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Molecular and Cellular Biology, December 2003, p. 8786-8794, Vol. 23, No. 23
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.23.8786-8794.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Antioxidants Enhance Mammalian Proteasome Expression through the Keap1-Nrf2 Signaling Pathway

Mi-Kyoung Kwak,1 Nobunao Wakabayashi,1,2 Jennifer L. Greenlaw,1 Masayuki Yamamoto,2 and Thomas W. Kensler1*

Department of Environmental Health Sciences, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland 21205,1 Institute of Basic Medical Sciences and Center for Tsukuba Advanced Research Alliance, University of Tsukuba, Tennoudai, Tsukuba 305-8577, Japan2

Received 20 June 2003/ Returned for modification 6 August 2003/ Accepted 26 August 2003

Proteasomes degrade damaged proteins formed during oxidative stress, thereby promoting cell survival. Neurodegenerative and other age-related disorders are associated with reduced proteasome activity. We show herein that expression of most subunits of 20S and 19S proteasomes, which collectively assemble the 26S proteasome, was enhanced up to threefold in livers of mice following treatment with dithiolethiones, which act as indirect antioxidants. Subunit protein levels and proteasome activity were coordinately increased. No induction was seen in mice where the transcription factor Nrf2 was disrupted. Promoter activity of the PSMB5 subunit of the 20S proteasome increased with either Nrf2 overexpression or treatment with antioxidants in mouse embryonic fibroblasts. Tandem antioxidant response elements in the proximal promoter of PSMB5 that controlled these responses were identified. We propose that induction of the 26S proteasome through the Nrf2 pathway represents an important indirect action of these antioxidants that can contribute to their protective effects against chronic diseases.

* Corresponding author. Mailing address: Department of Environmental Health Sciences, Johns Hopkins University Bloomberg School of Public Health, 615 N. Wolfe St., Baltimore, MD 21205. Phone: (410) 955-4712. Fax: (410) 955-0116. E-mail: tkensler{at}jhsph.edu.

Molecular and Cellular Biology, December 2003, p. 8786-8794, Vol. 23, No. 23
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.23.8786-8794.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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