Molecular targeting the translational control axis in Wnt/beta-catenin signaling pathway

Wnt/β-catenin 信号通路中翻译控制轴的分子靶向

基本信息

批准号：
10456829
负责人：
Jian-Ting Zhang
金额：
$ 34.49万
依托单位：
UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10456829
关键词：
APC gene APC mutation Affect Binding Binding Proteins Colon Colon Carcinoma Colonic Adenoma Colonic Diseases Complex Drug Targeting Epithelial Cells Eukaryotic Initiation Factors Exercise Familial Adenomatous Polyposis Syndrome GADD45A gene Gene Expression Genes Genetic Transcription Genetic Translation Goals Human Intestines Malignant - descriptor Malignant Neoplasms Mediating Messenger RNA Molecular Molecular Target Oncogenic Pathway interactions Polyps Polyribosomes Process Protein Biosynthesis Proteins Regulation Role Signal Pathway Signal Transduction Spectrin TP53 gene Testing Tissues Transcriptional Regulation Translation Initiation Translational Regulation Translations Tumor Suppressor Proteins Untranslated Regions autism spectrum disorder beta catenin cell growth colon cancer treatment colon tumorigenesis drug discovery human disease intestinal epithelium new therapeutic target novel overexpression response theories therapeutic target tumorigenesis whole genome

项目摘要

Gene expression is regulated mainly at both transcriptional and translational levels. Compared with transcriptional regulation, translational control is under-studied and the roles of eukaryotic initiation factors (eIFs) in regulating gene expression, in signal transduction, and in regulating cell growth have not been appreciated to the level of their importance. The prevailing theory of translational control in gene expression is that the expression level of eIFs directly relates to the rate of translation initiation and level of protein synthesis. According to this theory, the increased expression of eIFs such as eIF4E, a putative subunit of eIF4F complex, would increase translation initiation rate and protein synthesis. However, we recently found that over- expression of eIF3a, a putative subunit of eIF3 complex, inhibited synthesis of tumor suppressor proteins and caused malignant transformation of intestinal epithelial cells. We also found that eIF3a expression was up-regulated in colon cancers and adenoma polyps possibly due to APC mutation and activation of β-catenin signaling. We hypothesize that eIF3a may serve as a turning point in the canonical Wnt/β-catenin signaling pathway and add an additional translational control axis to this pathway in colon tumorigenesis/familial adenomatous polyposis and that the elevated eIF3a expression due to β-catenin activation generates free unbound eIF3a that may gain a non-canonical activity in inhibiting synthesis of tumor suppressor proteins by binding to their mRNAs. The long-term goal of this project is to understand the mechanisms of translational control in gene expression, signal transduction, and in aberrant proliferation of intestinal/colon epithelial cells. Specifically, we will investigate the non-canonical function of eIF3a in Wnt/β-catenin signal transduction and in colon tumorigenesis and FAP with an ultimate goal to establish eIF3a as a potential target for drug discovery. To this end, we plan to accomplish the following specific aims to determine (1) the mechanism of eIF3a action in translational regulation and in colon tumorigenesis; (2) the mechanism of translational regulation in tumor suppressor expression, and (3) the mechanism of transcriptional regulation of eIF3a expression and to establish eIF3a as potential target. The information and probes obtained from this study will help us understand the molecular mechanisms of translational control axis in Wnt/β- catenin signaling pathway, the role of eIF3a in translational regulation of tumor suppressor mRNAs, and to establish eIF3a as a potential target for cancer treatemnts.

基因表达主要在转录水平和翻译水平上调节。与转录调节相比，翻译控制不足，并且在控制基因表达，信号转移和在中调节细胞生长的重要性水平并不理解。盛行基因表达中翻译控制的理论是直接的EIF表达水平与翻译起始率和蛋白质合成水平有关。根据这个理论， EIF4E（例如EIF4F复合物的推定亚基）等EIF的表达增加将增加翻译起始率和蛋白质合成。但是，我们最近发现 EIF3A的表达是EIF3复合物的推定亚基，抑制了肿瘤抑制剂的合成蛋白质并引起肠上皮细胞的恶性转化。我们还发现由于APC，在结肠癌和腺瘤息肉中上调了EIF3A的表达 β-catenin信号传导的突变和激活。我们假设EIF3A可以用作规范Wnt/β-catenin信号通路中的转折点，并添加额外结肠肿瘤发生/家族性腺瘤性息肉病中的这一途径的翻译控制轴并且由于β-catenin激活引起的EIF3A表达升高会产生自由的未结合 EIF3A可能会在抑制肿瘤抑制蛋白的合成中获得非典型活性通过与他们的mRNA结合。该项目的长期目标是了解机制基因表达，信号翻译和异常增殖的转化控制肠/结肠上皮细胞。具体而言，我们将研究 Wnt/β-catenin信号转移和结肠肿瘤发生和FAP中的EIF3A和最终建立EIF3A作为药物发现的潜在目标的目标。为此，我们计划完成以下特定目的，以确定（1）在翻译调节和结肠肿瘤发生；（2）转化调节的机制肿瘤抑制剂表达和（3）EIF3A转录调控的机理表达并确定EIF3A作为潜在目标。从这项研究将有助于我们了解Wnt/β-中平移控制轴的分子机制 Catenin信号通路，EIF3A在肿瘤抑制器mRNA的翻译调节中的作用，并建立EIF3A作为癌症治疗的潜在目标。