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성낙균,김혜민,Yukihiro Asami,김동현,조양래,Ravi Naik,장예린,장구식,한호진,Srinivas Rao Ganipisetti,차현주,황준성,이경호,고성균,장재혁,류인자,권용태,이경상,Hiroyuki Osada,이경,김보연,안종석 생화학분자생물학회 2019 Experimental and molecular medicine Vol.51 No.-
Hypoxia-inducible factor-1α (HIF-1α) mediates tumor cell adaptation to hypoxic conditions and is a potentially important anticancer therapeutic target. We previously developed a method for synthesizing a benzofuran-based natural product, (R)-(-)-moracin-O, and obtained a novel potent analog, MO-460 that suppresses the accumulation of HIF-1α in Hep3B cells. However, the molecular target and underlying mechanism of action of MO-460 remained unclear. In the current study, we identified heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1) as a molecular target of MO-460. MO-460 inhibits the initiation of HIF-1α translation by binding to the C-terminal glycinerich domain of hnRNPA2B1 and inhibiting its subsequent binding to the 3’-untranslated region of HIF-1α mRNA. Moreover, MO-460 suppresses HIF-1α protein synthesis under hypoxic conditions and induces the accumulation of stress granules. The data provided here suggest that hnRNPA2B1 serves as a crucial molecular target in hypoxiainduced tumor survival and thus offer an avenue for the development of novel anticancer therapies.