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Permanent link (DOI): https://doi.org/10.7939/R3445HS0W

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Activation of transcription factor Nrf2 signalling by the sphingosine kinase inhibitor SKI-II is mediated by the formation of Keap1 dimers Open Access

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Author or creator
Mercado, Nicolas
Kizawa, Yasuo
Ueda, Keitaro
Xiong, Yeping
Kimura, Genki
Moses, Audric
Curtis, Jonathan M.
Ito, Kazuhiro
Barnes, Peter J.
Additional contributors
Subject/Keyword
Dimers (Chemical Physics)
Chronic Obstructive Pulmonary Disease
Oxidative Stress
Immunoblotting
Sphingolipids
Kinase Inhibitors
Antioxidants
Smoking Habits
Type of item
Journal Article (Published)
Language
English
Place
Time
Description
Anti-oxidant capacity is crucial defence against environmental or endogenous oxidative stress. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a redox-sensitive transcription factor that plays a key defensive role against oxidative and cytotoxic stress and cellular senescence. However, Nrf2 signalling is impaired in several aging-related diseases, such as chronic pulmonary obstructive disease (COPD), cancer, and neurodegenerative diseases. Thus, novel therapeutics that enhance Nrf2 signalling are an attractive approach to treat these diseases. Methodology/Principal Findings Nrf2 was stabilized by SKI-II (2-(p-hydroxyanilino)-4-(p-chlorophenyl) thiazole), which is a known sphingosine kinase inhibitor, in human bronchial epithelial cell line, BEAS2B, and in primary human bronchial epithelial cells, leading to enhancement of anti-oxidant proteins, such as HO-1, NQO1 and GCLM. The activation of Nrf2 was achieved by the generation of inactive dimerized form of Keap1, a negative regulator of Nrf2 expression, which was independent of sphingosine kinase inhibition. Using mice that were exposed to cigarette smoke, SKI-II induced Nrf2 expression together with HO-1 in their lungs. In addition, SKI-II reduced cigarette smoke mediated oxidative stress, macrophages and neutrophil infiltration and markers of inflammation in mice. Conclusions/Significance SKI-II appears to be a novel activator of Nrf2 signalling via the inactivation of Keap1.
Date created
2014
DOI
doi:10.7939/R3445HS0W
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Attribution 4.0 International
Citation for previous publication
Mercado, N., Kizawa, Y., Ueda, K., Xiong, Y., Kimura, G., Moses, A., Curtis, J., Ito, K., & Barnes, P. (2014). Activation of transcription factor Nrf2 signalling by the sphingosine kinase inhibitor SKI-II is mediated by the formation of Keap1 dimers. PLoS ONE, 9(2), e88168 [11 pages].  http://dx.doi.org/10.1371/journal.pone.0088168

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