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J. Biol. Chem., Vol. 283, Issue 4, 2021-2030, January 25, 2008

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Deletion of the Selenocysteine tRNA Gene in Macrophages and Liver Results in Compensatory Gene Induction of Cytoprotective Enzymes by Nrf2^*

Takafumi Suzuki¹, Vincent P. Kelly¹², Hozumi Motohashi^¶, Osamu Nakajima^||, Satoru Takahashi, Susumu Nishimura, and Masayuki Yamamoto^¶3

From the Exploratory Research for Advanced Technology Environmental Response Project and Center for Tsukuba Advanced Research Alliance and the Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba 305-8577, Japan, the ^||Research Laboratory for Molecular Genetics, Yamagata University, Yamagata 990-9585, Japan, and the ^¶Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai 980-8575, Japan

The selenocysteine tRNA (tRNA^Sec) molecule is the sight of synthesis for the amino acid selenocysteine and the adaptor for its translational insertion into selenoprotein enzymes, the majority of which contribute to cellular redox homeostasis. To examine the consequences of selenoprotein depletion on the oxidative environment of the cell, we generated a conditional knock-out mouse for the tRNA^Sec gene (Trsp). Deletion of Trsp in either macrophages or liver elevated oxidative stress and activated the transcriptional induction of cytoprotective antioxidant and detoxification enzyme genes, including glutathione S-transferase P1 and NAD(P)H:quinone oxidoreductase 1, and other well known target genes of the transcription factor Nrf2 (NF-E2-related factor 2). Simultaneous disruption of Trsp and Nrf2 severely compromised the cytoprotective response. Double knock-out macrophages displayed reduced viability, elevated oxidative stress, and increased susceptible to hydrogen peroxide treatment compared with deletion of either gene alone. Mice carrying a liver-specific deletion of Trsp on an Nrf2-null background experienced hepatocellular apoptosis and displayed a severely reduced survival rate compared with loss of Trsp alone. Our results thus demonstrate that reduced selenoprotein activity is counterbalanced by an Nrf2-mediated cytoprotective response, which is essential for maintaining cellular redox homeostasis and viability.

Received for publication, October 9, 2007 , and in revised form, November 26, 2007.

^* This work was supported by grants from Exploratory Research for Advanced Technology, Japan Science and Technology Corp.; the Ministry of Education, Science, Sports, and Culture; the Ministry of Health, Labor, and Welfare; the Atherosclerosis Foundation; and the Naito Foundation. 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.

This article was selected as a Paper of the Week.

¹ Both authors contributed equally to this work.

² Present address: School of Biochemistry and Immunology, Trinity College, College Green, Dublin 2, Ireland.

³ To whom correspondence should be addressed: Dept. of Medical Biochemistry, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai 980-8575, Japan. Tel.: 81-22-717-8084; Fax: 81-22-717-8090; E-mail: masi{at}mail.tains.tohoku.ac.jp.

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