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KMID : 0620920090410110824
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Experimental & Molecular Medicine
2009 Volume.41 No. 11 p.824 ~ p.831
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Chemical inhibitors destabilize HuR binding to the AU-rich element of TNF-α mRNA
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Chae Min-Ju
Sung Hye-Youn
Kim Eun-Hye
Lee Mi-Ra
Kwak Ho-Joong
Chae Chong-Hak
Kim Sun-Woo
Park Woong-Yang
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Abstract
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Hu protein R (HuR) binds to the AU-rich element (ARE) in the 3’UTR to stabilize TNF-α mRNA. Here, we identified chemical inhibitors of the interaction between HuR and the ARE of TNF-α 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 (IC50) below 10 μM. The IC50 of quercetin, b-40, and b-41 were 1.4, 0.38, and 6.21 μM, respectively, for binding of HuR protein to TNF-α mRNA. Quercetin and b-40 did not inhibit binding of tristetraprolin to the ARE of TNF-α mRNA. When LPS-treated RAW264.7 cells were treated with quercetin and b-40, we observed decreased stability of TNF-α mRNA and decreased levels of secreted TNF-α. From these results, we could find inhibitors for the TNF-α mRNA stability, which might be used advantageously for both the study for post-transcriptional regulation and the discovery of new anti-inflammation drugs.
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KEYWORD
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anti-inflammatory agents, ELAV-like protein 1, lipopolysaccharides, macrophages, quercetin, tumor necrosis factor-α
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