Ezrin-radixin-moesin (ERM) Binding Phosphoprotein 50 (EBP50) Coordinates β-catenin/TCF-1 Signaling
Date Issued
2012
Date
2012
Author(s)
Lin, Yu-Yu
Abstract
β-Catenin plays a pivotal role in Wnt signaling pathway which controls a variety of cellular processes during development, such as body patterning, migration during morphogenesis and cell proliferation. T-cell factor (TCF) family transcriptional factors cooperate with β-catenin in the nucleus to regulate the expression of Wnt-responsive genes. EBP50 is a β-catenin-associated protein and overexpression of EBP50 has been known to enhance β-catenin transcriptional activity. However, the underlying mechanism has remained elusive. According to our data, EBP50 displayed a nuclear translocation modulated by cell density. Through ChIP-on-chip assay, we disclosed that nuclear EBP50 predominantly associates with the promoter regions containing TCF/LEF consensus binding sequence. By database search, we found TCF-1B has a PDZ binding motif in its C-terminal end. Thus, we further revealed a novel interaction between nuclear EBP50 and TCF-1 through PDZ1 domain. In spite of stabilizing the interaction between β-catenin and full-length TCF-1, binding of nuclear EBP50 also restores the dnTCF-1/β-catenin binding and converts the dominantly negative dnTCF-1 which lacks a β-catenin binding domain into a tumor facilitator. Also, we demonstrated that nuclear EBP50 was recruited to the promoter regions of β-catenin target genes and participated in β-catenin mediated transcriptional activity. EBP50 knockdown in colonic cancer cells led to reduced cell proliferation, anchorage independent growth, and tumorigenesis in nude mice. Moreover, the immunohistochemistry study identified abnormal EBP50 localization in the nucleus at the tumor invasive fronts the colorectal carcinoma specimens that manifested a poor
clinical outcome.
Subjects
EBP50
β-catenin
TCF-1
colorectal cancer
SDGs
Type
thesis
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