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Wnt/β-catenin Pathway Functions by Inactivation of Tcf7l1 Protein

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Title: Wnt/β-catenin Pathway Functions by Inactivation of Tcf7l1 Protein
Author(s): Wu, Chun-I
Advisor(s): Merrill, Bradley
Contributor(s): Benevolenskaya, Elizaveta; Frolov, Maxim; Lau, Lester; Schmidt, Jennifer
Department / Program: Biochemistry and Molecular Genetics
Graduate Major: Biochemistry and Molecular Genetics
Degree Granting Institution: University of Illinois at Chicago
Degree: PhD, Doctor of Philosophy
Genre: Doctoral
Subject(s): T-cell factor (Tcf3) T-cell factor 7l1 (Tcf7l1) Wnt signaling Mouse embryogenesis beta-catenin Embryonic stem cells
Abstract: The canonical Wnt/β-catenin signaling pathway classically functions through the activation of target genes by Tcf/Lef–β-catenin complexes. Each Tcf/Lef in mammals is believed to function as a switch, going from a transcriptional repressor in the absence of Wnt stabilized β-catenin to a transcriptional activator in the presence of Wnt-stabilized β-catenin. I determined that mouse Tcf7l1 (formerly named Tcf3) mediates a distinct and new form of regulation of the pathway, which is independent of transactivator activity of Tcf7l1-β-catenin complexes. Instead of switching Tcf7l1 into a transactivator, Wnt/β-catenin reduces Tcf7l1 protein levels, which relieves repression of target genes, such as Lef1. Experiments using mouse embryonic stem cells show that recombinant Wnt3a, GSK3-inhibition, or simply increasing β-catenin levels were all sufficient to reduce Tcf7l1 protein independent of mRNA levels. The effect did not occur in Tcf7l1ΔN/ΔN ES cells, which lack nine Tcf7l1 residues necessary for binding to β-catenin. Thus, β-catenin binding to Tcf7l1 is necessary and sufficient for destabilizing Tcf7l1 protein in stem cells. We ablated the Tcf7l1-β-catenin interaction by generating a mouse Tcf7l1ΔN knockin allele and show Tcf7l1ΔN blocks Wnt-reduction of Tcf7l1, inhibits Lef1 expression, and causes peri-natal lethality in Tcf7l1ΔN/ΔN mice. Interestingly, Tcf7l1-/ΔN mice developed into viable and ostensibly normal adult mice, demonstrating that reducing the amount of Tcf7l1 replaced the requirement for Tcf7l1-β-catenin interaction. These findings impact understanding of the mechanisms whereby Wnt/β-catenin mediates its effects, especially in Tcf7l1-expressing stem cells and tumor cells.
Issue Date: 2014-06-20
Genre: thesis
Rights Information: Copyright 2014 Chun-I Wu
Date Available in INDIGO: 2014-06-20
Date Deposited: 2014-05

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