Wnt-1 but not epidermal growth factor induces beta-catenin/T-cell factor-dependent transcription in esophageal cancer cells.
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.
Mizushima
Takaaki
T
Gastroenterology Division, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Nakagawa
Hiroshi
H
Kamberov
Yana G
YG
Wilder
Elizabeth L
EL
Klein
Peter S
PS
Rustgi
Anil K
AK
D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D004815:Epidermal Growth Factor / Q000502:physiology*; D066246:ErbB Receptors / Q000502:physiology; D004938:Esophageal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D038362:Glycogen Synthase Kinase 3; D038341:Glycogen Synthase Kinases; D006801:Humans; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D015398:Signal Transduction; D051820:TCF Transcription Factors; D015534:Trans-Activators; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors / Q000502:physiology*; D015533:Transcriptional Activation / Q000502:physiology; D014162:Transfection; D014407:Tumor Cells, Cultured; D051153:Wnt Proteins; D051155:Wnt1 Protein; D029867:Xenopus Proteins; D014982:Xenopus laevis; D029961:Zebrafish Proteins; D051176:beta Catenin
C495266:CTNNB1 protein, Xenopus; C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D011518:Proto-Oncogene Proteins; D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; D015534:Trans-Activators; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors; C495249:WNT1 protein, Xenopus; C495247:WNT1 protein, human; D051153:Wnt Proteins; D051155:Wnt1 Protein; D029867:Xenopus Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin; C544896:tcf7l2 protein, Xenopus; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D038341:Glycogen Synthase Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3