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Title: Identification of BCL-3 as a novel regulator of β-catenin activity : implications on colorectal carcinogenesis
Author: Shephard , Alexandra P.
ISNI:       0000 0004 5921 0790
Awarding Body: University of Bristol
Current Institution: University of Bristol
Date of Award: 2014
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Colorectal cancer is the third most common cancer worldwide and one of the leading causes of cancer related death in the UK. Most instances of colorectal cancer arise due to deregulation of the Wnt signalling pathway, although chronic inflammation has also been identified as a risk factor. Production of pro-inflammatory cytokines by immune cells activates cellular signalling pathways such as the NF-KB pathway, known to be constitutively active in colorectal cancer and induce transcription of a range of genes involved in cell growth and survival. Evidence has emerged which suggests that crosstalk may occur between the NF-KB and Wnt signalling pathways, raising the intriguing possibility of suppressing two of the major drivers of colorectal carcinogenesis by therapeutically targeting proteins involved in crosstalk. To date, the majority of studies have focused on reciprocal regulation between the NF-KB p6S-pSO heterodimers and the Wnt transcriptional coactivator b-catenin, with the role of the atypical NF -KB signalling pathway yet to be investigated. Results presented in this study show that the NF-KB homodimeric regulator and proto-oncogene B-cell lymphoma 3 (BCL-3), known to be overexpressed in colorectal cancer, induces the transcriptional activity of b - catenin and drives expression of Wnt target genes in a b-catenin dependent manner in colorectal carcinoma cell lines. Interestingly, BCL-3 was shown to upregulate expression of ~-catenin target genes involved in cell growth and survival (SOX9), angiogenesis (VEGFA), and the intestinal stem cell phenotype (LGRS), while downregulating expression of the tumour suppressor and cell adhesion protein E-cadherin. The impact on tumour vascularity and metastatic potential was further investigated in vivo. Intriguingly, BCL-3 was not shown to regulate the protein levels or phosphorylation state of b-catenin, however the ankyrin repeat domain of BCL-3 was required for regulation of ~ - catenin activity. Results to date consequently suggest an indirect mechanism of action whereby BCL-3 acts via a coactivator or repressor of b-catenin transcriptional function. Interestingly, suppression of b-catenin expression in colorectal carcinoma cells revealed a negative feedback loop involving repression of BCL-3 by b-catenin.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available