title: Ultraviolet A irradiation induces NF-E2-related factor 2 activation in dermal fibroblasts: protective role in UVA-induced apoptosis.
abstract: Ultraviolet (UV) radiation is one of the most important environmental factors involved in the pathogenesis of skin aging and cancer. Many harmful effects of UV radiation are associated with the generation of reactive oxygen species, and cellular antioxidants act to prevent the occurrence and reduce the severity of UV-induced skin disorders. Transcription factor NF-E2-related Factor 2 (Nrf2) and its cytoplasmic anchor protein Kelch-like-ECH-associated protein 1 (Keap1) are central regulators of the cellular antioxidant response. In this study, we investigated the effects of UV irradiation on the activation of Nrf2 in dermal fibroblasts. We found that UVA irradiation, but not UVB, causes nuclear translocation and accumulation of Nrf2 by a factor of 6.5 as compared with unirradiated controls. The nuclear accumulation of Nrf2 induced by UVA was enhanced by the photosensitizer hematoporphyrin. To evaluate the protective role of Nrf2 against UVA radiation, we examined UVA-induced apoptosis using dermal fibroblasts derived from nrf2 or keap1 gene knockout mice. Whereas disruption of nrf2 increased the number of apoptotic cells following UVA irradiation by 1.7-fold, disruption of keap1 decreased the apoptotic cell number by half as compared with wild-type controls. These findings thus demonstrate that the Nrf2-Keap1 pathway plays an important role in the protection of the skin against UVA irradiation.
authors.affiliation: Department of Dermatology, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Ayako
authors.initials: A
authors.lastname: Hirota
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Kawachi
authors.forename: Ken
authors.initials: K
authors.lastname: Itoh
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Xuezhu
authors.initials: X
authors.lastname: Xu
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Banno
authors.forename: Takenori
authors.initials: T
authors.lastname: Takahashi
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Fujio
authors.initials: F
authors.lastname: Otsuka
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism*; D020405:Dermis / Q000473:pathology / Q000502:physiology / Q000528:radiation effects*; D005347:Fibroblasts / Q000473:pathology / Q000502:physiology / Q000528:radiation effects*; D015971:Gene Expression Regulation, Enzymologic / Q000528:radiation effects; D005721:Glutamate-Cysteine Ligase / Q000235:genetics; D006415:Hematoporphyrins / Q000494:pharmacology; D000072019:Kelch-Like ECH-Associated Protein 1; D051379:Mice; D008813:Mice, Inbred ICR; D008817:Mice, Mutant Strains; D051267:NF-E2-Related Factor 2; D015534:Trans-Activators / Q000378:metabolism*; D014466:Ultraviolet Rays / Q000009:adverse effects*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D006415:Hematoporphyrins; C117301:Keap1 protein, mouse; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D015534:Trans-Activators; D005721:Glutamate-Cysteine Ligase