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

• 批准号: 10225293
• 负责人: Jian-Ting Zhang
• 金额: $ 35.19万
• 依托单位: UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10225293
• 关键词: APC gene; APC mutation; Affect; Binding; Binding Proteins; Colon; Colon Carcinoma; Colonic Adenoma; Complex; Disease; 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

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.

基因的表达主要在转录和翻译水平上进行调节。 与转录调控相比，翻译调控的研究还不够深入，而翻译调控在转录调控中的作用 真核生物启动因子在调控基因表达、信号转导和转录调控中的作用 调节细胞生长还没有意识到它们的重要性。盛行的 基因表达的翻译调控理论认为，EIFs的表达水平直接影响基因的表达 与翻译起始率和蛋白质合成水平有关。根据这一理论， EIF的表达增加，如eIF4E，eIF4F复合体的一个假定的亚单位，将 提高翻译起始率和蛋白质合成。然而，我们最近发现，过度- EIF3复合体的亚基eIF3a的表达抑制肿瘤抑制因子的合成 蛋白质，并引起肠上皮细胞恶性转化。我们还发现， EIF3a在结肠癌和腺瘤息肉中的表达上调可能与APC有关 β-连环蛋白信号的突变和激活。我们假设eIF3a可能作为一种 经典的Wnt/β-连环蛋白信号通路的转折点，并增加了一个额外的 结肠肿瘤发生/家族性腺瘤性息肉病中这一途径的翻译控制轴 由于β-连环蛋白的激活而升高的eIF3a表达产生游离的 可能获得抑制肿瘤抑制蛋白合成的非典型活性的eIF3a 通过与它们的mRNAs结合。这个项目的长期目标是了解这些机制 在基因表达、信号转导和异常增殖中的翻译控制 肠/结肠上皮细胞。具体地说，我们将研究非正则函数 EIF3a在Wnt/β-catenin信号转导及结肠癌发生和FAP中的作用 目标是将eIF3a确立为药物发现的潜在目标。为此，我们计划 完成以下具体目标以确定(1)eIF3a在 翻译调控与结肠肿瘤的发生；(2)翻译调控的机制 肿瘤抑制基因的表达；(3)eIF3a的转录调控机制 并将eIF3a作为潜在的靶标。从以下来源获得的信息和探测 这项研究将有助于我们理解WNT/β中翻译控制轴的分子机制。 连环蛋白信号通路，eIF3a在肿瘤抑制基因mRNAs翻译调控中的作用 并将eIF3a确立为癌症治疗的潜在靶点。