Abstract
beta-Catenin plays an important role in signal transduction pathways that regulate cellular differentiation and proliferation. The increased concentration of this protein in the cytoplasm favors its binding to the T-cell factor (TCF) family of DNA-binding proteins, and it subsequently translocates to the nucleus, where it induces transcription of specific genes. We explored mechanisms that lead to activation of beta-catenin/TCF-dependent transcription in esophageal squamous cell carcinoma (ESCC) independent of adenomatous polyposis coli and beta-catenin mutation. Electrophoresis mobility shift assay demonstrated that TCF4 and beta-catenin form a complex and have DNA binding activity. However, there was no constitutive activation of beta-catenin/TCF-dependent transcription. Coculture experiments demonstrated that Wnt-1, but not Wnt-5A and Wnt-7A, activated the TCF reporter gene. Additionally, when cultured with Wnt-1-conditioned media, ESCC cell lines showed an accumulation of beta-catenin in the cytoplasm. Although both Wnt and epidermal growth factor inactivate glycogen synthase kinase 3beta, activation of epidermal growth factor receptor did not stabilize beta-catenin. A comparison of extracellular stimuli suggests that specific Wnt family members stabilize beta-catenin with resulting activation of TCF-dependent transcription in ESCC.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Calcium-Calmodulin-Dependent Protein Kinases / antagonists & inhibitors
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism
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Cytoplasm / metabolism
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Cytoskeletal Proteins / biosynthesis
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Cytoskeletal Proteins / genetics
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Cytoskeletal Proteins / physiology*
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Epidermal Growth Factor / physiology*
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ErbB Receptors / physiology
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Esophageal Neoplasms / genetics
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Esophageal Neoplasms / metabolism*
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Esophageal Neoplasms / pathology
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Gene Expression Regulation, Neoplastic
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Glycogen Synthase Kinase 3
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Glycogen Synthase Kinases
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Humans
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Proto-Oncogene Proteins / physiology*
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Signal Transduction
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TCF Transcription Factors
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Trans-Activators*
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Transcription Factor 7-Like 2 Protein
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Transcription Factors / physiology*
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Transcriptional Activation / physiology
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Transfection
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Tumor Cells, Cultured
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Wnt Proteins
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Wnt1 Protein
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Xenopus Proteins
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Xenopus laevis
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Zebrafish Proteins*
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beta Catenin
Substances
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CTNNB1 protein, Xenopus
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CTNNB1 protein, human
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Cytoskeletal Proteins
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Proto-Oncogene Proteins
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TCF Transcription Factors
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TCF7L2 protein, human
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Trans-Activators
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Transcription Factor 7-Like 2 Protein
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Transcription Factors
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WNT1 protein, Xenopus
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WNT1 protein, human
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Wnt Proteins
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Wnt1 Protein
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Xenopus Proteins
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Zebrafish Proteins
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beta Catenin
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tcf7l2 protein, Xenopus
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Epidermal Growth Factor
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ErbB Receptors
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Glycogen Synthase Kinases
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Calcium-Calmodulin-Dependent Protein Kinases
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Glycogen Synthase Kinase 3