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Title: Identification, characterisation and functional analyses of novel beta-catenin associated protein, FLYWCH1
Author: Muhammad, Belal Abdul-Rahman
Awarding Body: University of Nottingham
Current Institution: University of Nottingham
Date of Award: 2013
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The growing knowledge of cell biology and evidence for the role of β-catenin signalling network in homeostasis and carcinogenesis encourages further investigation into the regulatory network of nuclear β-catenin signalling complex. While the role of canonical Wnt signalling in the development of both normal tissue and malignant tumours is well documented, the molecular basis of these functionally distinct nuclear transcriptional programs is poorly understood. Many proteins are associated with cytoplasmic β-catenin for regulation of Wnt/β-catenin pathway activities. However, in the nucleus, the LEF/TCF family of transcription factors, which have DNA binding properties, remains the sole focus as unambiguous partners of β-catenin. In addition to LEF/TCFs, interaction of β-catenin with several other transcriptional co-activators and/or co-repressors is required for gene regulation. This regulation may also be influenced by alterations of β-catenin protein such phosphorylation of β-catenin which dramatically alters its trafficking and function. Delineation and functional description of nuclear cofactors that interact with unphosphorylated (i.e. nuclear) β-catenin will further unravel the mechanisms of β-catenin-mediated nuclear transcription, and may also identify whether distinct patterns of transcriptional cofactors are engaged in normal development versus tumour progression. Human FLYWCH1, a conserved member of the mammalian C2H2 zinc finger proteins, was identified as one of the phosphorylation-independent Catenin- Interacting-Proteins (CIPs) in a recent screening performed in Dr Nateri's laboratory using a modified yeast-2-hybrid RRS. FLYWCH1 is a previously uncharacterized protein with no known function in mammals. Herein, we have shown that; i) in human cells, FLYWCH1 physically interacts with β-catenin and represses its transcriptional activity, ii) it regulates the expression of some if not all downstream target genes, iii) in the intestine, Flywch1 marks the crypt-based columnar-cells (CBCs), which function as stem cells, but does not mark any of the differentiated cells in normal villi, iv) FLYWCH1 expression is strongly down-regulated in CRC cell lines but its expression is up-regulated and restricted to a subpopulation of tumour cells in both human and ApcMin/+ mouse. Our data also showed that v) FLYWCH1 controls CRC cell morphology and inhibits cell migration through up-regulation of E-cadherin which may not be related to ZEB2-mediated EMT. Collectively, our data suggest that FLYWCH1 is a novel nuclear β-catenin interacting protein that inhibits cell motility by antagonizing the activity of Wnt/β-catenin signalling pathway. As changes in cell motility is a key step toward invasion and metastasis, FLYWCH1, therefore, may function as a metastasis-suppressing factor which could potentially be of use in the therapeutic field of colon cancer to control cancer spread.
Supervisor: Not available Sponsor: Medical Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QP Physiology