Cited by 175Genomics, phytochemicals, and oxidative stressSkin Protection and AgingRedox biology and oxidative stress

Nrf2 establishes a glutathione-mediated gradient of UVB cytoprotection in the epidermis

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Schäfer, Matthias, Dütsch, Sabine, auf dem Keller, Ulrich, Navid, Fatemeh, Schwarz, Agatha, Johnson, Delinda A., Johnson, Jeffrey A., Werner, Sabine·2010·Genes & Development

Abstract

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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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
Published
2010-05-15
Volume
24
Issue
10
Pages
1045-1058
ISSN
  • 0890-9369 (ISSN-L)
  • 1549-5477
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
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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