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Molecules 2012, 17(10), 12365-12377; doi:10.3390/molecules171012365
Article

Phenylmethimazole Blocks dsRNA-Induced IRF3 Nuclear Translocation and Homodimerization

1, 1,2, 3,4, 1,3,5 and 1,3,5,6,7,*
1 Department of Specialty Medicine, Ohio University, Athens, OH 45701, USA 2 Interthyr Corporation, Athens, OH 45701, USA 3 Biomedical Engineering Program, Ohio University Russ College of Engineering & Technology, Ohio University, Athens, OH 45701, USA 4 Department of Chemical and Biomolecular Engineering, Ohio University Russ College of Engineering & Technology, Ohio University, Athens, OH 45701, USA 5 Diabetes Institute, Ohio University College of Osteopathic Medicine, Ohio University, Athens, OH 45701, USA 6 Department of Biological Sciences, Ohio University College of Arts & Sciences, Ohio University, Athens, OH 45701, USA 7 Molecular & Cellular Biology Program, Ohio University College of Arts & Sciences, Ohio University, Athens, OH 45701, USA
* Author to whom correspondence should be addressed.
Received: 5 October 2012 / Revised: 16 October 2012 / Accepted: 19 October 2012 / Published: 22 October 2012
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Abstract

Previous studies revealed that phenylmethimazole (C10) inhibits IRF3 signaling, preventing dsRNA-induction of type 1 interferon gene expression, production, and downstream signaling. In the present study, we investigated the molecular basis for C10 inhibition of dsRNA-stimulated IRF3 signaling. IRF-3 Trans-AM assays were used to measure C10 effects on dsRNA induction of IRF3 DNA binding. Green fluorescent protein-labeled IRF3 was used to measure C10 effects on dsRNA-induced IRF3 nuclear translocation. Native PAGE, SDS PAGE, and western blotting were used to identify effects of C10 on IRF3 homodimer formation and phosphorylation, respectively. There was a significant impairment of dsRNA-induced IRF3 DNA binding activity in human embryonic kidney and pancreatic cancer cells with C10 treatment. C10 also blocked dsRNA-induced IRF3 nuclear translocation and homodimer formation without blocking serine 396 phosphorylation of IRF3. Together, these results indicate that C10 interferes with IRF3 signaling by blocking dsRNA-induced IRF3 homodimer formation, a prerequisite for nuclear translocation and DNA binding activities.
Keywords: phenylmethimazole (C10); IRF3 phenylmethimazole (C10); IRF3
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Courreges, M.C.; Kantake, N.; Goetz, D.J.; Schwartz, F.L.; McCall, K.D. Phenylmethimazole Blocks dsRNA-Induced IRF3 Nuclear Translocation and Homodimerization. Molecules 2012, 17, 12365-12377.

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