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Title: Understanding the role of Merkel cell polyomavirus oncoproteins in the cellular transformation of mammalian Merkel cells
Author: Knight, Laura M.
ISNI:       0000 0004 5363 4234
Awarding Body: University of Leeds
Current Institution: University of Leeds
Date of Award: 2014
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Merkel cell carcinoma (MCC) is a highly aggressive skin cancer of neuroendocrine origin with a high propensity for metastasis through the dermal lymphatic system. In 2008, Merkel cell polyomavirus (MCPyV) was discovered monoclonally integrated within the host genome of more than 80% of MCC tumours. MCPyV is known to contribute to the transformation and maintenance of MCC tumour cells through the expression of the Large and Small Tumour (LT and ST) antigens. To date, a number of mechanisms by which MCPyV T antigen expression promotes cell transformation and viral replication have been elucidated. Although, no studies have addressed the molecular mechanisms associated with MCPyV T antigen expression and the highly aggressive, metastatic nature of MCC. Herein, a quantitative proteomic approach has been used to identify cellular proteins and gene ontology pathways that are differentially expressed upon MCPyV ST expression. This highlighted that MCPyV ST expression promotes the upregulation of cellular proteins involved in microtubule-associated cytoskeletal organisation and dynamics. Further analysis, has demonstrated that MCPyV ST promotes cell motility, migration and invasion and that MCPyV ST-induced microtubule destabilisation is fundamental for this phenotype. Bioinformatical analysis highlighted the upregulation of stathmin, a microtubule destabilising protein, which is required for MCPyV ST-induced cell motility. Furthermore, through protein interaction studies and cell motility assays, the cellular phosphatase catalytic subunit PP4C has been implicated in the regulation of this process. Herein, these findings present the first study into the metastatic nature of MCC and the underlying mechanisms by which MCPyV T antigen expression can promote cell migration. This in turn should allow for enhanced therapeutic studies and chemotherapy regimes, in order to improve current treatments of MCC.
Supervisor: Whitehouse, Adrian Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available