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The roles of the APC proteins in homeostasis and tumourigenesis

Daly, Carl S. 2013. The roles of the APC proteins in homeostasis and tumourigenesis. PhD Thesis, Cardiff University.
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Abstract

The adenomatous polyposis coli (APC) gene encodes a multifunctional tumour suppressor protein that is essential for normal development. The most characterised role of APC is its ability to mediate the Wnt signaling pathway, a pathway disrupted in the majority of human cancers. The identification of a second adenomatous polyposis coli gene (APC2) which possesses many shared structural characteristics with APC and potentially comparable functions raises the possibility that APC2 also functions both in development and in tumour suppression, and that some redundancy may exist between the two proteins. Analysis of these proteins in the mouse has been hampered due to the lethality of the Apc mutation and the lack of a suitable Apc2 mutation. However, to circumvent the first of these difficulties, Cre-lox technology was employed to conditionally delete Apc in adult mouse tissues and so study its function in vivo. To circumvent the second difficulty, a novel Apc2 null allele had become available from the laboratory of Professor Hans Clevers. Remarkably, constitutive deletion of Apc2 does not lead to embryonic lethality, permitting study of the effects of Apc2 deficiency within adult tissues. In this thesis I aimed to characterise the consequences of Apc2 loss alone, and in the context of tissue specific Apc loss, in a range of tissues. Apc2 deficiency led to subtle changes in Wnt signaling in the intestines and liver however, no detectable differences of this pathway were apparent within the mammary gland. Phenotypically, altered homeostasis was only observed within the intestines. Apc2 deficiency led to an increase in epithelial cell division, an increase in markers of intestinal stemness and increases in intestinal cell migration. However, loss of Apc2 failed to induce tumourigenesis in the intestines or indeed any other tissue. In the context of Apc loss, the effect was dependent upon the tissue. Within the intestines, additional loss of Apc2 altered the immediate phenotype of Apc loss but failed to modify Apc induced tumourigenesis. Within the mammary gland, whilst either Apc protein alone was dispensable, combined loss synergised to disrupt homeostasis and drive tumourigenesis. Contrary to this, in the liver the additional loss of Apc2 attenuated tumourigenesis induced by reduced levels of Apc. Together, these studies highlight the importance of these proteins and their interactions and redundancies in homeostasis and tumourigenesis.

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Biosciences
European Cancer Stem Cell Research Institute (ECSCRI)
Subjects: Q Science > QH Natural history > QH426 Genetics
R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Date of First Compliant Deposit: 30 March 2016
Last Modified: 19 Mar 2016 23:25
URI: http://orca-mwe.cf.ac.uk/id/eprint/51008

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