TGFβ3 Inhibits E-Cadherin Gene Expression in Palate Medial-Edge Epithelial Cells Through a Smad2-Smad4- LEF1 Transcription Complex

Introduction E-cadherin, the primary cell adhesion molecule within adherens junctions, is essential for maintaining apical-basal polarity in epithelial cells (Takeichi, 1988; Hay, 1995). During epithelial-mesenchymal transformation (EMT), loss of E-cadherin expression correlates with a transition to front-end to back-end polarity, leading to subsequent migration of the newly created mesenchymal cells (Thiery, 2003). This molecular mechanism is essential for correct development during embryogenesis and is a common initiator of tumor metastasis (Birchmeier et al., 1996; Thiery, 2002). Many transcription factor proteins, such as Snail, Slug, E12/E47, SIP-1, ZEB-1 and Twist directly bind to the E-cadherin gene promoter to inhibit its transcription (Peinado et al., 2004). Lymphoid enhancer factor 1 (LEF1), a molecule typically associated with Wnt signaling (Behrens et al., 1996; Eastman and Grosschedl, 1999), has been proved do the same when activated by ␤-catenin (Jamora et al., 2003; Medici et al., 2006). A strong correlation has been made between ␤-catenin–LEF1 signaling and acquisition of the invasive morphology in colon carcinoma cells (Kim et al., 2002) and malignant melanomas (Murakami et al., 2001; Chen et al., 2003). LEF1 is also localized in most embryonic tissues that undergo EMT, including the neural crest, somites, primitive streak (Mohamed et al., 2004) and palate (Nawshad and Hay, 2003). During embryogenesis, the formation of the palate occurs