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Translational control of EMT by the CELF1 RNA Binding Protein

CELF1 RNA 结合蛋白对 EMT 的翻译控制

基本信息

批准号：
9319243
负责人：
Joel R Neilson
金额：
$ 36.26万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-09 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9319243
关键词：
3&apos Untranslated Regions Adherens Junction Behavior Binding Biochemical Breast Breast Epithelial Cells Carcinoma Cell Line Cells Clinical Data Development Disease E-Cadherin Elements Embryo Epithelial Epithelial Cells Event Experimental Models Family Gene Targeting Genes Genetic Transcription Human Investigation Lung MCF10A cells Malignant Neoplasms Maps Mediating Mesenchymal Messenger RNA MicroRNAs Modeling Molecular Molecular Genetics Myotonic Dystrophy Neoplasm Metastasis Normal tissue morphology Outcome Pathway interactions Phase Phenotype Phosphorylation Play Post-Translational Protein Processing Process Protein Kinase Proteins RNA Interference RNA-Binding Proteins Regulatory Element Repression Role Signal Pathway Site Snails Solid Neoplasm Surveys System Testing Tissue Microarray Transcript Transcriptional Regulation Transforming Growth Factor beta Translational Activation Translations Ubiquitination Work cancer cell cell motility cytokine epithelial to mesenchymal transition experimental study gene product in vitro Model in vivo in vivo Model insight knock-down malignant breast neoplasm metastasis prevention mortality multicatalytic endopeptidase complex novel overexpression prevent public health relevance therapeutic candidate therapeutic target transcription factor tumor ubiquitin-protein ligase

项目摘要

DESCRIPTION (provided by applicant): By some estimates, tumor metastasis is responsible for over 90% of cancer mortality. At the cellular level, epithelial to mesenchymal transition (EMT) is the initiating event in tumor metastasis. We have been investigating the contribution of translational control to TGF-ß-induced EMT in a breast epithelial model. Our preliminary data unambiguously demonstrate that the CELF1 RNA binding protein, most well-known for its role in Type 1 Myotonic Dystrophy, is both necessary and sufficient for EMT in this system. In epithelial cells, the CELF1 protein is actively degraded via the proteasome. However, upon TGF-ß addition and EMT, this protein is stabilized and appears to increase the translation of several target genes, some of which have already been defined as positive regulators of EMT. To our knowledge this is the first data directly demonstrating the role of this gene product in EMT. Our overall objective is to further elucidate the mechanism by which TGF-ß induces EMT via the CELF1 protein. We predict that a more developed understanding of the cellular mechanisms at play in this pathway will reveal enzymatic activities playing critical roles in EMT, and that eventual therapeutic targeting of these activities may be viable therapeutic targets for the prevention of metastasis in early stage cancers. We hope to achieve our objective by testing our core hypothesis that induced stability of CELF1 protein drives EMT via translational activation of distinct downstream effector proteins. We propose doing this via three Specific Aims. First, we will identify the downstream effectors by which CELF1 promotes EMT and tumor metastasis in experimental models via a candidate approach. Using classical biochemical approaches, we will next establish the mechanism by which TGF-ß treatment leads to an increase in CELF1 protein levels. Finally, we will determine to what extent misexpression of CELF1 impacts tumor colonization and metastasis in in vivo models, and survey a broad range of human breast cancers to determine whether CELF1 is misexpressed in these tumors as compared to normal tissue. The proposed work is directly relevant to cancer because EMT is a core mechanism underlying tumor metastasis. Identification of the enzymatic activities by which CELF1 stability and function are controlled in the context of EMT will reveal candidate therapeutic targets for the prevention of metastasis of early-stage cancers. Downstream effectors of the CELF1 protein may also prove to be potential therapeutic targets, but are certain to provide insight into the cellular mechanisms underlying EMT that may be translatable to a broad range of solid tumors.