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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 α-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 α 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 α 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.
| Abbreviations | ||
| AP-1 | = | Activator Protein 1 |
| BOB | = | 2,3-dihydro-5-hydroxy-2,2-dimethyl-4,6-di-tert-butylbenzofuran |
| BOM | = | 2,3-dihydro-5-hydroxy-2,2-dimethyl-4,6-dimethylbenzofuranand |
| BO-653 | = | 2,3-dihydro-5-hydroxy-2,2-dipentyl-4,6-di-tert-butylbenzofuran |
| BZ1044 | = | 2,3-dihydro-5-hydroxy-2,2-dipentyl-4,6-di-methylbenzofuran |
| GCLM | = | glutamate cysteine lygase modifier-1 |
| HO-1 | = | hemeoxygenase-1 |
| HUVEC | = | Human umbilical vein endothelial cells |
| Met-BO | = | 4,6-di-tert-butyl-2,3-dihydro-5-methoxy-2,2-dipentylbenzofuran |
| NQO-1 | = | NADPH quinone oxidoreductase 1 |
| PSMAs | = | proteasome α-type subunits |
| tBHQ | = | tert-butyl hydroquinone |
| Abbreviations | ||
| AP-1 | = | Activator Protein 1 |
| BOB | = | 2,3-dihydro-5-hydroxy-2,2-dimethyl-4,6-di-tert-butylbenzofuran |
| BOM | = | 2,3-dihydro-5-hydroxy-2,2-dimethyl-4,6-dimethylbenzofuranand |
| BO-653 | = | 2,3-dihydro-5-hydroxy-2,2-dipentyl-4,6-di-tert-butylbenzofuran |
| BZ1044 | = | 2,3-dihydro-5-hydroxy-2,2-dipentyl-4,6-di-methylbenzofuran |
| GCLM | = | glutamate cysteine lygase modifier-1 |
| HO-1 | = | hemeoxygenase-1 |
| HUVEC | = | Human umbilical vein endothelial cells |
| Met-BO | = | 4,6-di-tert-butyl-2,3-dihydro-5-methoxy-2,2-dipentylbenzofuran |
| NQO-1 | = | NADPH quinone oxidoreductase 1 |
| PSMAs | = | proteasome α-type subunits |
| tBHQ | = | tert-butyl hydroquinone |