MicroRNA/protein interactions in the regulation of gene expression

基因表达是利用基因信息合成功能性基因产物（蛋白质或RNA）的过程。基因表达的调控是一系列现象的集合，通过这些现象，遗传密码被解释为产生细胞、器官和生物体的特性。最近的几项发现使人们认为RNA是基因表达的主要调节器。将RNA与基因调控联系起来的最重要的发现之一是RNA干扰，梅洛和菲尔因此获得了2006年诺贝尔医学奖。RNA干扰涉及被称为microrna （mirna）的小非编码RNA，它们构成了多细胞生物中最大的基因调控分子家族之一。众所周知，哺乳动物mirna主要靶向来自发育基因的mrna，并且它们的失调与各种疾病，特别是几种形式的癌症有关。然而，涉及mirna的调控网络及其在癌症发展中的作用才刚刚开始被理解。最近的研究表明，一些mirna的前体形式被蛋白质特异性识别，从而调节mirna依赖的基因表达。我们的研究计划的长期目标是功能和结构表征特异性蛋白质/ miRNA相互作用如何调节miRNA依赖的细胞过程。在这些与细胞分化和癌症相关的mirna中，来自let 7家族的mirna被研究得最彻底。先前的研究表明，let-7g的生物发生在转录后受到控制，并且Lin28蛋白通过与let-7g未成熟形式的miRNA直接相互作用负责这种调节。我们的短期目标是表征涉及Lin28蛋白和let 7g miRNA的特定相互作用。我们对Lin28 / pre-let-7g复合物的结构和功能研究将为我们了解miRNA的生物发生和活性提供关键和及时的见解。鉴于let-7 miRNA在肿瘤抑制中的作用，我们的研究也可以促进新型癌症治疗方法的开发。

Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product, either a protein or an RNA. The regulation of gene expression is an ensemble of phenomena by which the genetic code is interpreted to give rise to the properties of cells, organs and organisms. Several recent discoveries have led to the idea that RNA is a master regulator of gene expression. One of the most important discoveries linking RNA to gene regulation was that of RNA interference, for which Mello and Fire were awarded the 2006 Nobel Prize in Medicine. RNA interference involves small non-coding RNAs called microRNAs (miRNAs) that constitute one of the largest families of transacting gene regulatory molecules in multi-cellular organisms. It is well known that mammalian miRNAs largerly target mRNAs from developmental genes and that their misregulation is linked to various diseases, in particular several forms of cancers. However, the regulatory networks involving miRNAs and their role in cancer development are only starting to be understood. Recent studies demonstrate that the precursor forms of some miRNAs are specifically recognized by proteins to enable regulation of miRNA-dependent gene expression. The long-term objective of our research program is to functionally and structurally characterize how specific protein / miRNA interactions regulate miRNA-dependent cellular processes. Among those miRNAs that have been associated with cellular differentiation and cancer, miRNAs from the let 7 family have been the most thoroughly investigated. Previous studies have demonstrated that the let-7g biogenesis is controlled post-transcriptionally and that the Lin28 protein is responsible for this regulation through direct interactions with the immature forms of the let 7g miRNA. Our short-term goal is to characterize specific interactions involving the Lin28 protein and the let 7g miRNA. Our structural and functional studies of the Lin28 / pre-let-7g complex will provide critical and timely insights to our understanding of miRNA biogenesis and activity. Given the role of the let-7 miRNA in tumor suppression, our studies could also enable the development of novel cancer therapeutics.