Translational control by poly(A)-binding protein and its modulators (Paips)

Poly(A) 结合蛋白及其调节剂 (Paips) 的翻译控制

基本信息

批准号：
7645791
负责人：
NAHUM SONENBERG
金额：
$ 21.06万
依托单位：
MCGILL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-09-01 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7645791
关键词：
Adipose tissue Affect Animal Model Beta Cell Binding Biological Process Brain Cells Complex Defect Development Diabetes Mellitus Disease Drug or chemical Tissue Distribution Eukaryota Eukaryotic Initiation Factor-4F Genetic Materials Growth In Vitro Knock-out Knockout Mice Laboratories Malignant Neoplasms Memory Messenger RNA Molecular Mus Obesity Pancreas Peptide Initiation Factors Phosphorylation Physiological Play Poly A Poly(A) Tail Poly(A)-Binding Proteins Process Protein Binding Protein Biosynthesis Protein Family Proteins RNA Recognition Motif Regulation Research Research Proposals Role Signal Pathway Signal Transduction Pathway Stimulus Synaptic plasticity Tail Translation Initiation Translations Ubiquitination Virus Diseases base blood glucose regulation cell growth extracellular fly helicase in vivo lipid metabolism member novel public health relevance scaffold ubiquitin-protein ligase

项目摘要

DESCRIPTION (provided by applicant): The long-term objective of our research is to understand the mechanism of translation initiation in eukaryotes, its control under physiological conditions, and deregulation in diseases, such as cancer, diabetes and virus infection. Here, we propose to pursue our studies on the mechanism of function of the mRNA poly(A) binding protein (PABP) in translation initiation, and its regulation by members of a family of proteins known as PABP- interacting proteins (Paips), which were discovered in our laboratory. We demonstrated that Paip1 stimulates translation, whereas Paip2A and Paip2B inhibit translation. We propose three specific aims, which are as follows: 1. Investigate the function of a newly discovered complex, eIF3-Paip1. The molecular mechanism by which Paip1 stimulates translation will be studied, including a detailed structural characterization of the Paip1- eIF3 interaction. 2. Characterize the signaling pathways that regulate eIF3-Paip1 complex formation. We will determine whether phosphorylation of eIF3 regulates Paip1 binding and activity. Mutational analyses will be performed to study downstream effects of eIF3 phosphorylation on Paip1 function in translation. 3. Elucidate the physiological roles of Paip2A and Paip2B in animal models. Single knockout (KO) of Paip2A and Paip2B mice have recently been generated in our lab. Based on the known tissue distribution of the Paip2 proteins, we also intend to generate brain- and pancreas-specific KO mice. Mice will be subjected to complete phenotypic, pathological and histological examinations, and will be studied for effects on beta-cell regulation in the pancreas and on synaptic plasticity and memory formation in the brain. PUBLIC HEALTH RELEVANCE Many major diseases including cancer, diabetes and obesity arise because of defects in the control of the synthesis of proteins. We are studying an important example of such control, which involves a protein called poly(A) binding protein and its binding partners. Poly(A) binding protein binds to the tail of the genetic material (messenger RNA) that serves as template for the synthesis of all proteins in the cell.

描述（由申请人提供）：我们研究的长期目标是了解真核生物中翻译起始的机制，其在生理条件下的控制以及疾病（例如癌症，糖尿病和病毒感染）的消失。在这里，我们建议在翻译起始中对mRNA poly（a）结合蛋白（PABP）的功能机理进行研究，并由称为PABP相互作用蛋白（PAIPS）的蛋白质成员调节，该蛋白质的调节是在我们的实验室中发现的。我们证明PAIP1刺激翻译，而PAIP2A和PAIP2B抑制翻译。我们提出了三个特定目标，如下：1。研究新发现的复合物EIF3-PAIP1的功能。将研究PAIP1刺激翻译的分子机制，包括PAIP1- EIF3相互作用的详细结构表征。 2。表征调节EIF3-PAIP1复合形成的信号通路。我们将确定EIF3的磷酸化是否调节PAIP1结合和活性。将进行突变分析以研究EIF3磷酸化对PAIP1函数翻译中的下游影响。 3。阐明PAIP2A和PAIP2B在动物模型中的生理作用。最近在我们的实验室中生成了PAIP2A和PAIP2B小鼠的单元基因（KO）。根据PAIP2蛋白的已知组织分布，我们还打算产生脑和胰腺特异性KO小鼠。小鼠将接受完整的表型，病理和组织学检查，并将研究以对胰腺中的β细胞调节以及大脑中突触可塑性和记忆形成的影响。公共卫生相关性许多主要疾病，包括癌症，糖尿病和肥胖症，因为控制蛋白质的合成缺陷。我们正在研究这种对照的重要例子，它涉及一种称为poly（a）结合蛋白及其结合伴侣的蛋白质。聚（a）结合蛋白与遗传材料（Messenger RNA）的尾巴结合，该蛋白用作合成细胞中所有蛋白质的模板。