Roles of Eukaryotic Translation Initiation Factors in Gene Expression

摘要 本项目的目标是阐明真核生物翻译启动的基本机制。 结构和其他生化方法。真核生物的翻译启动受到高度调控 MRNAs的5‘非编码区和3’非编码区的元件，由细胞浓度决定 启动因子，通过调节蛋白的作用和通过由 外部消息或蜂窝事件。翻译启动水平升高对翻译启动的调节失调 因子存在于多种形式的癌症中。因此，对于不平衡的启动，使用小 分子制剂是治疗癌症的一条很有前途的新途径。建议的研究主要集中在 小核糖体的作用机制 颗粒被招募到mRNA，由启动因子eIF4E、eIF4G和调控因子eIF4E介导 磷酸蛋白4EBP-1。第二个方面集中在将预起爆复合体扫描到 AUG起始密码子，辅助起始因子eIF4A、eIF4G和eIF4H之间的相互作用。这个 第三个主题是阐明Mnk1/2激酶与eIF4G和eIF4G的HEAT3结构域的相互作用。 它在eIF4E磷酸化中的作用，而eIF4E与转移有关。一个重要的方面是 发现和表征起始抑制剂，目标是开发具有以下特点的抗癌药物 广泛的专一性。这项研究将追求三个具体目标： -- 1.4EBP蛋白及其抑制剂对eIF4E/eIF4G相互作用的调节 2.分析并定位eIF4G与eIF4A、RNA和eIF4H的相互作用。 3.抑制eIF4G-MNK1/2相互作用，防止eIF4E磷酸化和肿瘤转移。

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.