title: Compensatory role of the Nrf2-ARE pathway against paraquat toxicity: Relevance of 26S proteasome activity.
abstract: Oxidative stress and the ubiquitin-proteasome system play a key role in the pathogenesis of Parkinson disease. Although the herbicide paraquat is an environmental factor that is involved in the etiology of Parkinson disease, the role of 26S proteasome in paraquat toxicity remains to be determined. Using PC12 cells overexpressing a fluorescent protein fused to the proteasome degradation signal, we report here that paraquat yielded an inhibitory effect on 26S proteasome activity without an obvious decline in 20S proteasome activity. Relative low concentrations of proteasome inhibitors caused the accumulation of nuclear factor erythroid 2-related factor 2 (Nrf2), which is targeted to the ubiquitin-proteasome system, and activated the antioxidant response element (ARE)-dependent transcription. Paraquat also upregulated the protein level of Nrf2 without increased expression of Nrf2 mRNA, and activated the Nrf2-ARE pathway. Consequently, paraquat induced expression of Nrf2-dependent ARE-driven genes, such as γ-glutamylcysteine synthetase, catalase, and hemeoxygenase-1. Knockdown of Nrf2 or inhibition of γ-glutamylcysteine synthetase and catalase exacerbated paraquat-induced toxicity, whereas suppression of hemeoxygenase-1 did not. These data indicate that the compensatory activation of the Nrf2-ARE pathway via inhibition of 26S proteasome serves as part of a cellular defense mechanism to protect against paraquat toxicity.
authors.affiliation: Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Izumi
authors.affiliation: Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Yamamoto
authors.affiliation: Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Sayaka
authors.initials: S
authors.lastname: Matsushima
authors.affiliation: Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Takamori
authors.initials: T
authors.lastname: Yamamoto
authors.affiliation: Department of Rational Medicinal Science, Faculty of Pharmaceutical Sciences, Doshisha Women's College, Kodo, Kyotanabe, Kyoto 610-0395, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Takada-Takatori
authors.affiliation: Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan; Department of Cellular Pharmacology, Graduate School of Pharmaceutical Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan.
authors.forename: Akinori
authors.initials: A
authors.lastname: Akaike
authors.affiliation: Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan. Electronic address: tkume@pharm.kyoto-u.ac.jp.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Kume
mesh_terms: D000818:Animals; D061745:Antioxidant Response Elements / Q000235:genetics / Q000502:physiology*; D002374:Catalase / Q000502:physiology; D005721:Glutamate-Cysteine Ligase / Q000502:physiology; D006540:Herbicides / Q000494:pharmacology*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D016716:PC12 Cells; D010269:Paraquat / Q000494:pharmacology*; D010300:Parkinson Disease / Q000209:etiology; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology*
chemical_list: D006540:Herbicides; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; D002374:Catalase; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease; D005721:Glutamate-Cysteine Ligase; D010269:Paraquat
keywords: Nrf2–ARE pathway; Oxidative stress; Paraquat; Parkinson disease; Proteasome activity