Investigation of the role of ASPP2 in tumourigenesis

Thesis

The skin is the site where two of the most common types of epithelial cancer, basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), arise. In this work, we have investigated how ASPP2, a member of a family of proteins that interact with the p53 family, can affect skin tumourigenesis. ASPP2 is expressed in the squamous epithelia of various organs, localising exclusively in the upper and most differentiated layers. We show here that Balb/c ASPP2-null and heterozygous mice develop spontaneous SCCs. To investigate how the absence of ASPP2 from the epithelial compartment could lead to tumour formation, we analysed ASPP2’s relationship with pathways involved in the normal homeostasis of the epithelium, such as p63 and Notch. ΔNp63 is the main p63 isoform expressed in the adult epidermis, and its function is to drive the proliferation of the basal keratinocytes. Aberrant or misplaced activation of ΔNp63 in the epithelium is a known initiating cause for SCC. Consistent with this, ΔNp63 was found to be highly expressed in tumours derived from ASPP2-deficient mice. Our results indicate that ASPP2 is important in limiting ΔNp63 expression in the differentiated epithelium, preventing cell proliferation in the upper layers of the skin. This is achieved by antagonising ΔNp63 transcript and protein expression, resulting in a mutually exclusive expression pattern during differentiation of keratinocytes, as well as in epithelial cancer. ASPP2 expression was found reduced or lost in human SCC cell lines and during head and neck cancer progression, reflecting what was observed in ASPP2-deficient mice. Overall, our results indicate a possible mechanism by which p63 expression can be regulated in the skin, and provide a new model for the spontaneous formation of SCC in vivo. Additionally, we found that ASPP2 can cooperate with and enhance the activity of skin pro-differentiation pathways, such as Notch. In contrast to p63, ASPP2 and Notch1 are co-expressed in the differentiated layers of the squamous epithelium. Moreover, ASPP2 can interact with components of Notch nuclear transcriptional machinery, and it is shuttled into the nuclear compartment upon activation of Notch pathway. This recruitment results in modulation of Notch transcriptional activity on specific target genes with a differential pattern of binding sites, providing new insights into the understanding of Notch transcriptional regulation.

Authors: Tordella, L

• Publication date: 2012
• DOI: 10.5287/ora-xkzqxmby8
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: Oxford University, UK
• Language: English
• Keywords: squamous cell carcinoma; epithelium; notch; ASPP2; p63
• Subjects: Medical sciences; Tumours; Biology (medical sciences)