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Title: A study of the links in between the ASPPs and the Wnt/beta-catenin signalling pathway
Author: Royer, C.
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2008
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The identification of the ASPP family of proteins has helped towards a better understanding of how the function of the tumour suppressor p53 could be specifically regulated. Hence, ASPP1 and ASPP2 bind to- and specifically enhance the transactivation function of p53 on the promoters of proapoptotic genes, whereas iASPP acts as an inhibitor. However, yeast-two-hybrid experiments have shown that the ASPPs, and in particular ASPP2, also interacts with a large number of proteins involved in other major signalling pathways, suggesting that they could be a multi-function family of proteins. One of ASPP2-interacting partners is Adenomatous Polyposis Coli 2/L (APC2/APCL). APCL is a central nervous system-specific homologue of APC, a key factor in the Wnt signalling pathway. As the biological significance of this interaction remains unknown, we explored the interplay between the ASPPs and the APC family. We show that APC and APCL can affect the subcellular localization of ASPP1 and ASPP2 as well as positively regulate their function on p53. As APCL, like APC. is believed to be able to target p-catenin for degradation, we investigated whether ASPP2 could play a role in the regulation of P-catenin. Herein, we show that ASPP2 is a negative regulator of p-catenin transcriptional activity and that they can form a complex at the level of the adherens junctions. In vivo, ASPP2-null mice exhibit severe anomalies in the central nervous system (CNS) formation during embryonic development. Hence, the eyes and the brain were characterized by increased number of cells, poor cellular differentiation and tissue disorganization. Cells expressing nuclear p-catenin were found in a very limited and organized apical region of the developing cortex in the wild-type, whereas in the ASPP2-deficient embryos, they were disseminated throughout the overgrown regions of the brain, suggesting that ASPP2 may regulate p-catenin function during CNS development. Finally, the involvement of ASPP2 in the regulation of p-catenin transcriptional activity could contribute to its function as a tumour suppressor and, importantly, its role in epithelial integrity suggests that it could be determinant in preventing cellular invasion and metastasis.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available