Type
Text
Type
Dissertation
Advisor
Thomsen, Gerald H | Li, Feng-Qian | Levine, Joel | Brown, Deborah A.
Date
2012-05-01
Keywords
Pharmacology--Cellular biology--Molecular biology | beta-catenin, Chibby, colon cancer, epithelial-to-mesenchymal transition, Wnt-signaling
Department
Department of Molecular and Cellular Pharmacology
Language
en_US
Source
This work is sponsored by the Stony Brook University Graduate School in compliance with the requirements for completion of degree.
Identifier
http://hdl.handle.net/11401/71219
Publisher
The Graduate School, Stony Brook University: Stony Brook, NY.
Format
application/pdf
Abstract
The Wnt/beta-catenin signaling pathway is well known for its prominent role in tumorigenesis of colon cancers, but also of some other tumors. Beta-Catenin, the downstream mediator of canonical Wnt-signaling, is continuously degraded in the absence of Wnt signaling but stabilized upon activation of the pathway. Beta-Catenin then activates transcription of target genes in the nucleus, leading e.g. to proliferation, invasiveness and anoikis resistance, and can induce epithelial-to-mesenchymal transition (EMT). Apart from its function as a transcriptional coactivator, beta-catenin forms part of adherens junctions where it plays a pivotal role mediating the connection between the adherens junction protein E-cadherin and the actin cytoskeleton, and its loss from the membrane entrails reduced cell-cell adhesion. This role contrasts beta-catenin's function in the nucleus since formation of E-cadherin-mediated adherens junctions reverses a malignant phenotype, effectuating mesenchymal-to-epithelial transition (MET), in a variety of tumor cell lines. The small, evolutionarily conserved protein Chibby was initially discovered as beta-catenin binding partner. Our lab has shown that Chibby shuttles beta-catenin out of the nucleus, in cooperation with 14-3-3 proteins. By this mechanism and by competing with T-cell factor/lymphoid enhancer factor (TCF/LEF) transcription factors for beta-catenin binding, Chibby inhibits nuclear beta-catenin signaling. We show here that Chibby counteracts both of beta-catenin's opposing roles in that a) Chibby can reduce beta-catenin nuclear signaling and cell proliferation in human colon cancer cells bearing stabilized beta-catenin by reducing nuclear levels of beta-catenin, and that b) Chibby knock-down leads to increased proteins levels of E-cadherin and beta-catenin at the plasma membrane, to the point of inducing mesenchymal-to-epithelial reversion with reduced tumor characteristics in human embryonic kidney and human colon cancer cells, and that this is due at least in part to increased transcription of the E-cadherin gene. These findings are relevant to further development of treatment options for Wnt/beta-catenin-dependent tumors. | 79 pages
Recommended Citation
Fischer, Victoria, "Dual Role of Chibby in Regulation of Cell Growth and Mesenchymal-to-Epithelial Transition-like Processes" (2012). Stony Brook Theses and Dissertations Collection, 2006-2020 (closed to submissions). 425.
https://commons.library.stonybrook.edu/stony-brook-theses-and-dissertations-collection/425