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

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.

Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.01010-15.

ACKNOWLEDGMENTS

We thank Alan Perantoni for providing materials and support and Ruth Wolfe for assistance with mouse colony management.

M.W.K. designed the screen. A.K. and R.B.C. performed the majority of experiments with assistance from M.W.K., R.J.G., S.T., and S.N.I. R.J.G. and T.P.Y. wrote the manuscript.

Additional information

Funding

This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research.