Mechanism of Regulation of mRNA Stability

描述（由申请人提供）：我们的总体目标是阐明一般而言参与调节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中起着非常重要的作用。我们的办法有三个方面。首先，我们将扩大我们对核磷蛋白的研究， 作为一种新的多聚腺苷酸化标记沉积在mRNA上的蛋白质，并决定其在基因表达协调中的作用。这项工作将涉及鉴定参与多聚腺苷酸化标记的辅助蛋白，确定nucleophosmin沉积的要求和机制，描绘mRNA靶点，并确定nucleophosmin在转录后控制中的功能。其次，我们将进行一系列体内和体外试验，以阐明CUG-BP（一种人细胞中poly（A）尾缩短的调节剂）及其靶向去腺苷酸酶PARN（沿着）通过调节mRNA稳定性对基因表达控制的全面影响。最后，我们已经确定了一个新的功能，为细胞质Lsm复合物在mRNA的稳定性。该提议的第三个目的的目标是确定Lsm介导的靶mRNA稳定化的潜在机制。总之，这些研究应该提供新的见解的机制和调节mRNA的稳定性，以及一般的转录后控制。考虑到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见解，并可能改进分子治疗策略。

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.