Translational Regulation by the TNF Alpha AU-rich Element

富含 TNF Alpha AU 元素的翻译调控

• 批准号: 7668600
• 负责人: STUART W PELTZ
• 金额: $ 30.61万
• 依托单位: UNIV OF MED/DENT NJ-R W JOHNSON MED SCH
• 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/7668600
• 关键词: Autoimmune Diseases; Be++ element; Beryllium; Binding Proteins; Cell Line; Cells; Cloning; Condition; Crohn' s disease; Elements; Eukaryota; Eukaryotic Cell; Genes; Genetic Screening; Genetic Transcription; Genetic Translation; Goals; Homologous Gene; Hour; Indium; Infection; Inflammatory; Injury; Interphase Cell; Link; Lipopolysaccharides; Mediating; Mediator of activation protein; Messenger RNA; Mus; Numbers; Pathway interactions; Peptide Initiation Factors; Poly(A) Tail; Poly(A)-Binding Proteins; Process; Production; Proteins; Regulation; Repression; Rheumatoid Arthritis; Role; Saccharomyces cerevisiae; Signal Pathway; Stimulus; System; TIS11 protein; Trans-Activators; Transcriptional Activation; Translational Regulation; Translational Repression; Translations; Tumor Necrosis Factor-alpha; Untranslated Regions; Up-Regulation; Virus Diseases; Yeasts; cell type; cis acting element; cytokine; design; human TNF protein; insight; mRNA Decay; mRNA Stability; macrophage; novel; research study; response

TNFalpha is a pro-inflammatory cytokine produced transiently by several cell types in response to infection or injury. Production of TNFalpha is tightly regulated at the levels of transcription, mRNA decay and translation and aberrant expression of this potent molecule has been linked to autoimmune disorders, rheumatoid arthritis, Crohn's disease and other inflammatory conditions. The translational regulation of TNFalpha is mediated by AU-rich elements (AREs) located in the 3'-UTR of the mRNA. The ARE is involved in translational repression in resting cells as well as in activation of translation under stimulatory conditions. Several ARE-binding proteins have been identified and, of these, TIA-1 and TIAR have been implicated in translational repression. However, the factors involved in up-regulation of TNFalpha translation are not known. A system for studying this phenomenon has been developed in the yeast Saccharomyces cerevisiae. The yeast homologues of the ARE-binding protein Tristetraprolin (TTP) and a yeast homologue of TIA-1/TIAR were found to be key mediators of translation regulation by the ARE. The goals of this proposal are to utilize the yeast system to characterize the mechanism of translational regulation by the TNFalpha ARE, and to perform a genetic screen to identify the trans-acting factors required for accurate regulation. In addition, the role of TTP and its murine homologues (Tis 11 b and Tis 11 d) in modulating TNFalpha translation in mouse macrophages will be investigated. The experiments described here aim to increase our understanding of both general ARE function and regulation of TNFalpha expression.

肿瘤坏死因子α是一种促炎细胞因子，由几种类型的细胞在感染或损伤时瞬时产生。肿瘤坏死因子α的产生受到转录、mRNA衰退和翻译水平的严格调控，这种有效分子的异常表达与自身免疫性疾病、类风湿性关节炎、克罗恩病和其他炎症条件有关。肿瘤坏死因子α的翻译调控是由位于基因3‘端非编码区的富含AU元件(Ares)介导的。ARE参与静息细胞的翻译抑制以及刺激条件下翻译的激活。已鉴定出几种ARE结合蛋白，其中TIA-1和TIAR与翻译抑制有关。然而，上调TNFpha翻译所涉及的因素尚不清楚。在酿酒酵母中已经建立了一个研究这一现象的系统。ARE蛋白结合蛋白Tristetraprolin(TTP)的酵母同源物和TIA-1/TIAR的酵母同源物被发现是ARE翻译调控的关键介质。这项建议的目标是利用酵母系统来表征由TNFAlpha调控的翻译机制，并进行遗传筛选以识别反式作用 准确监管所需的因素。此外，还将研究TTP及其小鼠同系物(Tis 11b和Tis 11d)在调节小鼠巨噬细胞中的TNFpha翻译中的作用。本文介绍的实验旨在增加我们对肿瘤坏死因子α表达的一般功能和调控的理解。