Upregulation of TCF4 expression as a transcriptional target of beta-catenin/p300 complexes during trans-differentiation of endometrial carcinoma cells.
Nuclear stabilization of beta-catenin and its interaction with TCF/LEF factors are key events in transduction of the Wnt/beta-catenin signal pathway. Our previous study indicated that nuclear beta-catenin accumulation provides an initial signal for trans-differentiation toward the squamoid phenotype of endometrial carcinoma (Em Ca) cells in a TCF4-dependent manner, which makes ... this a possible factor for a positive prognosis. However, little is known about regulation of TCF4 expression in Em Cas. We show here that beta-catenin can directly induce transcription from the TCF4 promoter, the effect being enhanced by the p300 coactivator. In clinical cases, nuclear beta-catenin accumulation was found to frequently overlap with TCF4 immunoreactivity in morules and surrounding glandular carcinoma lesions, showing a significant positive correlation (r = 0.82, P < 0.0001), in contrast to areas of squamous metaplasia (SqM) within Em Cas. In cases with coexistence of two squamoid features in trans-differentiated areas, loss of nuclear beta-catenin and TCF4 immunoreactivity was closely related to change in the morphology from the morular to the SqM phenotype. The TCF4 promoter contains a single consensus TCF-binding site that is critical for activation by beta-catenin. The p300 coactivator, in particular N-terminal residues 1 to 670, appears sufficient to enhance beta-catenin-dependent transcription, again with TCF4-dependence. These findings indicate that a positive feedback loop of TCF4 expression mediated by beta-catenin/p300 may be important for initial steps during trans-differentiation of Em Ca cells. In addition, its downregulation is associated with induction of a more-differentiated squamoid phenotype.
Mesh Terms:
Base Sequence, Carcinoma, Squamous Cell, Cell Differentiation, Cell Line, Tumor, Cytoskeletal Proteins, DNA Primers, DNA-Binding Proteins, Endometrial Neoplasms, Female, Gene Expression Regulation, Neoplastic, Helix-Loop-Helix Motifs, Humans, Hysterectomy, Metaplasia, Nuclear Proteins, Phenotype, Promoter Regions, Genetic, Reverse Transcriptase Polymerase Chain Reaction, TCF Transcription Factors, Trans-Activators, Transcription Factor 7-Like 2 Protein, Transcription Factors, Transcription, Genetic, Transfection, beta Catenin
Base Sequence, Carcinoma, Squamous Cell, Cell Differentiation, Cell Line, Tumor, Cytoskeletal Proteins, DNA Primers, DNA-Binding Proteins, Endometrial Neoplasms, Female, Gene Expression Regulation, Neoplastic, Helix-Loop-Helix Motifs, Humans, Hysterectomy, Metaplasia, Nuclear Proteins, Phenotype, Promoter Regions, Genetic, Reverse Transcriptase Polymerase Chain Reaction, TCF Transcription Factors, Trans-Activators, Transcription Factor 7-Like 2 Protein, Transcription Factors, Transcription, Genetic, Transfection, beta Catenin
Lab. Invest.
Date: Jun. 01, 2005
PubMed ID: 15806138
View in: Pubmed Google Scholar
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