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J. Biol. Chem., Vol. 280, Issue 45, 37423-37429, November 11, 2005

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Redox Imbalance in Cystine/Glutamate Transporter-deficient Mice^*

Hideyo Sato1, Ayako Shiiya, Mayumi Kimata, Kanako Maebara, Michiko Tamba, Yuki Sakakura¶, Nobuo Makino¶, Fumihiro Sugiyama||, Ken-ichi Yagami||, Takashi Moriguchi**, Satoru Takahashi**||, and Shiro Bannai

From the Departments of Biochemistry and ^**Anatomy and Development, Institute of Basic Medical Sciences and the ^||Laboratory Animal Resource Center, University of Tsukuba, Tsukuba, Ibaraki 305-8575, the ^¶Center for Humanity and Sciences, Ibaraki Prefectural University of Health Sciences, Ami, Ibaraki 300-0394, and the Department of Bioresource Engineering, Faculty of Agriculture, Yamagata University, Tsuruoka, Yamagata 997-8555, Japan

Cystine/glutamate transporter, designated as system x^–_c, mediates cystine entry in exchange for intracellular glutamate in mammalian cells. This transporter consists of two protein components, xCT and 4F2 heavy chain, and the former is predicted to mediate the transport activity. This transporter plays a pivotal role for maintaining the intracellular GSH levels and extracellular cystine/cysteine redox balance in cultured cells. To clarify the physiological roles of this transporter in vivo, we generated and characterized mice lacking xCT. The xCT^–/– mice were healthy in appearance and fertile. However, cystine concentration in plasma was significantly higher in these mice, compared with that in the littermate xCT^–/– mice, while there was no significant difference in plasma cysteine concentration. Plasma GSH level in xCT^–/– mice was lower than that in the xCT^–/– mice. The embryonic fibroblasts derived from xCT^–/– mice failed to survive in routine culture medium, and 2-mercaptoethanol was required for survival and growth. When 2-mercaptoethanol was removed from the culture medium, cysteine and GSH in these cells dramatically decreased, and cells started to die within 24 h. N-Acetyl cysteine also rescued xCT^–/–-derived cells and permitted growth. These results demonstrate that system x^–_c contributes to maintaining the plasma redox balance in vivo but is dispensable in mammalian development, although it is vitally important to cells in vitro.

Received for publication, June 13, 2005 , and in revised form, August 18, 2005.

^* This work was supported by a grant-in-aid for scientific research from the Ministry of Education, Science, Sports and Culture in 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.

¹ To whom correspondence should be addressed: Dept. of Bioresource Engineering, Faculty of Agriculture, Yamagata University, Tsuruoka, Yamagata 997-8555, Japan. Tel./Fax: 81-235-28-2869; E-mail: shideyo{at}tds1.tr.yamagata-u.ac.jp.

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