A human cDNA for amino acid transport system x(C)(-) was isolated from diethyl maleate-treated human glioma U87 cells. U87 cells expressed two variants of system x(C)(-) transporters hxCTa and hxCTb with altered C-terminus regions probably generated by the alternative splicing at 3'-ends. Both hxCTa and hxCTb messages were also detected in spinal cord, brain and pancreas, although the level of hxCTb expression appears to be lower than that of hxCTa in these tissues. When expressed in Xenopus oocytes, hxCTb required the heavy chain of 4F2 cell surface antigen (4F2hc) and exhibited the Na(+)-independent transport of L-cystine and L-glutamate, consistent with the properties of system x(C)(-). In agreement with this, 137 kDa band was detected by either anti-xCT or anti-4F2hc antibodies in the non-reducing condition in western blots, whereas it shifted to 50 kDa or 90 kDa bands in the reducing condition, indicating the association of two proteins via disulfide bands. We found that the expression of xCT was rapidly induced in U87 cells upon oxidative stress by diethyl maleate treatment, which was accompanied by the increase in the L-cystine uptake by U87 cells. Because of this highly regulated nature, xCT in glial cells would fulfill the task to protect neurons against oxidative stress by providing suitable amount of cystine to produce glutathione.