Roles of Eukaryotic Translation Initiation Factors in Gene Expression

总结 本项目的目的是利用基因组学的方法阐明真核生物翻译起始的基本机制。 结构和其他生物化学方法。真核生物翻译起始受 mRNA的非翻译区的元件，5 'UTR和3' UTR，通过细胞浓度， 起始因子，通过调节蛋白的作用和由 外部消息或蜂窝事件。翻译起始水平升高导致的翻译起始失调 在许多形式的癌症中发现了这些因素。因此，用小的 分子药物是一种很有前途的肿瘤治疗新途径。拟议的研究重点是 小核糖体 颗粒被募集到mRNA，由起始因子eIF 4 E、eIF 4G和调节因子介导。 磷蛋白4 EBP-1。第二个方面集中于将前起始复合物扫描到 AUG起始密码子，由起始因子eIF 4A、eIF 4G和eIF 4 H之间的相互作用辅助。的 第三个主题是阐明Mnk 1/2激酶与eIF 4G的HEAT 3结构域的相互作用， 其在磷酸化eIF 4 E中的作用，这与转移有关。一个重要方面是 发现和表征起始抑制剂，目的是开发抗癌剂， 广泛的特异性。这项研究将追求三个具体目标： 1. 4 EBP蛋白和抑制剂对eIF 4 E/eIF 4G相互作用的调节 2.分析并靶向eIF 4G与eIF 4A、RNA和eIF 4 H的相互作用。 3.抑制eIF 4G-MNK 1/2相互作用，防止eIF 4 E磷酸化和癌症转移。

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.