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

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eIF4E（eIF4F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- eIF3a是eIF3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 eIF3a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eIF3a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eIF3a表达升高产生了游离的未结合的 eIF3a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， eIF3a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eIF3a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）eIF3a在 翻译调控和结肠肿瘤发生;（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 表达，并建立eIF3a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，eIF3a在肿瘤抑制基因翻译调控中的作用， 并建立eIF3a作为癌症治疗的潜在靶点。

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.