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

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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.