The role of Arf tumor suppressor in translational reprogramming

Arf肿瘤抑制因子在翻译重编程中的作用

• 批准号: 9894641
• 负责人: Kyle Cottrell
• 金额: $ 6.53万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-01 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9894641
• 关键词: 3' Untranslated Regions; 5' Untranslated Regions; Address; Amino Acids; Area; Binding; Biogenesis; Cell Nucleolus; Codon Nucleotides; Core Protein; Coupled; Cytogenetics; Cytoplasm; Data; Embryo; Environment; Event; Fibroblasts; Genetic Translation; Internal Ribosome Entry Site; Knockout Mice; Lead; Luciferases; Malignant Neoplasms; Maps; Mass Spectrum Analysis; Messenger RNA; Modeling; Mus; Mutate; Phenocopy; Play; Process; Protein Biosynthesis; Proteins; Publishing; RNA Processing; RNA chemical synthesis; Regulation; Reporter; Research; Ribosomal Proteins; Ribosomal RNA; Ribosomes; Role; Structure; TP53 gene; Testing; Therapeutic; Translating; Translational Regulation; Translations; Tumor Suppressor Proteins; VEGFA gene; Viral; Viral Physiology; Wild Type Mouse; base; carcinogenesis; cricket paralysis virus; embryonic stem cell; insight; knock-down; neoplastic cell; overexpression; polysome profiling; programs; rapid growth; response; ribosome profiling; transcriptome sequencing; transcriptomics

ABSTRACT The ARF tumor suppressor is frequently mutated or downregulated in cancer. The major role of ARF is to activate p53 by sequestering the p53 regulator Mdm2. ARF also plays a significant role in ribosome biogenesis and mRNA translation. Previously, loss of Arf has been shown to cause a bulk increase in ribosome biogenesis, ribosome export into the cytoplasm and an increase in global protein synthesis. Activation of ARF inhibits these processes. Notably, ARF is known to specifically regulate the translation of several mRNAs. Based on previously published data we hypothesize that ARF regulates the translation of IRES containing mRNAs through displacement of RpL11 from the ribosome. To address our hypothesis, we propose three aims: 1) To map global translational regulation upon ARF loss or gain using ribosome profiling. 2) To assess the regulation of IRES containing mRNAs by ARF. 3) To identify proteins involved in ARF- dependent translational reprogramming

抽象的 在癌症中，ARF肿瘤抑制剂经常突变或下调。 ARF的主要作用是 通过隔离p53调节剂MDM2激活p53。 ARF在核糖体生物发生中也起着重要作用 和mRNA翻译。以前，已显示ARF的损失会导致核糖体大量增加 生物发生，核糖体导出到细胞质中，全球蛋白质合成的增加。 ARF的激活 抑制这些过程。值得注意的是，已知ARF专门调节了几个mRNA的翻译。 基于先前发布的数据，我们假设ARF调节了包含IRES的翻译 通过核糖体从RPL11移位的mRNA。为了解决我们的假设，我们提出了三个 目的：1）使用核糖体分析绘制ARF损失或增益后的全局翻译调节。 2） 评估ARF对含有mRNA的IRE的调节。 3）确定参与ARF-的蛋白质 依赖的翻译重编程