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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和翻译水平上调节。与转录调控相比，翻译调控研究较少，真核起始因子（eIFs）在调节基因表达、信号转导和免疫调节中的作用调节细胞生长尚未被认识到其重要性的水平。现行基因表达中的翻译控制理论认为eIFs的表达水平直接影响基因的表达，与翻译起始速率和蛋白质合成水平有关。根据这一理论， eIFs如eIF 4 E（eIF 4F复合物的假定亚基）的表达增加，增加翻译起始速率和蛋白质合成。然而，我们最近发现，过度- eIF 3a是eIF 3复合物的一个亚基，其表达可抑制肿瘤抑制因子的合成。蛋白质并导致肠上皮细胞恶性转化。我们还发现 eIF 3a在结肠癌和腺瘤息肉中表达上调，可能是APC所致 β-catenin信号的突变和激活。我们假设eIF 3a可能作为一种在经典的Wnt/β-catenin信号通路的转折点，并添加一个额外的结肠肿瘤发生/家族性腺瘤性息肉病中该途径的翻译控制轴并且由于β-连环蛋白激活引起的eIF 3a表达升高产生了游离的未结合的 eIF 3a可能在抑制肿瘤抑制蛋白的合成中获得非典型活性通过与它们的mRNA结合。本项目的长期目标是了解在基因表达，信号转导和细胞异常增殖中的翻译控制肠/结肠上皮细胞。具体来说，我们将研究的非典型功能， eIF 3a在Wnt/β-catenin信号转导和结肠肿瘤发生和FAP中的作用目标是将eIF 3a作为药物发现的潜在靶点。为此，我们计划实现以下具体目标，以确定（1）eIF 3a在翻译调控与结肠肿瘤发生的关系;（2）结肠肿瘤发生中的翻译调控机制。肿瘤抑制基因的表达;（3）eIF 3a的转录调控机制表达，并建立eIF 3a作为潜在的目标。信息和探测器从本研究将有助于我们了解Wnt/β- 连环蛋白信号通路，eIF 3a在肿瘤抑制基因翻译调控中的作用，并建立eIF 3a作为癌症治疗的潜在靶点。