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A more recent version of this article appeared on November 11, 2005
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M506439200v1
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Papers In Press, published online ahead of print September 6, 2005
J. Biol. Chem, 10.1074/jbc.M506439200
Submitted on June 13, 2005
Revised on August 18, 2005
Accepted on September 6, 2005

Redox imbalance in cystine/glutamate transporter-deficient mice

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

Department of Biochemistry, Yamagata University, Tsuruoka, Yamagata 997-8555

Corresponding Author: shideyo{at}tds1.tr.yamagata-u.ac.jp

Cystine/glutamate transporter, designated as system xc-, 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, whereas 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 the routine culture medium, and 2-mercaptoethanol was required for the survival and growth. When 2-mercaptoethanol was removed from the culture medium, cysteine and GSH in these cells drastically decreased and they started to die within 24 hours. N-acetyl cysteine also rescued xCT-/--derived cells and permitted growth. These results demonstrate that system xc- contributes to maintaining the plasma redox balance in vivo but is dispensable in the mammalian development although it is vitally important to the cells in vitro.


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