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Regulation of serine-arginine protein kinase 1 functions by human papillomavirus

Prescott, Emma Louise (2012)
Ph.D. thesis, University of Birmingham.

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Abstract

The role of the E4 protein in the human papillomavirus (HPV) life cycle is an enigma even though it has varied effects on cell behaviour and organisation in overexpression studies. Full-length E4 proteins are derived from E1^E4 spliced RNA transcripts and E1^E4 proteins from diverse HPV types interact with serine-arginine (SR)-specific protein kinase SRPK1, that regulates diverse cellular functions including RNA splicing. This thesis has sought to address the hypothesis that E1^E4 alters SRPK1 activity and influences SRPK1 functions in the HPV life cycle. This study has uncovered the novel finding that E1^E4 protein of HPV1, but not HPV5, 16 and 18, is a potent inhibitor of SRPK1 activity in vitro and in vivo and inhibition is dependent upon E1^E4 binding to SRPK1. Whilst HPV1 E1^E4 inhibits SRPK1 phosphorylation of cellular (ASF/SF2, SRp20, SC35, 9G8 and SRp75) and viral (HPV E2) SR protein substrates, it has only weak effects on SR protein cellular localisation and on cellular and viral RNA splicing in minigene systems. Addition of the small molecule inhibitor of SRPK, SRPIN340 to organotypic raft cultures of HPV18 genome-containing keratinocytes enhances the morphological features of HPV viral replication suggesting that the HPV may modulate SRPK activity to facilitate the virus life cycle.

Type of Work:Ph.D. thesis.
Supervisor(s):Roberts, Sally
School/Faculty:Colleges (2008 onwards) > College of Medical & Dental Sciences
Department:School of Cancer Sciences
Subjects:QH301 Biology
QH426 Genetics
QR355 Virology
RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Institution:University of Birmingham
ID Code:3482
This unpublished thesis/dissertation is copyright of the author and/or third parties.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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