](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/2634824/bin/nihms86940f1.gif)
![Fig. 2](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/2634824/bin/nihms86940f2.gif)
![Fig. 3](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/2634824/bin/nihms86940f3.gif)
![Fig. 4](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/2634824/bin/nihms86940f4.gif)
![Fig. 5](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/2634824/bin/nihms86940f5a.gif)
![Fig. 5](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/2634824/bin/nihms86940f5a.gif)
![Fig. 6](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/2634824/bin/nihms86940f6.gif)
Similar articles
-
Glutathione peroxidase 2, the major cigarette smoke-inducible isoform of GPX in lungs, is regulated by Nrf2.Am J Respir Cell Mol Biol. 2006 Dec;35(6):639-50. doi: 10.1165/rcmb.2005-0325OC. Epub 2006 Jun 22. Am J Respir Cell Mol Biol. 2006. PMID: 16794261 Free PMC article.
-
Activation of the Nrf2-regulated antioxidant cell response inhibits HEMA-induced oxidative stress and supports cell viability.Biomaterials. 2015 Jul;56:114-28. doi: 10.1016/j.biomaterials.2015.03.047. Epub 2015 Apr 16. Biomaterials. 2015. PMID: 25934285
-
Coordinate regulation of glutathione biosynthesis and release by Nrf2-expressing glia potently protects neurons from oxidative stress.J Neurosci. 2003 Apr 15;23(8):3394-406. doi: 10.1523/JNEUROSCI.23-08-03394.2003. J Neurosci. 2003. PMID: 12716947 Free PMC article.
-
Regulation of the human thioredoxin gene promoter and its key substrates: a study of functional and putative regulatory elements.Biochim Biophys Acta. 2014 Jan;1840(1):303-14. doi: 10.1016/j.bbagen.2013.09.013. Epub 2013 Sep 13. Biochim Biophys Acta. 2014. PMID: 24041992 Review.
-
Redox status in mammalian cells and stem cells during culture in vitro: critical roles of Nrf2 and cystine transporter activity in the maintenance of redox balance.Redox Biol. 2014 Apr 18;2:786-94. doi: 10.1016/j.redox.2014.04.008. eCollection 2014. Redox Biol. 2014. PMID: 25009780 Free PMC article. Review.
Cited by
-
Prolactin is an Endogenous Antioxidant Factor in Astrocytes That Limits Oxidative Stress-Induced Astrocytic Cell Death via the STAT3/NRF2 Signaling Pathway.Neurochem Res. 2024 Jul;49(7):1879-1901. doi: 10.1007/s11064-024-04147-3. Epub 2024 May 17. Neurochem Res. 2024. PMID: 38755517 Free PMC article.
-
Opposing Interplay between Nuclear Factor Erythroid 2-Related Factor 2 and Forkhead BoxO 1/3 is Responsible for Sepantronium Bromide's Poor Efficacy and Resistance in Cancer cells: Opportunity for Combination Therapy in Triple Negative Breast Cancer.ACS Pharmacol Transl Sci. 2024 Apr 29;7(5):1237-1251. doi: 10.1021/acsptsci.3c00279. eCollection 2024 May 10. ACS Pharmacol Transl Sci. 2024. PMID: 38751638
-
The Experimental and In Silico-Based Evaluation of NRF2 Modulators, Sulforaphane and Brusatol, on the Transcriptome of Immortalized Bovine Mammary Alveolar Cells.Int J Mol Sci. 2024 Apr 12;25(8):4264. doi: 10.3390/ijms25084264. Int J Mol Sci. 2024. PMID: 38673850 Free PMC article.
-
Melatonin: a ferroptosis inhibitor with potential therapeutic efficacy for the post-COVID-19 trajectory of accelerated brain aging and neurodegeneration.Mol Neurodegener. 2024 Apr 19;19(1):36. doi: 10.1186/s13024-024-00728-6. Mol Neurodegener. 2024. PMID: 38641847 Free PMC article. Review.
-
Frataxin deficiency shifts metabolism to promote reactive microglia via glucose catabolism.Life Sci Alliance. 2024 Apr 17;7(7):e202402609. doi: 10.26508/lsa.202402609. Print 2024 Jul. Life Sci Alliance. 2024. PMID: 38631900 Free PMC article.
References
-
- Rahman I, Biswas SK, Jimenez LA, Torres M, Forman HJ. Glutathione, stress responses, and redox signaling in lung inflammation. Antioxid Redox Signaling. 2005;7:42–59. - PubMed
-
- May JM, Qu ZC, Whitesell RR, Cobb CE. Ascorbate recycling in human erythrocytes: role of GSH in reducing dehydroascorbate. Free Radic Biol Med. 1996;20:543–551. - PubMed
-
- Rahman I. Regulation of nuclear factor-kappa B, activator protein-1, and glutathione levels by tumor necrosis factor-alpha and dexamethasone in alveolar epithelial cells. Biochem Pharmacol. 2000;60:1041–1049. - PubMed
-
- Markovic J, Borras C, Ortega A, Sastre J, Vina J, Pallardo FV. Glutathione is recruited into the nucleus in early phases of cell proliferation. J Biol Chem. 2007;282:20416–20424. - PubMed
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Other Literature Sources
Molecular Biology Databases