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Wnt-1 but not Epidermal Growth Factor Induces ß-Catenin/T-Cell Factor-dependent Transcription in Esophageal Cancer Cells¹

Gastroenterology Division [T. M., H. N., A. K. R.], Department of Medicine [T. M., H. N., P. S. K., A. K. R.], Department of Genetics [A. K. R.], Cancer Center [A. K. R.], Abramson Family Cancer Research Institute [T. M., H. N., A. K. R.], University of Pennsylvania, Philadelphia, Pennsylvania 19104; Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6100 [Y. G. K., E. L. W.]; and Howard Hughes Medical Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6144 [P. S. K.]

ß-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 ß-catenin/TCF-dependent transcription in esophageal squamous cell carcinoma (ESCC) independent of adenomatous polyposis coli and ß-catenin mutation. Electrophoresis mobility shift assay demonstrated that TCF4 and ß-catenin form a complex and have DNA binding activity. However, there was no constitutive activation of ß-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 ß-catenin in the cytoplasm. Although both Wnt and epidermal growth factor inactivate glycogen synthase kinase 3ß, activation of epidermal growth factor receptor did not stabilize ß-catenin. A comparison of extracellular stimuli suggests that specific Wnt family members stabilize ß-catenin with resulting activation of TCF-dependent transcription in ESCC.

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