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The role of the PSD95/Dlg/ZO-1 (PDZ) binding motif of human papillomavirus type 18 E6 oncoprotein in the virus life cycle

Delury, Craig Phillip (2012)
Ph.D. thesis, University of Birmingham.

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Abstract

A PSD95/Dlg/ZO-1(PDZ)-binding motif (PBM) in the E6 protein of high-risk, cancer-causing human papillomaviruses (HPV) targets a subset of cellular PDZ domain-containing proteins involved in diverse regulatory processes including cell polarity and proliferation, for proteasome-mediated degradation. Interaction with this select group of PDZ domain-containing proteins is negatively regulated by cAMP-dependent protein kinase (PKA) mediated phosphorylation of the E6 PBM. This thesis has sought to address the hypothesis that the PBM of E6 plays an important role within the HPV life cycle. This study has shown that deletion of the E6 PBM from HPV18 genomes affects the morphology and growth of viral episome-containing human keratinocytes and furthermore links E6 PBM function to viral episome replication (maintenance replication and differentiation-dependent amplification). Loss of negative regulation of the E6 PBM by mutation of the PKA recognition motif was associated with increased cell growth and indeed the growth of wildtype HPV18 genome-containing cells responded to changes in PKA signalling. Constitutive E6 PBM function was also associated with invasion of cells suggesting that malignant progression of HPV-infected cells may be linked to changes in PKA signalling. Modulation of the E6 PBM function in the viral genome-containing cells was associated with a change in protein levels of the PDZ domain-containing protein discs large (hDlg) and changes in the non receptor protein phosphastase PTPN13 specific species.

Type of Work:Ph.D. thesis.
Supervisor(s):Roberts, Sally
School/Faculty:Colleges (2008 onwards) > College of Medical & Dental Sciences
Department:School of Cancer Science
Subjects:QR355 Virology
Institution:University of Birmingham
ID Code:3345
This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder.
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