Activation of transcription factor Nrf2 signalling by the sphingosine kinase inhibitor SKI-II is mediated by the formation of Keap1 dimers.
<h4>Background</h4>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 cellul...
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2014
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oai:doaj.org-article:ee0a259b16ce4562b54b96c98ae158ca2021-11-18T08:33:38ZActivation of transcription factor Nrf2 signalling by the sphingosine kinase inhibitor SKI-II is mediated by the formation of Keap1 dimers.1932-620310.1371/journal.pone.0088168https://doaj.org/article/ee0a259b16ce4562b54b96c98ae158ca2014-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24505412/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>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.<h4>Methodology/principal findings</h4>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.<h4>Conclusions/significance</h4>SKI-II appears to be a novel activator of Nrf2 signalling via the inactivation of Keap1.Nicolas MercadoYasuo KizawaKeitaro UedaYeping XiongGenki KimuraAudric MosesJonathan M CurtisKazuhiro ItoPeter J BarnesPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 2, p e88168 (2014) |
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Medicine R Science Q Nicolas Mercado Yasuo Kizawa Keitaro Ueda Yeping Xiong Genki Kimura Audric Moses Jonathan M Curtis Kazuhiro Ito Peter J Barnes Activation of transcription factor Nrf2 signalling by the sphingosine kinase inhibitor SKI-II is mediated by the formation of Keap1 dimers. |
| description |
<h4>Background</h4>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.<h4>Methodology/principal findings</h4>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.<h4>Conclusions/significance</h4>SKI-II appears to be a novel activator of Nrf2 signalling via the inactivation of Keap1. |
| format |
article |
| author |
Nicolas Mercado Yasuo Kizawa Keitaro Ueda Yeping Xiong Genki Kimura Audric Moses Jonathan M Curtis Kazuhiro Ito Peter J Barnes |
| author_facet |
Nicolas Mercado Yasuo Kizawa Keitaro Ueda Yeping Xiong Genki Kimura Audric Moses Jonathan M Curtis Kazuhiro Ito Peter J Barnes |
| author_sort |
Nicolas Mercado |
| title |
Activation of transcription factor Nrf2 signalling by the sphingosine kinase inhibitor SKI-II is mediated by the formation of Keap1 dimers. |
| title_short |
Activation of transcription factor Nrf2 signalling by the sphingosine kinase inhibitor SKI-II is mediated by the formation of Keap1 dimers. |
| title_full |
Activation of transcription factor Nrf2 signalling by the sphingosine kinase inhibitor SKI-II is mediated by the formation of Keap1 dimers. |
| title_fullStr |
Activation of transcription factor Nrf2 signalling by the sphingosine kinase inhibitor SKI-II is mediated by the formation of Keap1 dimers. |
| title_full_unstemmed |
Activation of transcription factor Nrf2 signalling by the sphingosine kinase inhibitor SKI-II is mediated by the formation of Keap1 dimers. |
| title_sort |
activation of transcription factor nrf2 signalling by the sphingosine kinase inhibitor ski-ii is mediated by the formation of keap1 dimers. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2014 |
| url |
https://doaj.org/article/ee0a259b16ce4562b54b96c98ae158ca |
| work_keys_str_mv |
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