title: Partial contribution of the Keap1-Nrf2 system to cadmium-mediated metallothionein expression in vascular endothelial cells.
abstract: Cadmium is an environmental electrophile that modifies protein reactive thiols such as Kelch-like ECH-associated protein 1 (Keap1), a negative regulator of nuclear factor-erythroid 2-related factor 2 (Nrf2). In the present study, we investigated a role of the Keap1-Nrf2 system in cellular response to cadmium in vascular endothelial cells. Exposure of bovine aortic endothelial cells to cadmium resulted in modification of Keap1 and Nrf2 activation, thereby up-regulating not only its typical downstream proteins but also metallothionein-1/2. Experiments with siRNA-mediated knockdown of Nrf2 or Keap1 supported participation of the Keap1-Nrf2 system in the modulation of metallothionein-1/2 expression. Furthermore, chromatin immunoprecipitation assay showed that Nrf2 was recruited to the antioxidant response element of the promoter region of the bovine metallothionein-2 gene in the presence of cadmium. These results suggest that the transcription factor Nrf2 plays, at least in part, a role in the changes in metallothionein expression mediated by exposure to cadmium.
authors.affiliation: Environmental Biology Laboratory, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Shinkai
authors.affiliation: Faculty of Science and Engineering, Setsunan University, 17-8 Ikedanaka-machi, Neyagawa, Osaka 572-8508, Japan.
authors.forename: Tomoki
authors.initials: T
authors.lastname: Kimura
authors.affiliation: Faculty of Pharmaceutical Sciences, Hokuriku University, Ho-3 Kanagawa, Kanazawa, 920-1181, Ishikawa, Japan.
authors.forename: Ayaka
authors.initials: A
authors.lastname: Itagaki
authors.affiliation: Faculty of Pharmaceutical Sciences, Hokuriku University, Ho-3 Kanagawa, Kanazawa, 920-1181, Ishikawa, Japan; Faculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi, Chiba 274-8510, Japan.
authors.forename: Chika
authors.initials: C
authors.lastname: Yamamoto
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai 980-8575, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Taguchi
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai 980-8575, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
authors.affiliation: Environmental Biology Laboratory, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan. Electronic address: yk-em-tu@md.tsukuba.ac.jp.
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Kumagai
authors.affiliation: Faculty of Pharmaceutical Sciences, Hokuriku University, Ho-3 Kanagawa, Kanazawa, 920-1181, Ishikawa, Japan; Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan. Electronic address: t-kaji@rs.tus.ac.jp.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Kaji
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis*; D000818:Animals; D061745:Antioxidant Response Elements / Q000187:drug effects; D002104:Cadmium / Q000494:pharmacology*; D002417:Cattle; D018929:Cell Culture Techniques; D002853:Chromatography, Liquid; D003598:Cytoskeletal Proteins / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000378:metabolism*; D000072019:Kelch-Like ECH-Associated Protein 1; D013058:Mass Spectrometry; D008668:Metallothionein / Q000096:biosynthesis*; D051267:NF-E2-Related Factor 2 / Q000096:biosynthesis*; D034741:RNA, Small Interfering; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; C117301:Keap1 protein, mouse; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D034741:RNA, Small Interfering; D002104:Cadmium; D008668:Metallothionein
keywords: Antioxidant response element; Cadmium; Keap1; Metallothionein; Nrf2