title: Sox17 modulates Wnt3A/beta-catenin-mediated transcriptional activation of the Lef-1 promoter.
abstract: Wnt/β-catenin-dependent activation of lymphoid enhancer factor 1 (Lef-1) plays an important role in numerous developmental processes. In this context, transcription of the Lef-1 gene is increased by Wnt-mediated TCF4/β-catenin activation on the Lef-1 promoter through mechanisms that remain poorly defined. In mouse airway submucosal gland progenitor cells, Wnt3A transiently induces Lef-1 gene expression, and this process is required for epithelial cell proliferation and glandular morphogenesis. In the present study, we sought to identify additional candidate transcriptional regulators of the Lef-1 gene during glandular morphogenesis. To this end, we found that Sox17 expression is dramatically downregulated in early glandular progenitor cells that induce Lef-1 expression. Wnt stimulation of undifferentiated primary airway epithelial cells induced similar changes in Sox17 and Lef-1 expression. Reporter assays revealed that ectopic expression of Sox17 suppresses Wnt3A/β-catenin activation of the Lef-1 promoter in cell lines. EMSA and ChIP analyses defined several Sox17- and TCF4-binding sites that collaborate in transcriptional control of the Lef-1 promoter. More specifically, Sox17 bound to four sites in the Lef-1 promoter, either directly or indirectly through TCF complexes. The DNA- or β-catenin-binding domains of Sox17 controlled context-specific binding of Sox17/TCF complexes on the Lef-1 promoter. Combinatorial site-directed mutagenesis of Sox17- or TCF-binding sites in the Lef-1 promoter demonstrated that these sites control Wnt/β-catenin-mediated induction and/or repression. These findings demonstrate for the first time that Sox17 can directly regulate Wnt/β-catenin-dependent transcription of the Lef-1 promoter and reveal new context-dependent binding sites in the Lef-1 promoter that facilitate protein-protein interactions between Sox17 and TCF4.
authors.affiliation: Department of Anatomy and Cell Biology, Carver College of Medicine, The University of Iowa, Iowa City, Iowa 52240, USA.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Liu
authors.forename: Meihui
authors.initials: M
authors.lastname: Luo
authors.forename: Weiliang
authors.initials: W
authors.lastname: Xie
authors.forename: James M
authors.initials: JM
authors.lastname: Wells
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Goodheart
authors.forename: John F
authors.initials: JF
authors.lastname: Engelhardt
mesh_terms: D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism; D001665:Binding Sites; D002460:Cell Line; D004247:DNA / Q000378:metabolism; D005289:Ferrets / Q000033:anatomy & histology; D005786:Gene Expression Regulation; D024002:HMGB Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000235:genetics* / Q000378:metabolism; D046911:Macromolecular Substances; D051379:Mice; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012137:Respiratory System / Q000033:anatomy & histology / Q000254:growth & development / Q000378:metabolism; D055760:SOXF Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D060508:Wnt3 Protein; D060509:Wnt3A Protein
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D024002:HMGB Proteins; D051821:Lymphoid Enhancer-Binding Factor 1; D046911:Macromolecular Substances; D055760:SOXF Transcription Factors; C511606:Sox17 protein, mouse; C532096:TCF4 protein, human; D000073940:Transcription Factor 4; D014157:Transcription Factors; C555510:WNT3A protein, human; D051153:Wnt Proteins; D060508:Wnt3 Protein; D060509:Wnt3A Protein; C555511:Wnt3a protein, mouse; D004247:DNA
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