The new LAW of microRNA-mediated gene silencing

microRNA介导的基因沉默的新法则

• 批准号: BB/I007571/1
• 负责人: Tyson Sharp
• 金额: $ 74.11万
• 依托单位: University of Nottingham
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2011
• 资助国家: 英国
• 起止时间: 2011 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FI007571%2F1
• 关键词: new; LAW; microRNA; mediated; gene

MicroRNAs (miRNAs) are a class of small RNAs within all the cells of our body that have recently been found to inhibit gene expression. Their mechanism of action is far reaching and complex; each miRNA may control many genes and it is estimated that miRNAs regulate expression of up to 1/3 of all human genes. Human genes are expressed as proteins via a mRNA intermediate which is a copy of the DNA encoded gene in question. This mRNA then travels from the nucleus to the cytoplasm where the code is 'translated' or made into protein and thus expressed. MicroRNAs operate to inhibit gene expression by one of two hypothesised mechanisms: (1) by pairing with a mRNA- and stopping the mRNA being expressed very early on in its translation into protein, initiation block and (2) pairing with target mRNA - stopping the mRNA being expressed in the middle of its translation into protein therefore halting protein production, post-initiation block. In either case the mRNA is not translated into protein but (repressed) but the mRNA remains intact. MicroRNAs show distinct expression patterns in different organisms, cell development stages, and disease models and play an important role in regulating gene expression. Even though we have learnt a great deal about miRNA biology in recent years we still do not know the precise mechanism(s) of how the cell performs miRNA-mediated gene silencing and furthermore how it decides between the different types of miRNA silencing (initiation or post-initiation block). My research group has identified two distinct groups of proteins, (1) called LIMD1, Ajuba, WTIP (LAW) and (2) called Zyxin, LPP, TRIP6 (ZLT). Which we believe may represent the missing components to enable miRNA-directed gene silencing. Furthermore, these two groups of protein may then help the cell decide which type of miRNA silencing to perform. Employ the LAW group and use initiation block, or the ZLT group and induce a post-initiation block. Our research is aimed at determining these possibilities and therefore new biology which will ultimately impact on improved human and animal health in the long term.

MicroRNA（miRNAs）是我们身体所有细胞中的一类小RNA，最近发现它们抑制基因表达。它们的作用机制是深远和复杂的;每个miRNA可以控制许多基因，估计miRNA调节高达1/3的人类基因的表达。人类基因通过mRNA中间体表达为蛋白质，mRNA中间体是所讨论的DNA编码基因的拷贝。然后，这种mRNA从细胞核转移到细胞质，在细胞质中，编码被“翻译”或制成蛋白质并因此表达。MicroRNA通过两种假设机制之一来抑制基因表达：（1）通过与mRNA配对-并在其翻译成蛋白质的非常早期停止mRNA的表达，起始阻断，以及（2）与靶mRNA配对-在其翻译成蛋白质的中间停止mRNA的表达，因此停止蛋白质的产生，起始后阻断。在这两种情况下，mRNA都不被翻译成蛋白质，而是被抑制，但mRNA保持完整。microRNA在不同的生物体、细胞发育阶段和疾病模型中表现出不同的表达模式，并在调节基因表达方面发挥重要作用。尽管近年来我们已经了解了大量关于miRNA生物学的知识，但我们仍然不知道细胞如何进行miRNA介导的基因沉默的确切机制，以及它如何决定不同类型的miRNA沉默（起始或后起始阻断）。我的研究小组已经确定了两组不同的蛋白质，（1）称为LIMD 1，Ajuba，WTIP（LAW）和（2）称为Zyxin，LPP，TRIP 6（ZLT）。我们认为这可能代表了缺失的成分，使miRNA指导的基因沉默。此外，这两组蛋白质可以帮助细胞决定进行哪种类型的miRNA沉默。采用LAW组和起始阻滞，或ZLT组和诱导起始后阻滞。我们的研究旨在确定这些可能性，从而确定最终将对改善人类和动物健康产生长期影响的新生物学。

项目成果

PU.1 is a major transcriptional activator of the tumour suppressor gene LIMD1.

• DOI: 10.1016/j.febslet.2011.03.013
• 发表时间: 2011-04-06
• 期刊: FEBS letters
• 影响因子: 3.5
• 作者: Foxler DE;James V;Shelton SJ;Vallim TQ;Shaw PE;Sharp TV
• 通讯作者: Sharp TV

CSN1 Somatic Mutations in Penile Squamous Cell Carcinoma.

• DOI: 10.1158/0008-5472.can-15-3134
• 发表时间: 2016-08-15
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Feber A;Worth DC;Chakravarthy A;de Winter P;Shah K;Arya M;Saqib M;Nigam R;Malone PR;Tan WS;Rodney S;Freeman A;Jameson C;Wilson GA;Powles T;Beck S;Fenton T;Sharp TV;Muneer A;Kelly JD
• 通讯作者: Kelly JD

S6K2-mediated regulation of TRBP as a determinant of miRNA expression in human primary lymphatic endothelial cells.

• DOI: 10.1093/nar/gkw631
• 发表时间: 2016-11-16
• 期刊: Nucleic acids research
• 影响因子: 14.9
• 作者: Warner MJ;Bridge KS;Hewitson JP;Hodgkinson MR;Heyam A;Massa BC;Haslam JC;Chatzifrangkeskou M;Evans GJ;Plevin MJ;Sharp TV;Lagos D
• 通讯作者: Lagos D

Suppression of AGO2 by miR-132 as a determinant of miRNA-mediated silencing in human primary endothelial cells.

• DOI: 10.1016/j.biocel.2015.10.006
• 发表时间: 2015-12
• 期刊: The international journal of biochemistry & cell biology
• 作者: Leonov G;Shah K;Yee D;Timmis J;Sharp TV;Lagos D
• 通讯作者: Lagos D

Argonaute Utilization for miRNA Silencing Is Determined by Phosphorylation-Dependent Recruitment of LIM-Domain-Containing Proteins.

• DOI: 10.1016/j.celrep.2017.06.027
• 发表时间: 2017-07-05
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Bridge KS;Shah KM;Li Y;Foxler DE;Wong SCK;Miller DC;Davidson KM;Foster JG;Rose R;Hodgkinson MR;Ribeiro PS;Aboobaker AA;Yashiro K;Wang X;Graves PR;Plevin MJ;Lagos D;Sharp TV
• 通讯作者: Sharp TV