title: Redox imbalance in cystine/glutamate transporter-deficient mice.
abstract: 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.
authors.affiliation: Department of Biochemistry, Institute of Basic Medical Sciences, University of Tsukuba, Ibaraki, Japan.
authors.forename: Hideyo
authors.initials: H
authors.lastname: Sato
authors.forename: Ayako
authors.initials: A
authors.lastname: Shiiya
authors.forename: Mayumi
authors.initials: M
authors.lastname: Kimata
authors.forename: Kanako
authors.initials: K
authors.lastname: Maebara
authors.forename: Michiko
authors.initials: M
authors.lastname: Tamba
authors.forename: Yuki
authors.initials: Y
authors.lastname: Sakakura
authors.forename: Nobuo
authors.initials: N
authors.lastname: Makino
authors.forename: Fumihiro
authors.initials: F
authors.lastname: Sugiyama
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Yagami
authors.forename: Takashi
authors.initials: T
authors.lastname: Moriguchi
authors.forename: Satoru
authors.initials: S
authors.lastname: Takahashi
authors.forename: Shiro
authors.initials: S
authors.lastname: Bannai
mesh_terms: D027182:Amino Acid Transport System y+ / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D000596:Amino Acids / Q000097:blood; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003553:Cystine / Q000097:blood; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D017353:Gene Deletion; D005978:Glutathione / Q000097:blood / Q000378:metabolism; D006720:Homozygote; D008297:Male; D051379:Mice; D010084:Oxidation-Reduction
chemical_list: D027182:Amino Acid Transport System y+; D000596:Amino Acids; C492255:Slc7a11 protein, mouse; D003553:Cystine; D005978:Glutathione