E-cadherin regulates cell growth by modulating proliferation-dependent beta-catenin transcriptional activity.
beta-Catenin is essential for E-cadherin-mediated cell adhesion in epithelial cells, but it also forms nuclear complexes with high mobility group transcription factors. Using a mouse mammary epithelial cell system, we have shown previously that conversion of epithelial cells to a fibroblastoid phenotype (epithelial-mesenchymal transition) involves downregulation of E-cadherin and upregulation of beta-catenin transcriptional activity. Here, we demonstrate that transient expression of exogenous E-cadherin in both epithelial and fibroblastoid cells arrested cell growth or caused apoptosis, depending on the cellular E-cadherin levels. By expressing E-cadherin subdomains, we show that the growth-suppressive effect of E-cadherin required the presence of its cytoplasmic beta-catenin interaction domain and/or correlated strictly with the ability to negatively interfere with beta-catenin transcriptional activity. Furthermore, coexpression of beta-catenin or lymphoid enhancer binding factor-1 or T cell factor 3 with E-cadherin rescued beta-catenin transcriptional activity and counteracted E-cadherin-mediated cell cycle arrest. Stable expression of E-cadherin in fibroblastoid cells decreased beta-catenin activity and reduced cell growth. Since proliferating cells had a higher beta-catenin activity than G1 phase-arrested or contact-inhibited cells, we conclude that beta-catenin transcriptional activity is essential for cell proliferation and can be controlled by E-cadherin in a cell adhesion-independent manner.
Stockinger
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A
Department of Biochemistry and Molecular Cell Biology, Vienna Biocenter, University of Vienna, A-1030 Vienna, Austria.
Eger
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A
Wolf
J
J
Beug
H
H
Foisner
R
R
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015820:Cadherins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D002448:Cell Adhesion; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured / Q000166:cytology / Q000187:drug effects; D003598:Cytoskeletal Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D004847:Epithelial Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000187:drug effects*; D051379:Mice; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology; D015534:Trans-Activators; D014158:Transcription, Genetic / Q000187:drug effects; D051176:beta Catenin
C495267:CTNNB1 protein, mouse; D015820:Cadherins; D003598:Cytoskeletal Proteins; D010446:Peptide Fragments; D015534:Trans-Activators; D051176:beta Catenin