| dc.identifier.uri | http://hdl.handle.net/1951/59646 | |
| dc.identifier.uri | http://hdl.handle.net/11401/71219 | |
| dc.description.sponsorship | This work is sponsored by the Stony Brook University Graduate School in compliance with the requirements for completion of degree. | en_US |
| dc.format | Monograph | |
| dc.format.medium | Electronic Resource | en_US |
| dc.language.iso | en_US | |
| dc.publisher | The Graduate School, Stony Brook University: Stony Brook, NY. | |
| dc.type | Dissertation | |
| dcterms.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. | |
| dcterms.available | 2013-05-22T17:34:31Z | |
| dcterms.available | 2015-04-24T14:46:33Z | |
| dcterms.contributor | Li, Feng-Qian | en_US |
| dcterms.contributor | Thomsen, Gerald H | en_US |
| dcterms.contributor | Levine, Joel | en_US |
| dcterms.contributor | Brown, Deborah A. | en_US |
| dcterms.creator | Fischer, Victoria | |
| dcterms.dateAccepted | 2013-05-22T17:34:31Z | |
| dcterms.dateAccepted | 2015-04-24T14:46:33Z | |
| dcterms.dateSubmitted | 2013-05-22T17:34:31Z | |
| dcterms.dateSubmitted | 2015-04-24T14:46:33Z | |
| dcterms.description | Department of Molecular and Cellular Pharmacology | en_US |
| dcterms.extent | 79 pg. | en_US |
| dcterms.format | Monograph | |
| dcterms.format | Application/PDF | en_US |
| dcterms.identifier | Fischer_grad.sunysb_0771E_10991 | en_US |
| dcterms.identifier | http://hdl.handle.net/1951/59646 | |
| dcterms.identifier | http://hdl.handle.net/11401/71219 | |
| dcterms.issued | 2012-05-01 | |
| dcterms.language | en_US | |
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Previous issue date: 1 | en |
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| dcterms.publisher | The Graduate School, Stony Brook University: Stony Brook, NY. | |
| dcterms.subject | Pharmacology--Cellular biology--Molecular biology | |
| dcterms.subject | beta-catenin, Chibby, colon cancer, epithelial-to-mesenchymal transition, Wnt-signaling | |
| dcterms.title | Dual Role of Chibby in Regulation of Cell Growth and Mesenchymal-to-Epithelial Transition-like Processes | |
| dcterms.type | Dissertation | |
