Protein-RNA interactions in cancer

癌症中蛋白质-RNA 相互作用

基本信息

批准号：
10456887
负责人：
Dinesh S Rao
金额：
$ 59.86万
依托单位：
UNIVERSITY OF CALIFORNIA SANTA CRUZ
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10456887
关键词：
3&apos Splice Site 3&apos Untranslated Regions Acute leukemia Aggressive behavior Alternative Splicing Binding Binding Proteins Binding Sites Biological Assay Biology Cancer Biology Cells Chimeric Proteins Competitive Binding Data Development Diagnostic Disease Equilibrium Etiology Fetal Development Foundations Gene Combinations Gene Expression Gene Expression Regulation Genes Genetic Models Genetic Transcription Hematologic Neoplasms Human Immunoprecipitation In Situ In Vitro Insulin-Like Growth Factor II Investigation Knock-out Knowledge Maintenance Malignant - descriptor Malignant Neoplasms Measurement Mediating Mediator of activation protein Messenger RNA MicroRNAs Modeling Molecular Molecular Biology Mus Mutation Nature Oncogenic Oncology Pathogenesis Play Post-Transcriptional Regulation Production Prognosis Protein Isoforms Proteins Public Health Publishing RNA RNA Splice Sites RNA Splicing RNA Stability RNA-Binding Proteins RNA-Induced Silencing Complex RNA-Protein Interaction Regulation Regulator Genes Reporter Research Resistance Role Signal Transduction Signaling Protein Site Solid Structure Testing Therapeutic Transcript Translating Translations Untranslated RNA Work cancer initiation cancer type cell transformation clinical translation conditional knockout crosslink diagnostic value experimental study genetic approach in vivo insight insulin regulation leukemia mRNA Precursor mRNA Stability migration novel novel diagnostics novel therapeutic intervention overexpression prognostic reverse genetics stem cells targeted treatment therapeutic target therapy resistant transcription factor transcriptomics tumorigenesis

项目摘要

PROJECT SUMMARY/ ABSTRACT Protein-RNA interactions underlie an important and understudied component of gene regulation. RNA-binding proteins carry out numerous functions relating to the production, splicing, processing, and stability of mRNA molecules. A few years ago, we discovered that the oncofetal RNA binding protein, IGF2BP3, binds to the 3’ untranslated region of mRNA and regulates mRNA stability via a mechanism that involves the RNA-induced silencing complex. In more recent work, we found that IGF2BP3 also binds near 3’-splice sites, and may regulate alternative splicing. Together, our findings suggest dual roles in mRNA regulation for IGF2BP3. IGF2BP3 regulates genes that are related to proliferation, migration, and signaling- which are important in fetal development- but also in cancer. Concordant with this gene regulatory function, IGF2BP3 is overexpressed in a wide range of malignancies, including acute leukemia, and portends a poor prognosis when highly expressed. Using novel, murine genetic models of IGF2BP3 deficiency, we have now discovered that IGF2BP3 is required for the development of a fully-penetrant, lethal leukemia in vivo. Together, our extensive prior work, both published and unpublished, provides a mechanistic framework for its function, and a solid foundation for the importance of this protein in disease. To fully understand the nature of these protein-RNA interactions and to understand their role in cancer, we propose two aims. In the first aim, we will carefully delineate the mechanism underlying IGF2BP3 function by a combination of carefully executed experiments (Aim 1). In the second aim, we will characterize the importance of IGF2BP3 in leukemia initiation, propagation and maintenance using a set of carefully constructed genetic models and gene editing in primary cells. Next, we will characterize how the two proposed gene regulatory mechanisms- RNA stability and pre-mRNA splicing- play roles in cancer initiation, using a combination of reverse genetics, miRNA regulation, and isoform specific expression. Together, this work will lead to a layered, detailed understanding of how mechanistic basis of protein-RNA interactions is intimately connected to gene expression deregulation and the malignant transformation of cells. Importantly, it will pave the way to develop novel diagnostic and therapeutic approaches in malignancies characterized by massive transcriptomic dysregulation underpinned by alterations of RNA-binding proteins.

项目摘要/摘要蛋白-RNA相互作用是基因调节的重要且可理解的成分。 RNA结合蛋白质具有与mRNA的生产，剪接，加工和稳定性有关的许多功能分子。几年前，我们发现Oncofetal RNA结合蛋白IGF2BP3与3'结合 mRNA的未翻译区域，并通过涉及RNA诱导的机制调节mRNA稳定性沉默复合物。在最近的工作中，我们发现IGF2BP3也绑在3'Splice网站附近，并且可以调节替代剪接。总之，我们的发现表明在IGF2BP3的mRNA调控中发挥了双重作用。 IGF2BP3调节与增殖，迁移和信号传导相关的基因，这些基因在胎儿中很重要发展 - 但也从事癌症。与该基因调节功能一致，IGF2BP3在A中过表达高度表达时，包括急性白血病在内的广泛恶性肿瘤，预后不良。使用IGF2BP3缺乏症的新型鼠遗传模型，我们现在发现需要IGF2BP3 为了开发体内全渗透剂致死性白血病。一起，我们大量的先前工作已发布和未发表，为其功能提供了机械框架，并为这种蛋白质在疾病中的重要性。充分理解这些蛋白-RNA相互作用的性质和了解它们在癌症中的作用，我们提出了两个目标。在第一个目标中，我们将仔细描述机制通过精心执行的实验的组合（AIM 1），IGF2BP3的基础功能。在第二个目标中我们将描述IGF2BP3在白血病计划中的重要性，使用集合的传播和维护原代细胞中精心构建的遗传模型和基因编辑。接下来，我们将表征两个提出的基因调节机制 - RNA稳定性和MRNA前剪接 - 在癌症开始中起作用，使用反向遗传学，miRNA调节和同工型特异性表达的组合。在一起，这项工作将导致对蛋白-RNA相互作用的机械基础的分层，详细的理解与基因表达失调和细胞的恶性转化有关。重要的是，它将铺路开发新颖的诊断和治疗方法的方式，以大规模为特征由RNA结合蛋白改变的基础转录组失调。