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Effects of Merkel Cell Polyomavirus T Antigen Expression on Cell Transformation of Merkel Cells

Adzahar, Noor Suhana Binti (2016) Effects of Merkel Cell Polyomavirus T Antigen Expression on Cell Transformation of Merkel Cells. PhD thesis, University of Leeds.

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Abstract

Merkel cell carcinoma (MCC) is a rare but highly metastatic skin cancer that affects immunosuppressed individuals. The MCC tumour arises from mechanoreceptor merkel cells in the basal layer of the epidermis and is able to spread through the dermal lymphatic system. Merkel cell polyomavirus (MCPyV) has been detected in the majority of MCC tumour samples. Truncation mutations of the large tumour antigen (LT) are observed in the integrated genome rendering the virus replication defective. These replication-disabling mutations are only present in MCPyV isolates found in cancers and absent from viruses derived from non-tumour tissues. As such aberrant expression of truncated LT (tLT) and small T (ST) antigens is thought to be implicated in MCC development. Elucidating the cellular pathways affected by the MCPyV T antigens involved in oncogenesis and tumour progression is essential to understand the effects of these oncoproteins in cellular transformation and tumourigenesis. A quantitative proteomic approach has been used to identify cellular proteins and pathways that are differentially expressed upon expression of MCPyV tLT. Bioinformatic analysis of the stable isotope labelling by amino acid in cell culture (SILAC) datasets highlight several pathways that are dysregulated upon tLT expression. These pathways include cell cycle regulation, cell death and survival, and cell-cell connections. Further analysis confirmed the effects of MCPyV tLT on these pathways showing alterations within the cell cycle, specifically disrupting the G1 checkpoint to enhance entry to the Sphase, which may prolonged the S phase to allow viral DNA replication. In addition, results suggest that MCPyV tLT expression may also delay the apoptosis-inducing properties of various compounds but was not capable to fully inhibit the apoptotic cascade. In contrast, although proteomic analysis highlighted a number of cell-cell connections related pathways to be differentially altered upon tLT expression, follow up experiments were not able to confirm these results.

Item Type: Thesis (PhD)
Keywords: Merkel cell polyomavirus Truncated LT antigen Small T antigen Cell transformation
Academic Units: The University of Leeds > Faculty of Biological Sciences (Leeds)
Identification Number/EthosID: uk.bl.ethos.698253
Depositing User: Ms Noor Suhana Adzahar
Date Deposited: 22 Nov 2016 15:39
Last Modified: 18 Feb 2020 12:48
URI: http://etheses.whiterose.ac.uk/id/eprint/15589

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