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dc.contributor.advisorMerrill, Bradleyen_US
dc.contributor.authorWu, Chun-Ien_US
dc.date.accessioned2014-06-20T17:12:45Z
dc.date.available2014-06-20T17:12:45Z
dc.date.created2014-05en_US
dc.date.issued2014-06-20
dc.date.submitted2014-05en_US
dc.identifier.urihttp://hdl.handle.net/10027/18804
dc.description.abstractThe 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.en_US
dc.language.isoenen_US
dc.rightsen_US
dc.rightsCopyright 2014 Chun-I Wuen_US
dc.subjectT-cell factor (Tcf3)en_US
dc.subjectT-cell factor 7l1 (Tcf7l1)en_US
dc.subjectWnt signalingen_US
dc.subjectMouse embryogenesisen_US
dc.subjectbeta-cateninen_US
dc.subjectEmbryonic stem cellsen_US
dc.titleWnt/β-catenin Pathway Functions by Inactivation of Tcf7l1 Proteinen_US
thesis.degree.departmentBiochemistry and Molecular Geneticsen_US
thesis.degree.disciplineBiochemistry and Molecular Geneticsen_US
thesis.degree.grantorUniversity of Illinois at Chicagoen_US
thesis.degree.levelDoctoralen_US
thesis.degree.namePhD, Doctor of Philosophyen_US
dc.type.genrethesisen_US
dc.contributor.committeeMemberBenevolenskaya, Elizavetaen_US
dc.contributor.committeeMemberFrolov, Maximen_US
dc.contributor.committeeMemberLau, Lesteren_US
dc.contributor.committeeMemberSchmidt, Jenniferen_US
dc.type.materialtexten_US


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