Roles of Eukaryotic Translation Initiation Factors in Gene Expression

真核翻译起始因子在基因表达中的作用

基本信息

批准号：
9319245
负责人：
GERHARD WAGNER
金额：
$ 38.77万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-20 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9319245
关键词：
3&apos Untranslated Regions 5&apos Untranslated Regions Antineoplastic Agents Apoptosis Binding Binding Proteins Biochemical Biological Assay C-terminal Cancer cell line Cell Culture Techniques Complex Crystallization Development Disease EIF4EBP1 gene Elements Equilibrium Eukaryotic Initiation Factors Event Exhibits Gene Expression Genetic Translation Goals Homeostasis Human In Vitro Initiator Codon Libraries Ligands Malignant Neoplasms Maps Measures Mediating Messenger RNA Methods Migration Assay Molecular Molecular Machines Mus Neoplasm Metastasis Oncogenes Oncogenic Outcome Peptide Initiation Factors Phosphoproteins Phosphorylation Phosphotransferases Process Protein Biosynthesis Proteins Proteomics RNA RNA Binding RNA Cap-Binding Proteins RNA Helicase Recruitment Activity Regulation Research Resolution Ribosomes Role Route Scaffolding Protein Scanning Signal Pathway Specificity Structure Testing Translation Initiation Translations Tumor Promoters Tumor Suppressor Proteins Untranslated Regions Xenograft procedure base cancer therapy cell transformation design experimental study fighting genetic regulatory protein high throughput screening human disease in vivo inhibitor/antagonist interest mutant new therapeutic target novel novel anticancer drug particle prevent small molecule small molecule therapeutics therapeutic target

项目摘要

Summary The goal of this project is to elucidate basic mechanisms of eukaryotic translation initiation using structural and other biochemical methods. Eukaryotic translation initiation is highly regulated by elements of the untranslated regions of mRNAs, 5'UTR and 3'UTR, by the cellular concentration of initiation factors, by the action of regulatory proteins and by signaling pathways that are initiated by external messages or cellular events. Dysregulation of translation initiation by elevated levels of initiation factors is found in many forms of cancer. Thus, correcting for out-of-balance initiation with small molecule agents is a promising new route for cancer therapy. The proposed research is focused on the mechanisms by which the small ribosomal particle is recruited to mRNA, mediated by the initiation factors eIF4E, eIF4G and the regulatory phosphoprotein 4EBP-1. The second aspect is focused on scanning of the pre-initiation complex to the AUG initiation codon, aided by the interplay between the initiation factors eIF4A, eIF4G and eIF4H. The third topic is on elucidating the interaction of the Mnk1/2 kinases with the HEAT3 domain of eIF4G and its role in phosphorylating eIF4E, which has been related to metastasis. A significant aspect is to discover and characterize inhibitors of initiation with the goal of developing anti-cancer agents with broad specificity. The research will pursue three specific aims: 1. Regulation of the eIF4E/eIF4G interaction by 4EBP proteins and inhibitors 2. Analyze and target the eIF4G interactions with eIF4A, RNA and eIF4H. 3. Inhibit eIF4G-MNK1/2 interaction to prevent eIF4E phosphorylation and cancer metastases.

概括该项目的目标是阐明真核翻译起始的基本机制结构和其他生化方法受到高度调控。 mRNA 非翻译区、5'UTR 和 3'UTR 的元素，通过细胞浓度启动因子，通过调节蛋白的作用和信号通路启动翻译起始水平升高导致的外部信息或细胞事件。在许多形式的癌症中都发现了这些因素，因此，可以用小剂量来纠正不平衡的发生。分子制剂是一种有前景的癌症治疗新途径。小核糖体的机制颗粒被招募到 mRNA，由起始因子 eIF4E、eIF4G 和调节因子介导第二个方面是对起始前复合物的扫描。 AUG 起始密码子，由起始因子 eIF4A、eIF4G 和 eIF4H 之间的相互作用辅助。第三个主题是阐明 Mnk1/2 激酶与 eIF4G 的 HEAT3 结构域的相互作用它在磷酸化 eIF4E 中的作用与转移有关。发现并表征起始抑制剂，目标是开发抗癌药物该研究将追求三个具体目标： 1. 4EBP 蛋白和抑制剂对 eIF4E/eIF4G 相互作用的调节 2. 分析并靶向 eIF4G 与 eIF4A、RNA 和 eIF4H 的相互作用。 3. 抑制eIF4G-MNK1/2相互作用，防止eIF4E磷酸化和癌症转移。