Investigation of the translational regulation of terminal oligo pyrimidine (TOP) containing mRNAs

含末端寡嘧啶 (TOP) mRNA 的翻译调控研究

• 批准号: BB/H024980/1
• 负责人: Anne Willis
• 金额: $ 77.14万
• 依托单位: MRC Toxicology Unit
• 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%2FH024980%2F1
• 关键词: Investigation; translational; regulation; terminal; oligo

Our bodies' cells are built from a diverse set of building blocks called proteins. All proteins can be made by translating specific pieces of the DNA genetic code. An intermediate material called mRNA is used between DNA and proteins; it presents the parts of the genetic code for proteins needed at a particular time and place to the machinery that translates it into proteins. The 'molecular factory' that translates mRNA into proteins is called the ribosome, made itself of a mixture of about 80 RNAs and proteins. Without ribosomes, no proteins could ever be made. When our cells grow and divide, the number of each of the component parts of ribosomes also has to double so that enough proteins can continue to be made. Incorrect proportions of component parts of the ribosome can cause cells not to grow enough, or to grow too much, and so imbalances can lead to diseases such as cancer. The many proteins whose job is to work as part the ribosome have a unique 'tag' (called a TOP or terminal oligopyrimidine tract) in the mRNA that encodes them. All mRNAs with this tag have their translation closely co-ordinated by existing ribosomes so that their proteins are made at the same time and rate. While we know about the existence of the tag, we do not fully understand how it is recognized and used to control new ribosome manufacture. Our lab has done initial experiments which reveal a unique suite of proteins that bind to the tag. In this application we propose to study exactly how these proteins interact with the tag, and with each other, to co-ordinate ribosome manufacture so accurately. Our results could help us to understand how cancers develop when this goes wrong, and, in the longer term, could provide new ways to tackle this disease.

我们身体的细胞是由一组不同的称为蛋白质的构建模块组成的。所有蛋白质都可以通过翻译DNA遗传密码的特定片段来制造。在DNA和蛋白质之间使用一种称为mRNA的中间物质;它将特定时间和地点所需的蛋白质遗传密码的部分呈现给将其翻译成蛋白质的机器。将mRNA翻译成蛋白质的“分子工厂”被称为核糖体，由大约80种RNA和蛋白质的混合物组成。没有核糖体，蛋白质就不可能产生。当我们的细胞生长和分裂时，核糖体的每个组成部分的数量也必须加倍，以便能够继续制造足够的蛋白质。核糖体组成部分的不正确比例会导致细胞生长不足或生长过多，因此不平衡可能导致癌症等疾病。许多蛋白质的工作是作为核糖体的一部分，在编码它们的mRNA中有一个独特的“标签”（称为TOP或末端寡嘧啶段）。所有带有这个标签的mRNA的翻译都与现有的核糖体密切协调，因此它们的蛋白质在同一时间以相同的速度合成。虽然我们知道标签的存在，但我们并不完全了解它是如何被识别并用于控制新的核糖体制造的。我们的实验室已经做了初步实验，揭示了一套独特的蛋白质与标签结合。在这个应用程序中，我们建议确切地研究这些蛋白质如何与标签相互作用，以及相互作用，以准确地协调核糖体制造。我们的研究结果可以帮助我们了解当这种情况出现问题时癌症是如何发展的，并且从长远来看，可以提供解决这种疾病的新方法。

项目成果

Trans-acting translational regulatory RNA binding proteins.

• DOI: 10.1002/wrna.1465
• 发表时间: 2018-05
• 期刊: Wiley interdisciplinary reviews. RNA
• 作者: Harvey RF;Smith TS;Mulroney T;Queiroz RML;Pizzinga M;Dezi V;Villenueva E;Ramakrishna M;Lilley KS;Willis AE
• 通讯作者: Willis AE

Till stress do us ataRT: a novel toxin-antitoxin system targeting translation initiation.

直到压力降临 ataRT：一种针对翻译起始的新型毒素-抗毒素系统。

• DOI: 10.1038/cdd.2017.66
• 发表时间: 2017
• 期刊: Cell death and differentiation
• 影响因子: 12.4
• 作者: Pizzinga M

mTORC1-mediated translational elongation limits intestinal tumour initiation and growth.

• DOI: 10.1038/nature13896
• 发表时间: 2015-01-22
• 期刊: NATURE
• 影响因子: 64.8
• 作者: Faller, William J.;Jackson, Thomas J.;Knight, John R. P.;Ridgway, Rachel A.;Jamieson, Thomas;Karim, Saadia A.;Jones, Carolyn;Radulescu, Sorina;Huels, David J.;Myant, Kevin B.;Dudek, Kate M.;Casey, Helen A.;Scopelliti, Alessandro;Cordero, Julia B.;Vidal, Marcos;Pende, Mario;Ryazanov, Alexey G.;Sonenberg, Nahum;Meyuhas, Oded;Hall, Michael N.;Bushell, Martin;Willis, Anne E.;Sansom, Owen J.
• 通讯作者: Sansom, Owen J.

Cap-Independent Translation in Hematological Malignancies.

• DOI: 10.3389/fonc.2015.00293
• 发表时间: 2015
• 期刊: Frontiers in oncology
• 影响因子: 4.7
• 作者: Horvilleur E;Wilson LA;Bastide A;Piñeiro D;Pöyry TA;Willis AE
• 通讯作者: Willis AE

LARP1 post-transcriptionally regulates mTOR and contributes to cancer progression.

LARP1转录后调节MTOR并有助于癌症的进展。

• DOI: 10.1038/onc.2014.428
• 发表时间: 2015-09-24
• 期刊: Oncogene
• 影响因子: 8