title: Chemical structure-dependent gene expression of proteasome subunits via regulation of the antioxidant response element.
abstract: Antioxidants possess potent ability to regulate gene expression beyond their specific antioxidant activity. Genomic analysis reveals that three phenolic antioxidants, probucol, BO-653, and tBHQ, all of which have a phenoxyl group with one or two tert-butyl groups at the ortho-position, inhibit both the mRNA and protein levels of proteasome alpha-subunits in human endothelial cells. The chemical structure required for the gene regulation was studied by using derivatives of BO-653 and other antioxidants. It was found that the phenoxyl group and tert-butyl group at the ortho-position of the compounds were critical for down-regulation of the proteasome gene. Two antioxidant responsive elements (AREs) were identified in the promoter region of proteasome alpha subunit 3 (PSMA3). Results from promoter truncation analysis revealed that the proximal ARE region was necessary for the down-regulation of the expression of PSMA3. Electrophoretic mobility shift assays revealed that BO-653-mediated induction of DNA-binding to an upstream promoter region of PSMA3 containing the ARE motif was blocked by antibody against c-Jun but not Nrf2. These results indicate that the suppression of the proteasome alpha subunits expression by phenolic antioxidants is strictly dependent on both their chemical structure and the ARE consensus region in the promoter, which may be negatively regulated by AP-1.
authors.affiliation: Laboratory for Systems Biology and Medicine, Research Center for Advanced Science and Technology, University of Tokyo, 4-6-1 Komaba, Meguro, Japan.
authors.forename: Wakako
authors.initials: W
authors.lastname: Takabe
authors.forename: Naeko
authors.initials: N
authors.lastname: Matsukawa
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Kodama
authors.forename: Keiji
authors.initials: K
authors.lastname: Tanaka
authors.forename: Noriko
authors.initials: N
authors.lastname: Noguchi
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology*; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology*; D016166:Free Radical Scavengers / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D051267:NF-E2-Related Factor 2 / Q000096:biosynthesis / Q000235:genetics; D010636:Phenols / Q000737:chemistry / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000096:biosynthesis / Q000235:genetics; D061988:Proteasome Inhibitors; D021122:Protein Subunits; D012333:RNA, Messenger / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D020218:Response Elements / Q000187:drug effects* / Q000235:genetics; D013329:Structure-Activity Relationship; D018808:Transcription Factor AP-1 / Q000096:biosynthesis / Q000235:genetics
chemical_list: D000975:Antioxidants; D016166:Free Radical Scavengers; D051267:NF-E2-Related Factor 2; D010636:Phenols; D061988:Proteasome Inhibitors; D021122:Protein Subunits; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D004247:DNA; D046988:Proteasome Endopeptidase Complex