Zfp703 Is a Wnt/β-Catenin Feedback Suppressor Targeting the β-Catenin/Tcf1 Complex.

Author(s): Kumar A,  Chalamalasetty RB,  Kennedy MW,  Thomas S,  Inala SN,  Garriock RJ,  Yamaguchi TP

Journal: Mol Cell Biol

Date: 2016 Jun 15

Major Program(s) or Research Group(s): NSRG

PubMed ID: 27090637

PMC ID: PMC4907093

Abstract: The Wnt/β-catenin signaling pathway controls embryonic development and adult stem cell maintenance through the regulation of transcription. Failure to downregulate Wnt signaling can result in embryonic malformations and cancer, highlighting the important role of negative regulators of the pathway. The Wnt pathway activates several negative feedback targets, including axin2 and Dkk1, that function at different levels of the signaling cascade; however, none have been identified that directly target active β-catenin/Tcf1 transcriptional complexes. We show that Zfp703 is a Wnt target gene that inhibits Wnt/β-catenin activity in Wnt reporter assays and in Wnt-dependent mesoderm differentiation in embryonic stem cells. Zfp703 binds directly to Tcf1 to inhibit β-catenin/Tcf1 complex formation and does so independently of the Groucho/Tle transcriptional corepressor. We propose that Zfp703 is a novel feedback suppressor of Wnt/β-catenin signaling that functions by inhibiting the association of β-catenin with Tcf1 on Wnt response elements in target gene enhancers.