Molecular Mechanisms of eIF4E mediated transformation

eIF4E介导转化的分子机制

• 批准号: 10491774
• 负责人: KATHERINE L B BORDEN
• 金额: $ 28.57万
• 依托单位: UNIVERSITY OF MONTREAL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10491774
• 关键词: Acute Myelocytic Leukemia; Alternative Splicing; Antiviral Agents; Automobile Driving; Binding; Biochemical; Biological; Biological Models; Cancer Patient; Cells; Clinic; Code; Complex; DNA; Development; Disease remission; Dissection; Eukaryotic Initiation Factors; Event; Exhibits; Future; Geography; Goals; Guanosine; Head and Neck Cancer; Knowledge; MAP Kinase Gene; Malignant Neoplasms; Mediating; Molds; Molecular; Mutation; Nature; Neoplasm Metastasis; Normal Cell; Nuclear Export; Oncogenic; Pathway interactions; Patients; Phase I Clinical Trials; Physiological; Play; Post-Transcriptional Regulation; Process; Production; Prostate; Proteins; RNA; RNA Processing; RNA Splicing; Regulon; Ribavirin; Role; Signal Transduction; Spliceosomes; Structure; System; Transcript; Translations; Work; burden of illness; cell type; extracellular; functional outcomes; improved; insight; malignant phenotype; mouse model; novel; novel therapeutic intervention; novel therapeutics; overexpression; response; therapeutic target

Abstract This revised renewal application investigates novel mechanisms driving dysregulation of post- transcriptional control in cancer. Indeed, dysregulation of these events can drive the production of proteins that underpin proliferation, survival, invasion and metastases. Dysregulation can occur at many levels of RNA processing including splicing of RNAs, their nuclear export and translation. The eukaryotic translation initiation factor eIF4E, dysregulated in ~30% of cancers including in acute myeloid leukemia (AML), governs the RNA processing of networks of transcripts that ultimately underpin its oncogenic activities. Its ability to govern these regulons has been attributed to its well-established roles in nuclear export and translation of specific RNAs. Here, we discovered that eIF4E reprograms the splicing landscape of 1000s of transcripts both as a function of eIF4E dysregulation in AML patients as well as upon eIF4E overexpression in model systems. We compared alternative splicing (AS) events in high-eIF4E AML and upon eIF4E overexpression in cells, postulating those in common would represent pan-cancer targets of eIF4E-dependent splicing. We discovered a set of ~150 AS “core” transcripts, which encoded factors in the same biochemical networks. Importantly, these pathways also play roles in AML and in cancer more generally. Many of the AS events are predicted to produce proteins with different domain structures and thus altered functionalities. As to the mechanisms by which eIF4E modulates AS, our studies unearthed physical interactions between eIF4E and components of the spliceosome as well as revealed novel means to control the production of the splicing machinery i.e. via eIF4E. Three aims are proposed to dissect the mechanistic principles and biological impacts related to these novel findings: Aim 1. Explore eIF4E-dependent alterations to splicing where we will dissect the biochemical activities of eIF4E required for its AS activity, and assess the functional outcome of this activity; Aim 2. Elucidate the biochemical role that eIF4E plays in re-programming splicing by dissecting the physical interactions of eIF4E with components of the spliceosome and ascertain its relationship with active spliceosomes; and Aim 3. Determine the impact of dysregulated eIF4E-dependent splicing in AML where we will explore the impact of AS, and identify the splicing factors required for eIF4E’s activity. These studies will transform our view with regard to the impact of eIF4E dysregulation, which would now include altering the form of the transcript as well as regulating its protein-coding capacity.

抽象的 这种修订的更新应用调查了驱动后失调失调的新型机制 癌症的转录控制确实可以使事件失调 蛋白质的蛋白质是蛋白质的蛋白质，生存率，发明和转移的蛋白质 发生在许多水平的RNA处理中，包括RNA的剪接，其核出口和 翻译。 纳入急性髓样白血病（AML），控制着网络的RNA处理 支撑其致癌活动的笔录。 它归因于其在核出口中的良好作用和特定的翻译 RNA。 转录本均与AML患者以及EIF4E的EIF4E失调的函数 在模型系统中的过表达。 AML和EIF4E在细胞中的过表达后，发布共同的那些将代表 EIF4E依赖性剪接的泛癌目标我们发现了一组〜150 这些转录本在同一生化网络中编码这些因素 途径还在AML和癌症中扮演角色。 预计会产生具有不同域结构的蛋白质，从而改变了功能。 至于EIF4E调节的机制，我们的研究发现了物理 EIF4E与剪接体的组成部分之间的相互作用以及揭示的小说 控制剪接机械的生产，即EIF4E 支撑以显示与thesenovel相关的机械原理和生物学影响 调查结果：AIM1。探索对剪接的EIF4E偏置更改，我们将剖析您 EIF4E的生化活性为AS AS活动，并评估 这项活动;目标2。阐明EIF4E重新编程的生化作用 通过剖析EIF4E与剪接体组成部分的物理相互作用和 确定其与主动剪接体的关系； 在AML中，我们将探讨AS和 确定EIF4E活动所需的剪接因素。 关于EIF4E失调的影响，现在将包括改变形式 转录本以及调节其蛋白质编码能力。