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Regulation of Tcf7l1 DNA Binding and Protein Stability as Principal Mechanisms of Wnt/b-Catenin Signaling

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journal contribution
posted on 08.01.2014, 00:00 by Brian R. Shy, Chun-I. Wu, Galina F. Khramtsova, Jenny Y. Zhang, Olufunmilayo I. Olopade, Kathleen H. Goss, Bradley J. Merrill
Wnt/β-catenin signal transduction requires direct binding of β-catenin to Tcf/Lef proteins, an event that is classically associated with stimulating transcription by recruiting coactivators. This molecular cascade plays critical roles throughout embryonic development and normal postnatal life by affecting stem cell characteristics and tumor formation. Here, we show that this pathway utilizes a fundamentally different mechanism to regulate Tcf7l1 (formerly named Tcf3) activity. β-catenin inactivates Tcf7l1 without a switch to a coactivator complex by removing it from DNA, which leads to Tcf7l1 protein degradation. Mouse genetic experiments demonstrate that Tcf7l1 inactivation is the only required effect of the Tcf7l1-β-catenin interaction. Given the expression of Tcf7l1 in pluripotent embryonic and adult stem cells, as well as in poorly differentiated breast cancer, these findings provide mechanistic insights into the regulation of pluripotency and the role of Wnt/β-catenin in breast cancer.


This work was funded by grants from the National Institutes of Health (RO1-CA128571 to B.J.M. and UL1TR000050 to the UIC CCTS) and the American Cancer Society Illinois Division (215889 to K.H.G.).


Publisher Statement

NOTICE: This is the author’s version of a work that was accepted for publication in Cell Reports. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Elsevier, 4,1 2013 DOI: 10.1016/j.celrep.2013.06.001







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