The Role of Truncated mRNAs in Cancer

截短的 mRNA 在癌症中的作用

• 批准号: 9027407
• 负责人: Jeongsik Yong
• 金额: $ 29.15万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-17 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9027407
• 关键词: Amino Acid Sequence; Biological; Biological Assay; Biological Markers; Biology; Breast Cancer Patient; Breast Cancer cell line; C-terminal; Cancer Biology; Cancer Patient; Cancer cell line; Cataloging; Catalogs; Catalytic Domain; Cell Proliferation; Cell physiology; Cells; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Computer Simulation; Custom; DNA; Data; Data Set; Databases; Development; Diagnostic Neoplasm Staging; Disease; Elements; Embryo; Employee Strikes; Event; Exons; Fibroblasts; Gene Expression; Gene Expression Profile; Genes; Genetic Transcription; Genome; Goals; Growth; Introns; Knock-out; Length; Libraries; Malignant Neoplasms; Mediating; Messenger RNA; Metabolic Diseases; Molecular; Molecular Profiling; Mus; Mutation; Normal Cell; One-Step dentin bonding system; Outcome; Pathogenesis; Pathway interactions; Peptide Sequence Determination; Polyadenylation; Polyribosomes; Procedures; Process; Production; Proliferating; Protein Biosynthesis; Protein C; Protein Isoforms; Protein Truncation; Proteins; Proteome; Proteomics; RNA; RNA Processing; RNA Splicing; RNA chemical synthesis; Reporter; Research; Resolution; Role; Series; Signal Transduction; Site; Small Interfering RNA; System; Technology; The Cancer Genome Atlas; Transcript; Translating; anticancer research; base; cancer cell; cancer initiation; carcinogenesis; clinically relevant; data mining; design; gain of function; genetic regulatory protein; genome editing; genome-wide; human disease; in vivo; inhibitor/antagonist; mTOR protein; malignant breast neoplasm; next generation sequencing; novel; outcome forecast; protein aminoacid sequence; public health relevance; research study; screening; transcriptome sequencing; tumor

 DESCRIPTION (provided by applicant): Most, if not all, cancer cells proliferate much faster than normal cells. Thus, studying how cancer cells proliferate faster than normal cells is a key in understanding cancer biology. The mammalian target of rapamycin (mTOR) pathway is a cellular pathway that controls cell proliferation and this pathway is commonly dysregulated in many cancers. Therefore, understanding the role of mTOR pathway in cell proliferation is important. When cells are activated to proliferate, the first thing they do is producing a lot of proteins. To make more proteins in cells, they need to make more messenger RNAs (mRNAs) from DNA. The whole procedure is called gene expression and mRNA is a key molecule in this procedure. Thus, the questions of how mRNAs are made and how they are regulated in cancer mechanisms are important questions to ask to understand cancer at a molecular level. Generally, mRNA undergoes very complicated process to make it competent for protein synthesis in cells. Recently, we discovered a pervasive production of truncated mRNAs when mTOR is activated in cells. The truncated mRNAs are produced by dysregulation of one of the steps during mRNA synthesis in cells. The cellular consequence of this phenomenon is the production of truncated proteins. Usually, fundamental elements of many proteins are consisted of catalytically active domains and regulatory domains. The active domain represents the function of a protein and the regulatory domain is a platform for fine-tuning of the protein activiy regulated by other cellular proteins. Interestingly, many truncated proteins produced by mTOR activation were lacking the regulatory or catalytic domain. This suggests that mTOR activation produces many deregulated "super isoform" proteins by truncation and this could be a driver to fast cell proliferation and cancer initiation at a molecular level. Based on this, we hypothesize that the same phenomena happen when cancer cells are activated to proliferate by mTOR. We searched cancer databases and found numerous candidate mRNAs for truncation in cancer, which was not recognized previously. Our goals in this proposal are to find them and understand their function in cancer cell proliferation using a series of experiments employing high profiling technologies including next generation sequencing and multi-dimensional LC-MS/MS. More importantly, we will narrow down the list of cancer-specific truncated mRNAs and finalize the critical truncated mRNAs by validating their existence in cancer patient database. The identified cancer-specific truncated mRNAs will be new targets in cancer research and provide novel platforms for the development of multiple biomarkers at both protein and RNA levels.

 描述(申请人提供)：大多数，如果不是全部，癌细胞的增殖速度比正常细胞快得多。因此，研究癌细胞如何比正常细胞更快地增殖是 了解癌症生物学。哺乳动物靶向雷帕霉素(MTOR)途径是一种控制细胞增殖的细胞途径，在许多癌症中普遍存在调节失调。因此，了解mTOR通路在细胞增殖中的作用具有重要意义。当细胞被激活增殖时，它们所做的第一件事就是产生大量蛋白质。为了在细胞中制造更多的蛋白质，他们需要从DNA中制造更多的信使RNA(MRNAs)。整个过程被称为基因表达，而mRNA是这一过程中的关键分子。因此，如何制造mRNAs以及它们如何在癌症机制中受到调控的问题，是在分子水平上理解癌症的重要问题。一般来说，信使核糖核酸要经历非常复杂的过程才能在细胞内合成蛋白质。最近，我们发现当mTOR在细胞中被激活时，普遍会产生截短的mRNAs。截短的mRNAs是由于细胞中的mRNA合成过程中的一个步骤的失调而产生的。这种现象的细胞后果是产生截短的蛋白质。通常，许多蛋白质的基本元件由催化活性结构域和调控结构域组成。活性结构域代表蛋白质的功能，而调节域是微调受其他细胞蛋白调控的蛋白质活性的平台。有趣的是，许多由mTOR激活产生的截短蛋白缺乏调节或催化结构域。这表明mTOR的激活通过截断产生了许多非调控的“超级异构体”蛋白质，这可能是在分子水平上促进细胞快速增殖和癌症发生的驱动因素。基于此，我们假设当癌细胞被mTOR激活增殖时，同样的现象也会发生。我们搜索了癌症数据库，发现了大量用于癌症截断的候选mRNAs，这是以前没有认识到的。我们在这项建议中的目标是通过一系列实验来发现它们并了解它们在癌细胞增殖中的作用，这些实验采用了高轮廓技术，包括下一代测序和多维LC-MS/MS。更重要的是，我们将缩小癌症特异性截短mRNAs的列表，并通过验证它们在癌症患者数据库中的存在来最终确定关键截短mRNAs。识别的癌症特异性截短的mRNAs将成为癌症研究的新靶点，并为在蛋白质和RNA水平上开发多种生物标记物提供新的平台。