Mechanism of Regulation of mRNA Stability

mRNA稳定性调节机制

• 批准号: 7884916
• 负责人: Jeffrey Wilusz
• 金额: $ 11.03万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-20 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7884916
• 关键词: Address; Area; Binding; Binding Sites; Biological; Biology; Cell Nucleus; Cells; Cellular biology; Complex; Controlled Study; Cytoplasm; DNA Damage; DNA Repair; Data; Defect; Deposition; Disease; Dominant-Negative Mutation; Elements; Enzymes; Eukaryotic Cell; Event; Exhibits; Exons; Gene Expression; Gene Expression Regulation; Genetic Transcription; Goals; Grant; Hela Cells; Human; In Vitro; Laboratories; Length; Link; Malignant Neoplasms; Mediating; Messenger RNA; Molecular; Myotonic Dystrophy; Nuclear; Nuclear Extract; Oncogene Proteins; Pathway interactions; Peptides; Play; Poly A; Poly(A) Tail; Polyadenylation; Post-Transcriptional Regulation; Process; Proteins; Quality Control; RNA; RNA Binding; RNA Splicing; RNA-Protein Interaction; Reagent; Regulation; Regulatory Element; Role; Series; Therapeutic; Transcript; Translations; Work; base; cell growth; combinatorial; crosslink; design; improved; in vitro Assay; in vivo; insight; mRNA Decay; mRNA Export; mRNA Stability; mRNA Surveillance; messenger ribonucleoprotein; mutant; novel; nucleophosmin; research study; response

DESCRIPTION (provided by applicant): Our overall goal is to elucidate the pathways and mechanisms involved in regulated mRNA stability and post-transcriptional control in general. These processes play a very important role in controlling gene expression related to cell growth and differentiation. Our approach is three-fold. First, we will expand our studies on nucleophosmin, a protein that is deposited on mRNAs as a novel polyadenylation mark, and determine its role in the coordination of gene expression. This work will involve the identification of auxiliary proteins involved in the polyadenylation mark, a determination of the requirements and mechanism of nucleophosmin deposition, the delineation of mRNA targets and a determination of the function(s) of nucleophosmin in post-transcriptional control. Second, we will perform a series of in vivo and in vitro assays to elucidate the full impact of CUG-BP, a regulator of poly(A) tail shortening in human cells, along with its target deadenylase enzyme PARN on the control of gene expression via the modulation of mRNA stability. Finally, we have identified a novel function of for a cytoplasmic Lsm complex in mRNA stability. The goal of the third aim of this proposal is to determine the underlying mechanism for Lsm-mediated stabilization of targeted mRNAs. In summary, these studies should provide new insights into the mechanisms and regulation of mRNA stability as well as post-transcriptional control in general. Given the impact of RNA biology on cellular growth control, these studies may well provide significant insights into the molecular basis of disease (e.g. cancer, myotonic dystrophy) and possibly improved strategies for molecular therapeutics.

描述（由申请人提供）：我们的总体目标是阐明参与调节 mRNA 稳定性和转录后控制的途径和机制。这些过程在控制与细胞生长和分化相关的基因表达方面发挥着非常重要的作用。我们的方法有三个方面。首先，我们将扩大对核磷蛋白的研究，核磷蛋白是一种 蛋白质沉积在 mRNA 上作为新型多聚腺苷酸化标记，并确定其在协调基因表达中的作用。这项工作将涉及多腺苷酸化标记中涉及的辅助蛋白的鉴定、核磷蛋白沉积的要求和机制的确定、mRNA靶标的描绘以及核磷蛋白在转录后控制中的功能的确定。其次，我们将进行一系列体内和体外测定，以阐明 CUG-BP（人类细胞中聚腺苷酸尾缩短的调节剂）及其靶去腺苷酸酶 PARN 通过调节 mRNA 稳定性对基因表达控制的全面影响。最后，我们发现了细胞质 Lsm 复合物在 mRNA 稳定性方面的新功能。该提案的第三个目标是确定 Lsm 介导的目标 mRNA 稳定的潜在机制。总之，这些研究应该为 mRNA 稳定性的机制和调节以及转录后控制提供新的见解。鉴于RNA生物学对细胞生长控制的影响，这些研究很可能为疾病（例如癌症、强直性肌营养不良）的分子基础提供重要的见解，并可能改进分子治疗策略。