Mechanism of Regulation of mRNA Stability

mRNA稳定性调节机制

• 批准号: 7247210
• 负责人: Jeffrey Wilusz
• 金额: $ 28.87万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7247210
• 关键词: Class; Complex; Disease; Elements; Gene Expression; Goals; Immune; In Vitro; Malignant Neoplasms; Messenger RNA; Molecular; Pathway interactions; Placement; Play; Polyadenylation; Process; Proteins; Pyrimidine; Pyrimidines; RNA; Regulation; Role; System; TNFSF5 gene; Untranslated Regions; base; c-jun Proto-Oncogene; cell growth; gene therapy; improved; in vivo; insight; mRNA Stability; novel

DESCRIPTION (provided by applicant): Our goal is to elucidate the pathways and mechanisms involved in general and regulated mRNA stability, a process that plays an important role in controlling aspects of gene expression related to cell growth and differentiation. Our approach to this goal will largely center around a novel in vitro system we have developed and successfully exploited in the past that faithfully reproduces aspects of both general and regulated mRNA stability on exogenous RNA substrates. First, by strategic placement of structural blocks into RNA substrates, we will determine the in vivo pathways involved in the degradation of the body of the mRNA following deadenylation. Second, we will use an in vitro approach to determine how deadenylation of mRNA substrates is differentially regulated by distinct classes AU-rich elements. Third, we will determine how non-AU-rich elements, namely the pyrimidine-rich element of the important immune modulator CD154 and the U-rich element of the c-jun proto-oncogene, function to regulate mRNA stability. Finally, we have recently identified a complex of 3 proteins that assembles on the 3' UTR of an mRNA in a polyadenylation dependent manner. We will investigate the identity and functional significance of these proteins in a variety of post-transcriptional processes. These studies on the mechanisms and regulation of mRNA stability will have a profound impact on our appreciation of molecular mechanisms of cellular growth control, as well as providing insights into the molecular basis of disease (e.g. cancer) and possibly improved strategies for gene therapy.

描述（由申请人提供）：我们的目标是阐明一般和调节mRNA稳定性中涉及的途径和机制，该过程在控制与细胞生长和分化有关的基因表达方面起着重要作用。我们实现这一目标的方法将在很大程度上围绕着我们过去开发并成功利用的新型体外系统，该系统忠实地再现了一般和调节的MRNA稳定性对外源RNA底物的稳定性。首先，通过将结构块的策略放置在RNA底物中，我们将确定降解后mRNA降解的体内途径。其次，我们将使用一种体外方法来确定mRNA底物的去苯基化如何受到不同类别的元素的差异调节。第三，我们将确定重要的免疫调节剂CD154的非AU富元素，即C-JUN原始癌元素的富含嘧啶元素，以调节mRNA稳定性。最后，我们最近确定了3种蛋白质的复合物，该蛋白质以聚腺苷酸化的方式在mRNA的3'UTR上组装。我们将研究这些蛋白质在各种转录后过程中的身份和功能意义。这些关于mRNA稳定性机制和调节的研究将对我们对细胞生长控制的分子机制的认识产生深远的影响，并提供对疾病分子基础（例如癌症）的见解，并可能改善基因疗法的策略。