Regulation of translation through the human translation initiation factor eIF5B

通过人类翻译起始因子 eIF5B 调节翻译

• 批准号: 7253379
• 负责人: ASSEN G Marintchev
• 金额: $ 11.1万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7253379
• 关键词: Affect; Affinity; Amino Acids; Antineoplastic Agents; Attention; Binding; Biological Assay; C-terminal; Cell Proliferation; Cells; Cessation of life; Complex; Data; Eukaryotic Initiation Factors; Fluorescence Polarization; Foundations; GTP-Binding Proteins; GTPase-Activating Proteins; Guanosine Triphosphate; Human; Hydrolysis; In Vitro; Libraries; Mediating; NMR Spectroscopy; Nuclear Magnetic Resonance; Peptide Initiation Factors; Peptides; Pharmaceutical Preparations; Principal Investigator; Process; Protein Biosynthesis; Protein Synthesis Inhibition; Proteins; Rate; Regulation; Reporting; Research; Ribosomes; Role; Site; Site-Directed Mutagenesis; Solutions; Specificity; Staging; Structure; Surface; System; Tail; Testing; Translation Initiation; Translation Process Protein; Translations; Work; anticancer research; base; cancer cell; cancer therapy; career; eukaryotic initiation factor-5B; high throughput screening; in vivo; inhibitor/antagonist; insight; novel strategies; programs; reconstitution; response; small molecule; tool

DESCRIPTION (provided by applicant): Control of protein synthesis (translation) is vital for cell proliferation, differentiation or death. We found that human eukaryotic translation initiation factors elF1 A and elF5 compete for the same surface of the G-protein elF5B, and that elF5B may be transferred from elF5 to elF1 A, which would allow for a switch-type control of the corresponding step. elFSB and elF1 A are the only two translation initiation factors conserved among all kingdoms. elF5 is the GTPase-activating protein (GAP) for the other G-protein, elF2. GTP hydrolysis by elF2 upon start site recognition is required for ribosomal subunit joining, which is promoted by elFSB. Thus, the elF5B:elF5/elF1A interactions may coordinate the two GTP hydrolysis checkpoints in translation initiation. The competition between elF5 and elF1 A for elFSB allows to study both the spatial and the temporal aspects of the regulation of translation initiation. Furthermore, the potential of using inhibition of the interactions of elFSB for anti-cancer therapy remains to be explored. The research will pursue the following specific aims: 1. Determine the structure of the complex of human elF5B-CTD with the elF5 C-terminal tail by Nuclear Magnetic Resonance (NMR); establish the basis for binding affinity and specificity. 2. Identify the roles of the elF5B:elF5/elF1 A interactions in translation initiation, what types of mRNAs are affected and at which stages of initiation. Test whether and when elFSB is transferred from elF5 to elF1 A. 3. Screen for small-molecule inhibitors of the interactions of elFSB with elF1 A/elF5. Explore the potential of using these inhibitors as drug candidates for cancer therapy. The results anticipated from this project will answer important questions in translation initiation. They will also allow me to expand my research in new directions, and serve as a foundation for building a successful career in cancer research. Relevance to cancer research: Actively dividing cells, such as cancer cells, require increased rates of protein synthesis. The potential of the regulation of protein synthesis for cancer therapy has only recently started to attract attention. The work outlined in this proposal will help establish new targets and explore new approaches in using modulation of the rates of protein synthesis for cancer therapy, such as blocking the increase in the supply of amino acids in response to the high demands in rapidly dividing cells.

描述（由申请人提供）：蛋白质合成（翻译）的控制对于细胞增殖、分化或死亡至关重要。我们发现人真核翻译起始因子eIFlA和eIF 5竞争G蛋白eIF 5 B的相同表面，并且eIF 5 B可以从eIF 5转移到eIFlA，这将允许相应步骤的开关型控制。eIFSB和eIF 1A是仅有的两个在所有界中保守的翻译起始因子。eIF 5是另一种G蛋白eIF 2的GTP酶激活蛋白（GAP）。在起始位点识别后，eIF 2的GTP水解是核糖体亚基连接所需的，这是由eIFSB促进的。因此，eIF 5 B：eIF 5/eIF 1A相互作用可以协调翻译起始中的两个GTP水解检查点。 eIF 5和eIFlA之间对eIFSB的竞争允许研究翻译起始调节的空间和时间方面。此外，使用抑制eIFSB的相互作用用于抗癌治疗的潜力仍有待探索。研究将追求以下具体目标： 1.通过核分析确定人eIF 5 B-CTD与eIF 5C-末端尾的复合物的结构 磁共振（NMR）;建立结合亲和力和特异性的基础。 2.鉴定eIF 5 B：eIF 5/eIFlA相互作用在翻译起始中的作用，什么类型的mRNA受到影响以及在起始的哪个阶段。测试eIFSB是否以及何时从eIF 5转移到eIFlA。 3.筛选eIFSB与eIFlA/eIF 5相互作用的小分子抑制剂。探索使用这些抑制剂作为癌症治疗候选药物的潜力。 这个项目的预期结果将回答翻译启动中的重要问题。他们还将使我能够在新的方向上扩展我的研究，并作为建立一个成功的职业生涯在癌症研究的基础。 与癌症研究的相关性：活跃分裂的细胞，如癌细胞，需要增加蛋白质合成的速率。调节蛋白质合成用于癌症治疗的潜力直到最近才开始引起人们的注意。该提案中概述的工作将有助于建立新的靶点，并探索利用调节蛋白质合成速率进行癌症治疗的新方法，例如阻断氨基酸供应的增加以应对快速分裂细胞的高需求。