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J. Biol. Chem., Vol. 276, Issue 44, 40497-40501, November 2, 2001

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Anti-atherogenic Antioxidants Regulate the Expression and Function of Proteasome -Type Subunits in Human Endothelial Cells^*

Wakako Takabe, Tatsuhiko Kodama, Takao Hamakubo, Keiji Tanaka^§, Toshiaki Suzuki^§, Hiroyuki Aburatani^¶, Naeko Matsukawa^¶, and Noriko Noguchi^¶

From the  Department of Molecular Biology and Medicine, Research Center for Advanced Science and Technology, University of Tokyo, 4-6-1 Komaba, Meguro, Tokyo 153-8904, Japan, the ^§ Tokyo Metropolitan Institute of Medical Science and CREST, Japan Science and Technology Corporation, 3-18-22 Komagome, Bunkyo, Tokyo 113-8613, Japan, and ^¶ Genome Sciences, Research Center for Advanced Science and Technology, University of Tokyo, 4-6-1 Komaba, Meguro, Tokyo 153-8904, Japan

It has been proposed that phenolic antioxidants such as probucol exert their anti-atherogenic effects through scavenging lipid-derived radicals. In this study the potential for genomics to reveal unanticipated pharmacological properties of phenolic antioxidants is explored. It was found that two anti-atherogenic compounds, BO-653 and probucol, inhibited the expression of three -type proteasome subunits, PMSA2, PMSA3, and PMSA4 in human umbilical vein endothelial cells. Here we report that both BO-653 and probucol caused not only inhibition of the mRNA levels of these three subunits but also inhibition of both the gene expression and protein synthesis of the -type subunit, PMSA1. Other subunit components of the proteasome such as the -type subunits (PMSB1, PMSB7), the ATPase subunit of 19 S (PMSC6), the non-ATPase subunit of 19 S (PMSD1), and PA28 (PMSE2) were not significantly affected by treatment with these compounds. The specific inhibition of -type subunit expression in response to these antioxidants resulted in functional alterations of the proteasome with suppression of degradation of multiubiquitinated proteins and IB. These results suggest that certain compounds previously classified solely as antioxidants are able to exert potentially important modulatory effects on proteasome function.

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