Nrf2 establishes a glutathione-mediated gradient of UVB cytoprotection in the epidermis
Open accessAbstract
Ultraviolet (UV) B irradiation can severely damage the skin and even induce tumorigenesis. It exerts its effects by direct DNA modification and by formation of reactive oxygen species (ROS). We developed a strategy to genetically activate target gene expression of the transcription factor NF-E2-related factor 2 (Nrf2) in keratinocytes in vivo based on expression of a constitutively active Nrf2 mutant. Activation of Nrf2 target genes strongly reduced UVB cytotoxicity through enhancement of ROS detoxification. Remarkably, the protective effect was extended to neighboring cells. Using different combinations of genetically modified mice, we demonstrate that Nrf2 activates the production, recycling, and release of glutathione and cysteine by suprabasal keratinocytes, resulting in protection of basal cells in a paracrine, glutathione/cysteine-dependent manner. Most importantly, we found that endogenous Nrf2 controls selective protection of suprabasal keratinocytes from UVB-induced apoptosis through activation of cytoprotective genes. This finding explains the preferential UVB-induced apoptosis of basal cells, which is important for elimination of mutated stem cells as well as for preservation of skin integrity. Taken together, our results identify Nrf2 as a key regulator in the UV response of the skin.
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UV-B-induced apoptosis of basal keratinocytes in murine epidermis is blocked by suprabasal keratinocytes capable of controlling their survival through Nrf2-regulated antioxidant defenses including GSH.
“UV-B-induced apoptosis of basal keratinocytes in murine epidermis was blocked by suprabasal keratinocytes capable of controlling their survival through Nrf2-regulated antioxidant defenses including GSH [154].”
From Ultraviolet Radiation‐Induced Skin Aging: The Role of DNA Damage and Oxidative Stress in Epidermal Stem Cell Damage Mediated Skin Aging (2016) · cites this paper as [154]
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- Authors
- Schäfer, M., Dütsch, S., auf dem Keller, U., Navid, F., Schwarz, A., Johnson, D. A., Johnson, J. A., & Werner, S.
- Affiliations
- ETH Zurich (CH)
- Christian-Albrechts-Universität zu Kiel (DE)
- University of Wisconsin–Madison (US)
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2010-05-15
- Volume
- 24
- Issue
- 10
- Pages
- 1045-1058
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC2867209
- OpenAlex
- W2169145907
- Cited by
- 175
- References
- 56
- Citations by year
- 2026: 5 · 2025: 11 · 2024: 8 · 2023: 8 · 2022: 14 · 2021: 13 · 2020: 11 · 2019: 7 · 2018: 13 · 2017: 7 · 2016: 14 · 2015: 12 · 2014: 12 · 2013: 13 · 2012: 14
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Science Foundation
- University of Cincinnati
- Deutsches Krebsforschungszentrum
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (109340, 3100A0)
- Eidgenössische Technische Hochschule Zürich
- Universität Zürich
- Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Health Sciences › Medicine › Dermatology › Skin Protection and Aging
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- Nrf2, UVB-induced skin damage, keratinocytes, glutathione, cysteine, reactive oxygen species scavenging, paracrine signaling, UVB-induced apoptosis, basal keratinocytes, suprabasal keratinocytes, epidermis, skin integrity, cytoprotection
- MeSH terms
- Animals, Female, Gene Expression Regulation, Glutathione, Humans, Mice, Transgenic, Mutation, Ultraviolet Rays, Keratinocytes, Apoptosis, Reactive Oxygen Species, Cytoprotection, NF-E2-Related Factor 2, Mice
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