Regulation and functional effects of localized RNAs

局部RNA的调控和功能效应

• 批准号: 8763571
• 负责人: Stavroula Mili
• 金额: $ 92.46万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8763571
• 关键词: Address; Adenomatous Polyposis Coli; Affect; Amyotrophic Lateral Sclerosis; Area; Biochemical; Biological Assay; Cell Culture System; Cells; Colorectal Cancer; Complex; Cytoplasm; Cytoplasmic Granules; Destinations; Disease; Event; Goals; Link; Malignant Neoplasms; Methods; Microscopy; Mutation; Neurodegenerative Disorders; Pathway interactions; Process; Production; Property; Proteins; RNA; RNA-Binding Proteins; Regulation; Ribonucleoproteins; Site; Translating; Translations; Tumor Suppressor Proteins; base; mutant; novel; tumor progression

A large number of RNAs are not diffusely distributed in the cytoplasm, but are actively transported to various subcellular sites. After reaching their final destinations, localized RNAs are translated thus directing local protein production. While increasing numbers of localized RNA are being identified, the functional importance of these events is not well understood. We are focusing on a localization pathway that we have identified, which targets a number of RNAs to the tips of cellular protrusions. We have found that an important component of this pathway is the tumor-suppressor protein Adenomatous Polyposis Coli (APC) whose mutation is the initiating event in the progression of the majority of colorectal cancers. APC associates with RNAs at cellular protrusions in ribonucleoprotein complexes, which we term APC-RNPs. An additional component of APC-RNPs is the RNA-binding protein Fus/TLS, a protein whose mutation has been linked to both cancer and Amyotrophic Lateral Sclerosis. We have recently shown that ALS-associated mutants of Fus mislocalize APC-RNPs in internal cytoplasmic granules and misdirect their translation. We are using methods to isolate locally synthesized proteins and determine how RNA mislocalization and misdirection of translation affects protein properties and function. We are additionally addressing how these localized RNAs are affected and to what extent they contribute to colorectal cancer progression.

大量RNA并未扩散地分布在细胞质中，而是积极运输到各种亚细胞位点。到达最终目的地后，局部RNA被翻译，从而指导局部蛋白质产生。虽然识别出局部RNA数量的增加，但这些事件的功能重要性尚不清楚。我们专注于已确定的定位途径，该途径将许多RNA靶向细胞突起的尖端。我们发现，该途径的重要组成部分是肿瘤 -​​ 抑制蛋白腺瘤性息肉大肠杆菌（APC），其突变是大多数结直肠癌进展的起始事件。 APC与核糖核蛋白复合物中细胞突起的RNA相关联，我们称其为APC-RNP。 APC-RNP的另一个组成部分是RNA结合蛋白FUS/TLS，一种蛋白质的突变与癌症和肌萎缩性侧面硬化症都相关。我们最近表明，与ALS相关的FUS突变体错误地定位了内部细胞质颗粒中的APC-RNP，并误导了它们的翻译。我们正在使用方法来分离局部合成的蛋白质，并确定RNA错误定位和翻译错误如何影响蛋白质的性能和功能。我们还解决了这些局部RNA如何影响以及它们在多大程度上促进结直肠癌的进展。