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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：
10295914
负责人：
KATHERINE L B BORDEN
金额：
$ 29.35万
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/10295914
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.

摘要