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600902 
Journal Article 
The cystine/cysteine cycle: a redox cycle regulating susceptibility versus resistance to cell death 
Banjac, A; Perisic, T; Sato, H; Seiler, A; Bannai, S; Weiss, N; Kölle, P; Tschoep, K; Issels, RD; Daniel, PT; Conrad, M; Bornkamm, GW 
2008 
1 
Oncogene
ISSN: 0950-9232
EISSN: 1476-5594 
27 
11 
1618-1628 
The glutathione-dependent system is one of the key systems regulating cellular redox balance, and thus cell fate. Cysteine, typically present in its oxidized form cystine in the extracellular space, is regarded as the rate-limiting substrate for glutathione (GSH) synthesis. Cystine is transported into cells by the highly specific amino-acid antiporter system xc−. Since Burkitt's Lymphoma (BL) cells display limited uptake capacity for cystine, and are thus prone to oxidative stress-induced cell death, we stably expressed the substrate-specific subunit of system xc−, xCT, in HH514 BL cells. xCT-overexpressing cells became highly resistant to oxidative stress, particularly upon GSH depletion. Contrary to previous predictions, the increase of intracellular cysteine did not affect the cellular GSH pool, but concomitantly boosted extracellular cysteine concentrations. Even though cells were depleted of bulk GSH, xCT overexpression maintained cellular integrity by protecting against lipid peroxidation, a very early event in cell death progression. Our results show that system xc− protects against oxidative stress not by elevating intracellular GSH levels, but rather creates a reducing extracellular environment by driving a highly efficient cystine/cysteine redox cycle. Our findings show that the cystine/cysteine redox cycle by itself must be viewed as a discrete major regulator of cell survival.Oncogene (2008) 27, 1618–1628; doi:10.1038/sj.onc.1210796; published online 10 September 2007 [ABSTRACT FROM AUTHOR] Copyright of Oncogene is the property of Nature Publishing Group and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts) 
GLUTATHIONE; METABOLISM; OXIDATION-reduction reaction; GLUTAMIC acid; EXCITATORY amino acids; cystine-glutamate exchange; lipid peroxidation; redox regulation; system xc-