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J. Biol. Chem., Vol. 280, Issue 26, 25267-25276, July 1, 2005

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Selective Induction of the Tumor Marker Glutathione S-Transferase P1 by Proteasome Inhibitors^*

Hiroko Usami, Yuri Kusano, Takeshi Kumagai, Shigehiro Osada¶, Ken Itoh||, Akira Kobayashi||, Masayuki Yamamoto||, and Koji Uchida**

From the Graduate School of Bioagricultural Sciences and the ^**Institute for Advanced Research, Nagoya University, Nagoya 464-8601, Japan, the ^¶Graduate School of Pharmacological Sciences, Osaka University, Osaka 565-0871, Japan, and the ^||Center for Tsukuba Advanced Research Alliance and the Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba 305-8577, Japan

Exposure of cells to a wide variety of chemoprotective compounds confers resistance to a broad set of carcinogens. For a subset of the chemoprotective compounds, protection is generated by an increase in the abundance of phase 2 detoxification enzymes such as glutathione S-transferases (GSTs). Transcription factor Nrf2, which is sequestered in the cytoplasm by Keap1 (Kelch-like ECH-associated protein-1) under unstimulated conditions, regulates the induction of phase 2 enzymes. In this study, to explore the role of the proteasome in the detoxification response, we tested the effect of proteasome inhibitors such as MG132, clasto-lactacystin -lactone, and lactacystin on the induction of GST isozymes and found that these inhibitors selectively induced the class Pi GST isozyme (GST P1). Down-regulation of the proteasome by antisense oligonucleotides or RNA interference indeed resulted in significant up-regulation of GST P1, suggesting that a decline in the proteasome activity could be directly or indirectly linked to the induction of GST P1. From the functional analysis of various deletion constructs of the upstream regulatory region of the GST P1 promoter, GST P1 enhancer I was identified as the response element for proteasome inhibition. Overexpression of the wild-type and dominant-negative forms of Nrf2 and Keap1 had little effect on the induction of GST P1 not only by the proteasome inhibitor, but also by phase 2-inducing isothiocyanate, suggesting that there may be a process of GST P1 induction distinct from other phase 2 gene induction mechanisms. Because GST P1 is highly and specifically induced during early hepatocarcinogenesis as well as in hepatocellular carcinoma cells, these data may provide a potential critical role for the proteasome in the induction of a cellular defense program associated with carcinogenesis.

Received for publication, January 27, 2005 , and in revised form, April 12, 2005.

^* This work was supported in part by a research grant from the Ministry of Education, Culture, Sports, Science, and Technology and by the Center of Excellence Program in the 21st Century (Japan). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains Supplemental Figs. S1-S3.

Recipient of a research fellowship from the Japan Society for the Promotion of Science.

To whom correspondence should be addressed: Lab. of Food and Biodynamics, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya 464-8601, Japan. Tel.: 81-52-789-4127; Fax: 81-52-789-5741; E-mail: uchidak{at}agr.nagoya-u.ac.jp.

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