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A genomic screen for activators of the antioxidant response element
Open accessAbstract
The antioxidant response element (ARE) is a cis-acting regulatory enhancer element found in the 5′ flanking region of many phase II detoxification enzymes. Up-regulation of ARE-dependent target genes is known to have neuroprotective effects; yet, the mechanism of activation is largely unknown. By screening an arrayed collection of ≈15,000 full-length expression cDNAs in the human neuroblastoma cell line IMR-32 with an ARE-luciferase reporter, we have identified several cDNAs not previously associated with ARE activation. A subset of cDNAs, encoding sequestosome 1 (SQSTM1) and dipeptidylpeptidase 3 (DPP3), activated the ARE in primary mouse-derived cortical neurons. Overexpression of SQSTM1 and DPP3 in IMR-32 cells stimulated NF-E2-related factor 2 (NRF2) nuclear translocation and led to increased levels of NAD(P)H:quinone oxidoreductase 1, a protein which is transcriptionally regulated by the ARE. When transfected into IMR-32 neuroblastoma cells that were depleted of transcription factor NRF2 by RNA interference, SQSTM1 and DPP3 were unable to activate the ARE or induce NAD(P)H:quinone oxidoreductase 1 expression, indicating that the ARE activation upon ectopic expression of these cDNAs is mediated by NRF2. Studies with pharmacological inhibitors indicated that 1-phosphatidylinositol 3-kinase and protein kinase C signaling are essential for activity. Overexpression of these cDNAs conferred partial resistance to hydrogen peroxide or rotenone-induced toxicity, consistent with the induction of antioxidant and phase II detoxification enzymes, which can protect from oxidative stress. This work and other such studies may provide mechanisms for activating the ARE in the absence of general oxidative stress and a yet-unexploited therapeutic approach to degenerative diseases and aging.
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“One of these SNPs (rs242561) was located in the regulatory region of the microtubule-associated protein Tau gene, which induced a strong binding of the NRF2/sMAF complex, leading to increased transcription and a reduced risk of parkinsonian diseases61,62.”
From Key points for the development of antioxidant cocktails to prevent cellular stress and damage caused by reactive oxygen species (ROS) during manned space missions (2021) · cites this paper as [62]
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Metadata
- Authors
- Liu, Y., Kern, J. T., Walker, J. R., Johnson, J. A., Schultz, P. G., & Luesch, H.
- Affiliations
- University of Florida (US)
- University of Wisconsin–Madison (US)
- Genomics Institute of the Novartis Research Foundation (US)
- Scripps Research Institute (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2007-03-20
- Volume
- 104
- Issue
- 12
- Pages
- 5205-5210
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC1829287
- OpenAlex
- W2147984935
- Cited by
- 196
- References
- 53
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 8 · 2023: 6 · 2022: 11 · 2021: 15 · 2020: 15 · 2019: 5 · 2018: 7 · 2017: 13 · 2016: 12 · 2015: 14 · 2014: 11 · 2013: 12 · 2012: 12
- FWCI
- 4.91
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Ellison Medical Foundation
- American Heart Association
- McKnight Foundation
- National Institute of Environmental Health Sciences (ES10042, R01ES010042, ES08089, R01ES008089, R29ES008089)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glutathione Transferases and Polymorphisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- antioxidant response element, Nrf2, NAD(P)H:quinone oxidoreductase 1, p62, phase II enzymes, oxidative stress, neuroprotection, PI3K signaling, protein kinase C signaling, neuroblastoma cells, cortical neurons, neurodegenerative diseases
- MeSH terms
- Sequestosome-1 Protein, Animals, Antioxidants, Cell Nucleus, Cells, Cultured, Cerebral Cortex, Enzyme Induction, Heat-Shock Proteins, NADPH Dehydrogenase, Trans-Activators, Gene Library, Gene Expression, NAD(P)H Dehydrogenase (Quinone), Genome, DNA, Complementary, Oxidative Stress, Response Elements, Oligonucleotide Array Sequence Analysis, Protein Transport, Genomics, RNA, Small Interfering, Protein Kinase Inhibitors, Adaptor Proteins, Signal Transducing, NF-E2-Related Factor 2, Mice
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