Compartmentation of Nrf-2 Redox Control: Regulation of Cytoplasmic Activation by Glutathione and DNA Binding by Thioredoxin-1 Export

@article{citeulike:3523372, abstract = {Nrf-2 is a redox-sensitive transcription factor that is activated by an oxidative signal in the cytoplasm but has a critical cysteine that must be reduced to bind to DNA in the nucleus. The glutathione (GSH) and thioredoxin (TRX) systems have overlapping functions in thiol/disulfide redox control in both the cytoplasm and the nucleus, and it is unclear whether these are redundant or have unique functions in control of Nrf-2-dependent signaling. To test whether GSH and Trx-1 have distinct functions in Nrf-2 signaling, we selectively modified GSH by metabolic manipulation and selectively modified Trx-1 expression by transient transfection. Cytoplasmic activation of Nrf-2 was measured by its nuclear translocation and nuclear activity of Nrf-2 was measured by expression of a luciferase reporter construct containing an ARE4 from glutamate cysteine ligase. Results showed that tert-butylhydroquinone (TBHQ), a transcriptional activator that functions through Nrf-2/ARE, promoted Nrf-2 nuclear translocation by a type I (thiylation) redox switch which was regulated by GSH not by Trx-1. In contrast, the ARE reporter was principally controlled by nuclear-targeted Trx-1 and not by GSH. The data show that the GSH and TRX systems have unique, compartmented functions in the control of transcriptional regulation by Nrf-2/ARE. 10.1093/toxsci/kfh231}, author = {Hansen, Jason M. and Watson, Walter H. and Jones, Dean P.}, citeulike-article-id = {3523372}, citeulike-linkout-0 = {http://dx.doi.org/10.1093/toxsci/kfh231}, citeulike-linkout-1 = {http://toxsci.oxfordjournals.org/cgi/content/abstract/82/1/308}, citeulike-linkout-2 = {http://view.ncbi.nlm.nih.gov/pubmed/15282410}, citeulike-linkout-3 = {http://www.hubmed.org/display.cgi?uids=15282410}, doi = {10.1093/toxsci/kfh231}, journal = {Toxicol. Sci.}, keywords = {glutathione, nrf-2, theioredoxin}, month = {November}, number = {1}, pages = {308--317}, posted-at = {2008-11-16 19:03:04}, priority = {3}, title = {Compartmentation of Nrf-2 Redox Control: Regulation of Cytoplasmic Activation by Glutathione and DNA Binding by Thioredoxin-1}, url = {http://dx.doi.org/10.1093/toxsci/kfh231}, volume = {82}, year = {2004} }

TY - JOUR ID - citeulike:3523372 L3 - citeulike-article-id:3523372 N2 - Nrf-2 is a redox-sensitive transcription factor that is activated by an oxidative signal in the cytoplasm but has a critical cysteine that must be reduced to bind to DNA in the nucleus. The glutathione (GSH) and thioredoxin (TRX) systems have overlapping functions in thiol/disulfide redox control in both the cytoplasm and the nucleus, and it is unclear whether these are redundant or have unique functions in control of Nrf-2-dependent signaling. To test whether GSH and Trx-1 have distinct functions in Nrf-2 signaling, we selectively modified GSH by metabolic manipulation and selectively modified Trx-1 expression by transient transfection. Cytoplasmic activation of Nrf-2 was measured by its nuclear translocation and nuclear activity of Nrf-2 was measured by expression of a luciferase reporter construct containing an ARE4 from glutamate cysteine ligase. Results showed that tert-butylhydroquinone (TBHQ), a transcriptional activator that functions through Nrf-2/ARE, promoted Nrf-2 nuclear translocation by a type I (thiylation) redox switch which was regulated by GSH not by Trx-1. In contrast, the ARE reporter was principally controlled by nuclear-targeted Trx-1 and not by GSH. The data show that the GSH and TRX systems have unique, compartmented functions in the control of transcriptional regulation by Nrf-2/ARE. 10.1093/toxsci/kfh231 IS - 1 JF - Toxicol. Sci. EP - 317 TI - Compartmentation of Nrf-2 Redox Control: Regulation of Cytoplasmic Activation by Glutathione and DNA Binding by Thioredoxin-1 VL - 82 SP - 308 KW - glutathione KW - nrf-2 KW - theioredoxin AU - Hansen, Jason AU - Watson, Walter AU - Jones, Dean PY - 2004/11/01/ UR - http://dx.doi.org/10.1093/toxsci/kfh231 ER -