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Transcriptional Regulation by Smads: Crosstalk between the TGF-ß and Wnt Pathways

Department of Anatomy and Cell Biology and Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
Ainhoa Letamendia, PhD Liliana Attisano, PhD Department of Anatomy and Cell Biology Etienne Labbé, PhD Department of Medical Biophysics Medical Sciences Building, Room 6336, 1 King's College Circle, University of Toronto, Toronto, ON M5S 1A8, Canada. E-mail address for L. Attisano: liliana.attisano{at}utoronto.ca
In support of their research or preparation of this manuscript, one or more of the authors received grants or outside funding from Canadian Institute for Health Research and National Cancer Institute of Canada. None of the authors received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, educational institution, or other charitable or nonprofit organization with which the authors are affiliated or associated.

Background: Several studies have shown that cooperation between transforming growth factor beta (TGF-ß) and Wnt/wingless signaling pathways plays a role in controlling certain developmental events. These factors elicit their biological effects through distinct pathways in which TGF-ß and Wnt signaling induce activation of the transcriptional regulators Smads and lymphoid enhancer binding factor/T-cell-specific factor (LEF/TCF), respectively. To understand the mechanism for cooperativity between these pathways, we have investigated the molecular mechanism for this synergistic effect.

Methods: Transcriptional assays were conducted by transient transfection of HepG2 cells with use of luciferase reporter constructs. Protein/protein interaction studies were conducted in vitro with the use of glutathione-S-transferase pull-down assays and in intact cells by immunoprecipitation and immunoblotting.

Results: We show that Smads physically interact with LEF1/TCF transcription factors and that specific DNA binding sites in the Xenopus twin promoter are required for synergistic activation by TGF-ß and Wnt pathways. In addition, we demonstrate that TGF-ß-dependent activation of LEF1/TCF target genes can occur independently of ß-catenin, an essential component of the Wnt signaling pathway.

Conclusions: TGF-ß and Wnt signaling pathways can independently or cooperatively regulate LEF1/TCF target genes. This suggests that the cooperation between these pathways may be important for the specification of cell fates during development.

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