Aberrant nuclear localization of EBP50 promotes colorectal carcinogenesis in xenotransplanted mice by modulating TCF-1 and ?-catenin interactions.
Dysregulation of canonical Wnt signaling is thought to play a role in colon carcinogenesis. ?-Catenin, a key mediator of the pathway, is stabilized upon Wnt activation and accumulates in the nucleus, where it can interact with the transcription factor T cell factor (TCF) to transactivate gene expression. Normal colonic epithelia ... express a truncated TCF-1 form, called dnTCF-1, that lacks the critical ?-catenin-binding domain and behaves as a transcriptional suppressor. How the cell maintains a balance between the two forms of TCF-1 is unclear. Here, we show that ERM-binding phosphoprotein 50 (EBP50) modulates the interaction between ?-catenin and TCF-1. We observed EBP50 localization to the nucleus of human colorectal carcinoma cell lines at low cell culture densities and human primary colorectal tumors that manifested a poor clinical outcome. In contrast, EBP50 was primarily membranous in confluent cell lines. Aberrantly located EBP50 stabilized conventional ?-catenin/TCF-1 complexes and connected ?-catenin to dnTCF-1 to form a ternary molecular complex that enhanced Wnt/?-catenin signaling events, including the transcription of downstream oncogenes such as c-Myc and cyclin D1. Genome-wide analysis of the EBP50 occupancy pattern revealed consensus binding motifs bearing similarity to Wnt-responsive element. Conventional chromatin immunoprecipitation assays confirmed that EBP50 bound to genomic regions highly enriched with TCF/LEF binding motifs. Knockdown of EBP50 in human colorectal carcinoma cell lines compromised cell cycle progression, anchorage-independent growth, and tumorigenesis in nude mice. We therefore suggest that nuclear EBP50 facilitates colon tumorigenesis by modulating the interaction between ?-catenin and TCF-1.
Mesh Terms:
Active Transport, Cell Nucleus, Aged, Aged, 80 and over, Animals, Base Sequence, Binding Sites, Carcinoma, Cell Line, Tumor, Cell Nucleus, Cell Proliferation, Cell Transformation, Neoplastic, Colorectal Neoplasms, Female, Gene Expression Regulation, Neoplastic, Humans, Male, Mice, Mice, SCID, Middle Aged, Multiprotein Complexes, Neoplasm Transplantation, PDZ Domains, Phosphoproteins, Promoter Regions, Genetic, Protein Binding, Signal Transduction, Sodium-Hydrogen Exchangers, T Cell Transcription Factor 1, beta Catenin
Active Transport, Cell Nucleus, Aged, Aged, 80 and over, Animals, Base Sequence, Binding Sites, Carcinoma, Cell Line, Tumor, Cell Nucleus, Cell Proliferation, Cell Transformation, Neoplastic, Colorectal Neoplasms, Female, Gene Expression Regulation, Neoplastic, Humans, Male, Mice, Mice, SCID, Middle Aged, Multiprotein Complexes, Neoplasm Transplantation, PDZ Domains, Phosphoproteins, Promoter Regions, Genetic, Protein Binding, Signal Transduction, Sodium-Hydrogen Exchangers, T Cell Transcription Factor 1, beta Catenin
J Clin Invest
Date: May. 01, 2012
PubMed ID: 22466651
View in: Pubmed Google Scholar
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