Kim Hyeon Ho, Kuwano Yuki, Srikantan Subramanya, Lee Eun Kyung, Martindale Jennifer L, Gorospe Myriam
Laboratory of Cellular and Molecular Biology, National Institute on Aging-Intramural Research Program, National Institutes of Health, Baltimore, Maryland 21224, USA.
Genes Dev. 2009 Aug 1;23(15):1743-8. doi: 10.1101/gad.1812509. Epub 2009 Jul 2.
RNA-binding proteins (RBPs) and microRNAs (miRNAs) are potent post-transcriptional regulators of gene expression. Here, we show that the RBP HuR reduced c-Myc expression by associating with the c-Myc 3' untranslated region (UTR) next to a miRNA let-7-binding site. Lowering HuR or let-7 levels relieved the translational repression of c-Myc. Unexpectedly, HuR and let-7 repressed c-Myc through an interdependent mechanism, as let-7 required HuR to reduce c-Myc expression and HuR required let-7 to inhibit c-Myc expression. Our findings suggest a regulatory paradigm wherein HuR inhibits c-Myc expression by recruiting let-7-loaded RISC (RNA miRNA-induced silencing complex) to the c-Myc 3'UTR.
RNA结合蛋白(RBPs)和微小RNA(miRNAs)是基因表达强有力的转录后调节因子。在此,我们表明RBP HuR通过与紧邻miRNA let-7结合位点的c-Myc 3'非翻译区(UTR)结合来降低c-Myc的表达。降低HuR或let-7的水平可解除对c-Myc的翻译抑制。出乎意料的是,HuR和let-7通过相互依赖的机制抑制c-Myc,因为let-7需要HuR来降低c-Myc的表达,而HuR需要let-7来抑制c-Myc的表达。我们的研究结果提示了一种调节模式,即HuR通过将装载有let-7的RNA诱导沉默复合体(RISC)募集到c-Myc 3'UTR来抑制c-Myc的表达。