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Molecular Mechanisms of eIF4E mediated transformation

eIF4E介导转化的分子机制

基本信息

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
项目类别：
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

项目摘要

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.

抽象的这个修订后的续展申请调查了导致后期失调的新机制癌症中的转录控制。事实上，这些事件的失调可以推动生产支撑增殖、存活、侵袭和转移的蛋白质。失调可以发生在 RNA 加工的许多水平，包括 RNA 剪接、核输出和翻译。真核翻译起始因子 eIF4E 在约 30% 的癌症中失调包括在急性髓性白血病 (AML) 中，控制网络的 RNA 加工最终支持其致癌活性的转录本。它控制这些调节子的能力归因于其在核出口和具体翻译方面的既定作用 RNA。在这里，我们发现 eIF4E 重新编程了数千个的拼接景观转录物既是 AML 患者中 eIF4E 失调的函数，也是 eIF4E 的函数模型系统中的过度表达。我们比较了高 eIF4E 中的选择性剪接 (AS) 事件 AML 和细胞中 eIF4E 过度表达，假设这些共同点代表 eIF4E 依赖性剪接的泛癌靶标。我们发现了一组约 150 个 AS“核心” 转录本，编码相同生化网络中的因子。重要的是，这些通路还在 AML 和更广泛的癌症中发挥作用。许多 AS 事件都是预计会产生具有不同结构域结构的蛋白质，从而改变功能。关于 eIF4E 调节 AS 的机制，我们的研究揭示了物理 eIF4E 和剪接体成分之间的相互作用以及揭示的新颖控制拼接机械生产的方式，即通过 eIF4E。三个目标是提议剖析与这些新颖相关的机械原理和生物影响研究结果：目标 1. 探索依赖于 eIF4E 的剪接改变，我们将在其中剖析 eIF4E 的 AS 活性所需的生化活性，并评估其功能结果这项活动；目标 2. 阐明 eIF4E 在重编程剪接中发挥的生化作用通过剖析 eIF4E 与剪接体成分的物理相互作用确定其与活性剪接体的关系；目标 3. 确定影响 AML 中 eIF4E 依赖性剪接失调，我们将探讨 AS 的影响，以及确定 eIF4E 活性所需的剪接因子。这些研究将改变我们的观点关于 eIF4E 失调的影响，现在包括改变转录物以及调节其蛋白质编码能力。