Beyond antioxidant genes in the ancient Nrf2 regulatory network
Open accessAbstract
Nrf2, a basic leucine zipper transcription factor encoded by the gene NFE2L2, is a master regulator of the transcriptional response to oxidative stress. Nrf2 is structurally and functionally conserved from insects to humans, and it heterodimerizes with the small MAF transcription factors to bind a consensus DNA sequence (the antioxidant response element, or ARE) and regulate gene expression. We have used genome-wide chromatin immunoprecipitation and gene expression data to identify direct Nrf2 target genes in Drosophila and humans. These data have allowed us to construct the deeply conserved ancient Nrf2 regulatory network-target genes that are conserved from Drosophila to human. The ancient network consists of canonical antioxidant genes, as well as genes related to proteasomal pathways and metabolism and a number of less expected genes. We have also used enhancer reporter assays and electrophoretic mobility-shift assays to confirm Nrf2-mediated regulation of ARE activity at a number of these novel target genes. Interestingly, the ancient network also highlights a prominent negative feedback loop; this, combined with the finding that Nrf2-mediated regulatory output is tightly linked to the quality of the ARE it is targeting, suggests that precise regulation of nuclear Nrf2 concentration is necessary to achieve proper quantitative regulation of distinct gene sets. Together, these findings highlight the importance of balance in the Nrf2-ARE pathway and indicate that Nrf2-mediated regulation of xenobiotic metabolism, glucose metabolism, and proteostasis has been central to this pathway since its inception.
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Nrf2 is a master regulator of the transcriptional response to oxidative stress, structurally and functionally conserved from insects to humans.
“Finally, nuclear-factor-erythroid 2-related factor 2 (Nrf2) is a master regulator of the transcriptional response to oxidative stress, and it is structurally and functionally conserved from insects to humans [69].”
Equol can increase levels of the master gene Nrf2, which regulates endogenous expression of detoxifying proteins and many other antioxidant enzymes involved in wound repair and protection against skin cancer.
“equol itself is a very strong antioxidant, and, in turn, it can increase the levels of the master gene, Nrf2, which regulates the endogenous expression of detoxifying proteins and many other antioxidant enzymes that are involved in wound repair, protection against skin cancer”
Nrf2 activation guards against dermal damage from sunlight (ionizing radiation) and oxidative stress via ROS.
“where Nrf2 activation guards against dermal damage, from sunlight (ionizing radiation) and oxidative stress via ROS [2,69-73,76,99].”
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Skin aging and oxidative stress: Equol’s anti-aging effects via biochemical and molecular mechanisms
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- Authors
- Lacher, S. E., Lee, J. S., Wang, X., Campbell, M. R., Bell, D. A., & Slattery, M.
- Affiliations
- University of Minnesota (US)
- National Institutes of Health (US)
- Corresponding author
- Slattery, Matthew
- Venue
- Free Radical Biology and Medicine
- Publisher
- Elsevier BV
- Published
- 2015-11
- Volume
- 88
- Issue
- Pt B
- Pages
- 452-465
- ISSN
- 0891-5849 (ISSN-L)
- PMC
- PMC4837897
- OpenAlex
- W829805959
- Cited by
- 77
- References
- 76
- Citations by year
- 2026: 6 · 2025: 4 · 2024: 4 · 2023: 5 · 2022: 7 · 2021: 8 · 2020: 7 · 2019: 7 · 2018: 12 · 2017: 10 · 2016: 7
- FWCI
- 4.20
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Free Radical Biology and Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- University of Minnesota Foundation
- Intramural Research Program of the National Institute of Environmental Health Sciences
- National Institutes of Health (Z01-ES-100475, ES065079)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glutathione Transferases and Polymorphisms
- Keywords
- Nrf2, antioxidant response element, oxidative stress response, Nrf2 target genes, Maf transcription factors, Drosophila, negative feedback loop, xenobiotic metabolism, glucose metabolism, proteostasis, enhancer regulation
- MeSH terms
- Animals, Antioxidants, Base Sequence, Drosophila, Gene Expression Regulation, Humans, Molecular Sequence Data, Phylogeny, Repressor Proteins, Electrophoretic Mobility Shift Assay, Drosophila Proteins, Chromatin Immunoprecipitation, NF-E2-Related Factor 2, Transcriptome, Antioxidant Response Elements
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