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Nitric oxide activates Nrf2 through S-nitrosylation of Keap1 in PC12 cells

Cited 89 time in Web of Science Cited 87 time in Scopus
Authors
Um, Han-Cheon; Jang, Jung-Hee; Kim, Do-Hee; Lee, Chan; Surh, Young-Joon
Issue Date
2011-08
Citation
Nitric Oxide - Biology and Chemistry, Vol.25 No.2, pp.161-168
Keywords
Nrf2Keap1Nitric oxideNitrosative stressNitrosylationPC12 cells
Abstract
Nitric oxide (NO) exerts bifunctional effects on cell survival. While a high concentration of NO is cytotoxic, a relatively low concentration of NO promotes cytoprotection and cell survival. However, the molecular mechanism underlying the cytoprotective effect of NO remains poorly understood. One of the transcription factors that confer cellular protection against oxidative stress is NF-E2-related factor 2 (Nrf2), which is sequestered in the cytoplasm by forming an inactive complex with Klech-like ECH-associated protein 1 (Keap1). Previous studies suggested that various stimuli could induce the dissociation of Nrf2 from Keap1 in cytosol and/or promote its nuclear translocation by activating several upstream kinases. NO-mediated thiol modification in Keap1 has also been proposed as a possible mechanism of Nrf2 activation. Since NO can modify the function or activity of target proteins through S-nitrosylation of cysteine, we attempted to investigate whether the cytoprotective effect of NO is mediated through Nrf2 activation by directly modifying cysteine residues of Keap1. Our present study reveals that treatment of rat pheochromocytoma (PC12) cells with an NO donor S-nitroso-N-acetylpenicillamine (SNAP) induced nuclear translocation and DNA binding of Nrf2. Under the same experimental conditions, there was NO-mediated S-nitrosylation of Keap1 observed, which coincided with the Nrf2 activation. Moreover. SNAP treatment caused phosphorylation of Nrf2, and pharmacological inhibition of protein kinase C (PKC) abolished the phosphorylation and nuclear localization of Nrf2. In conclusion, NO can activate Nrf2 by S-nitrosylation of Keap1 and alternatively by PKC-catalyzed phosphorylation of Nrf2 in PC12 cells. (C) 2011 Elsevier Inc. All rights reserved.
ISSN
1089-8603
URI
https://hdl.handle.net/10371/172876
DOI
https://doi.org/10.1016/j.niox.2011.06.001
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Graduate School of Convergence Science and Technology (융합과학기술대학원)Dept. of Molecular and Biopharmaceutical Sciences (분자의학 및 바이오제약학과)Journal Papers (저널논문_분자의학 및 바이오제약학과)
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