Exp Mol Med.
2009 Nov;41(11):824-831. 10.3858/emm.2009.41.11.088.
Chemical inhibitors destabilize HuR binding to the AU-rich element of TNF-alpha mRNA
- Affiliations
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- 1Department of Biomedical Sciences, Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul 110-799, Korea. wypark@snu.ac.kr
- 2Department of Genomics Core Laboratory, Seoul National University College of Medicine, Seoul 110-799, Korea.
- 3Genomic Medicine Institute, MRC, Seoul National University College of Medicine, Seoul 110-799, Korea.
- 4Korea Chemical Bank, Korea Research Institute of Chemical Technologies, Daejeon 305-600, Korea.
- KMID: 1122283
- DOI: http://doi.org/10.3858/emm.2009.41.11.088
Abstract
- Hu protein R (HuR) binds to the AU-rich element (ARE) in the 3'UTR to stabilize TNF-alpha mRNA. Here, we identified chemical inhibitors of the interaction between HuR and the ARE of TNF-alpha mRNA using RNA electrophoretic mobility gel shift assay (EMSA) and filter binding assay. Of 179 chemicals screened, we identified three with a half-maximal inhibitory concentration (IC(50)) below 10 micrometer. The IC(50) of quercetin, b-40, and b-41 were 1.4, 0.38, and 6.21 micrometer, respectively, for binding of HuR protein to TNF-alpha mRNA. Quercetin and b-40 did not inhibit binding of tristetraprolin to the ARE of TNF-alpha mRNA. When LPS-treated RAW264.7 cells were treated with quercetin and b-40, we observed decreased stability of TNF-alpha mRNA and decreased levels of secreted TNF-alpha. From these results, we could find inhibitors for the TNF-alpha mRNA stability, which might be used advantageously for both the study for post-transcriptional regulation and the discovery of new anti-inflammation drugs.
Keyword
MeSH Terms
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*3' Untranslated Regions
Animals
Anti-Inflammatory Agents/*pharmacology
Antigens, Surface/metabolism
Antioxidants/pharmacology
Cell Line
Dose-Response Relationship, Drug
Drug Evaluation, Preclinical
Mice
Protein Binding/drug effects
Quercetin/*pharmacology
RNA Stability/*drug effects
RNA-Binding Proteins/*antagonists & inhibitors/metabolism
Tumor Necrosis Factor-alpha/*biosynthesis
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