QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

Vol. 19, Issue 11, 4875-4887, November 2008

This Article Full Text Full Text (PDF) Supplemental Materials All Versions of this Article: E08-05-0506v1 19/11/4875    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Medici, D. Articles by Olsen, B. R. Search for Related Content PubMed PubMed Citation Articles by Medici, D. Articles by Olsen, B. R.

Snail and Slug Promote Epithelial-Mesenchymal Transition through β-Catenin–T-Cell Factor-4-dependent Expression of Transforming Growth Factor-β3

Damian Medici^*,, Elizabeth D. Hay^*, and Bjorn R. Olsen^*,

*Department of Cell Biology, Harvard Medical School, Boston, MA 02115; and Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA 02115

Submitted May 21, 2008; Revised August 4, 2008; Accepted September 5, 2008
Monitoring Editor: Marianne Bronner-Fraser

Members of the Snail family of transcription factors have been shown to induce epithelial-mesenchymal transition (EMT), a fundamental mechanism of embryogenesis and progressive disease. Here, we show that Snail and Slug promote formation of β-catenin–T-cell factor (TCF)-4 transcription complexes that bind to the promoter of the TGF-β3 gene to increase its transcription. Subsequent transforming growth factor (TGF)-β3 signaling increases LEF-1 gene expression causing formation of β-catenin–lymphoid enhancer factor (LEF)-1 complexes that initiate EMT. TGF-β1 or TGF-β2 stimulates this signaling mechanism by up-regulating synthesis of Snail and Slug. TGF-β1- and TGF-β2-induced EMT were found to be TGF-β3 dependent, establishing essential roles for multiple TGF-β isoforms. Finally, we determined that β-catenin–LEF-1 complexes can promote EMT without upstream signaling pathways. These findings provide evidence for a unified signaling mechanism driven by convergence of multiple TGF-β and TCF signaling molecules that confers loss of cell–cell adhesion and acquisition of the mesenchymal phenotype.

Address correspondence to: Bjorn R. Olsen (bjorn_olsen{at}hms.harvard.edu)

Abbreviations used: APC, adenomatosis polyposis coli; AS, antisense; DN, dominant negative; EMT, epithelial-mesenchymal transition; GSK, glycogen synthase kinase; LEF, lymphoid enhancer factor; MAPK, mitogen-activated protein kinase; MDCK, Madin-Darby canine kidney; ODN, oligodeoxynucleotide; PI3K, phosphoinositide 3-kinase; TCF, T-cell factor; TGF, transforming growth factor.

This article has been cited by other articles:

				C.-F. Hong, Y.-T. Chou, Y.-S. Lin, and C.-W. Wu MAD2B, a Novel TCF4-binding Protein, Modulates TCF4-mediated Epithelial-Mesenchymal Transdifferentiation J. Biol. Chem., July 17, 2009; 284(29): 19613 - 19622. [Abstract] [Full Text] [PDF]

				Y.-P. Tsai, M.-H. Yang, C.-H. Huang, S.-Y. Chang, P.-M. Chen, C.-J. Liu, S.-C. Teng, and K.-J. Wu Interaction between HSP60 and {beta}-catenin promotes metastasis Carcinogenesis, June 1, 2009; 30(6): 1049 - 1057. [Abstract] [Full Text] [PDF]

				F. Guan, K. Handa, and S.-i. Hakomori Specific glycosphingolipids mediate epithelial-to-mesenchymal transition of human and mouse epithelial cell lines PNAS, May 5, 2009; 106(18): 7461 - 7466. [Abstract] [Full Text] [PDF]