期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2009
卷号：106
期号：34
页码：14547-14551
DOI：10.1073/pnas.0907539106
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：The transcription factor NF-E2-related nuclear factor 2 (Nrf2) regulates expression of genes that protect cells from oxidative damage. Here, we characterized nitric oxide ([bullet]NO)-induced Nrf2-Kelch-like ECH-associated protein 1 (Keap1) signaling and its role in counteracting [bullet]NO-induced apoptosis of human colon cancer HCT116 cells. Nrf2 was localized in the cytoplasm in control cells; [bullet]NO triggered its rapid nuclear accumulation, transcriptional activation, and up-regulation of HO-1, NQO1, and GCL, but not GST A4 and P1 subunits. Nrf2 accumulation in the nucleus was also associated with enhanced transcription and posttranscriptional modifications. (S)-nitrosation of Keap1 may contribute to nuclear accumulation of Nrf2 by facilitating its dissociation from Keap1, thus initiating [bullet]NO-mediated Nrf2-Keap1 signaling. [bullet]NO-mediated induction of ARE-dependent genes occurred well before apoptosis, as judged by caspase 3 activation. Collectively, these results show that the Nrf2-Keap1 signaling pathway mediates protective cellular responses to mitigate [bullet]NO-induced damage and may contribute to the relative resistance of HCT116 to [bullet]NO-induced cytotoxicity.
关键词：inflammation ; oxidative stress ; reactive nitrogen species ; ( S )-nitrosation
