ArticleThe Journal of biological chemistry2017
Glucocorticoid receptor signaling represses the antioxidant response by inhibiting histone acetylation mediated by the transcriptional activator NRF2.
Article in The Journal of biological chemistry, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 63 papers.
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Who cites it
63 citing papers in PubMed, 115 citations in OpenAlex.
- Interplay between NRF2 post-translational modifications and protein-protein interactions: Perspectives from emerging structural and functional evidence.Archives of biochemistry and biophysics · 2026Review
- Anti-Inflammatory Activity of In Vitro Digested Manna in a Caco-2 and RAW264.7 Cells Co-Culture Model of Inflammatory Bowel Disease.Antioxidants (Basel, Switzerland) · 2026Article
- Nrf2: A Promising Therapeutic Target for Glucocorticoid-Resistant Chronic Rhinosinusitis.Clinical and experimental otorhinolaryngology · 2026Review
- Psychological Stress and Male Infertility: Oxidative Stress as the Common Downstream Pathway.Biomedicines · 2026Review
- The Glucocorticoid Receptor Inhibits NRF2-Mediated Expression of SLC7A11.Free radical biology & medicine · 2025Article
- Glucocorticoid receptor epigenetic activity in the heart.Epigenetics · 2025Review
- Telomere-Related Gene Networks in the Ovary Shift Across Environmental Factors.Journal of experimental zoology. Part A, Ecological and integrative physiology · 2025Article
- NRF2 activation in cancer and overview of NRF2 small molecule inhibitors.Archives of pharmacal research · 2025Review
- The Antioxidant Effect of Selenium Is Enhanced by Cortisol Through Nrf2 Pathway in Bovine Endometrial Epithelial Cells.Animals : an open access journal from MDPI · 2025Article
- Social isolation: an integrated molecular web that disrupts cellular homeostasis.Frontiers in neuroscience · 2025Review
- The Potential of Nanotechnology in Anti-cancer Drug to Regulate Nrf2 Signaling for Cancer Therapeutic Purposes.Current medicinal chemistry · 2025Review
- Chronic Corticosterone Administration-Induced Mood Disorders in Laboratory Rodents: Features, Mechanisms, and Research Perspectives.International journal of molecular sciences · 2024Review
- Uncovering the impact of alcohol on internal organs and reproductive health: Exploring TLR4/NF-kB and CYP2E1/ROS/Nrf2 pathways.Animal models and experimental medicine · 2024Review
- PNPO-PLP axis senses prolonged hypoxia in macrophages by regulating lysosomal activity.Nature metabolism · 2024Article
- Clostridium butyricum inhibits the inflammation in children with primary nephrotic syndrome by regulating Th17/Tregs balance via gut-kidney axis.BMC microbiology · 2024Article
- Unique and overlapping roles of NRF2 and NRF1 in transcriptional regulation.Journal of clinical biochemistry and nutrition · 2024Article
- Glucocorticoid receptor: a harmonizer of cellular plasticity in breast cancer-directs the road towards therapy resistance, metastatic progression and recurrence.Cancer metastasis reviews · 2024Review
- Ascorbic Acid Protects Bone Marrow from Oxidative Stress and Transient Elevation of Corticosterone Caused by X-ray Exposure inAntioxidants (Basel, Switzerland) · 2024Article
- Sex-specific interactions between stress axis and redox balance are associated with internalizing symptoms and brain white matter microstructure in adolescents.Translational psychiatry · 2024Article
- Physiological roles of propolis and red ginseng nanoplatforms in alleviating dexamethasone-induced male reproductive challenges in a rat model.Molecular biology reports · 2024Article
3 more citing papers are in PubMed but not listed here.
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Authors and funding
10 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
NRF2 (nuclear factor erythroid 2-related factor 2) is a key transcriptional activator that mediates the inducible expression of antioxidant genes. NRF2 is normally ubiquitinated by KEAP1 (Kelch-like ECH-associated protein 1) and subsequently degraded by proteasomes. Inactivation of KEAP1 by oxidative stress or electrophilic chemicals allows NRF2 to activate transcription through binding to antioxidant response elements (AREs) and recruiting histone acetyltransferase CBP (CREB-binding protein). Whereas KEAP1-dependent regulation is a major determinant of NRF2 activity, NRF2-mediated transcriptional activation varies from context to context, suggesting that other intracellular signaling cascades may impact NRF2 function. To identify a signaling pathway that modifies NRF2 activity, we immunoprecipitated endogenous NRF2 and its interacting proteins from mouse liver and identified glucocorticoid receptor (GR) as a novel NRF2-binding partner. We found that glucocorticoids, dexamethasone and betamethasone, antagonize diethyl maleate-induced activation of NRF2 target genes in a GR-dependent manner. Dexamethasone treatment enhanced GR recruitment to AREs without affecting chromatin binding of NRF2, resulting in the inhibition of CBP recruitment and histone acetylation at AREs. This repressive effect was canceled by the addition of histone deacetylase inhibitors. Thus, GR signaling decreases NRF2 transcriptional activation through reducing the NRF2-dependent histone acetylation. Consistent with these observations, GR signaling blocked NRF2-mediated cytoprotection from oxidative stress. This study suggests that an impaired antioxidant response by NRF2 and a resulting decrease in cellular antioxidant capacity account for the side effects of glucocorticoids, providing a novel viewpoint for the pathogenesis of hypercorticosteroidism.
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