期刊
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
卷 138, 期 41, 页码 13630-13638出版社
AMER CHEMICAL SOC
DOI: 10.1021/jacs.6b06965
关键词
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资金
- Creative Research Initiative Grant through the National Research Foundation of Korea (NRF) - Korean Government (Ministry of Science, ICT & Future Planning) [2014R1A3A2030423]
- Bio & Medical Technology Development Program through the National Research Foundation of Korea (NRF) - Korean Government (Ministry of Science, ICT & Future Planning) [2012M3A9C4048780]
- BK21 Plus Program
MicroRNAs (miRNAs) regulate gene expression by targeting protein-coding transcripts that are involved in various cellular processes. Thus, miRNA biogenesis has been recognized as a novel therapeutic target. Especially, the let-7 miRNA family is well-known for its tumor suppressor functions and is downregulated in many cancer cells. Lin28 protein binds to let-7 miRNA precursors to inhibit their maturation. Herein, we developed a FRET-based, high-throughput screening system to identify small-molecule inhibitors of the Lin28 let-7 interaction. We employed unnatural amino acid mutagenesis and bioorthogonal chemistry for the site-specific fluorescent labeling of Lin28, which ensures the robustness and reliability of the FRET-based protein miRNA binding assay. Using this direct binding assay,, we identified an inhibitor of the oncogenic Lin28 let-7 interaction. The inhibitor enhanced the production of let-7 miRNAs in Lin28-expressing cancer cells and reduced the level of let-7 target oncogene products.
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