A study of PDZ protein expression during the human papillomavirus life cycle

James, Claire Deborah (2015). A study of PDZ protein expression during the human papillomavirus life cycle. University of Birmingham. Ph.D.

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The E6 protein of oncogenic α-human papillomaviruses encodes a conserved C-terminal PDZ binding motif (PBM). Conservation of an overlapping kinase recognition site has shown that phosphorylation negatively regulates the E6:PDZ interaction. Many E6 PDZ targets are associated with signalling complexes that regulate cell proliferation and polarity. This study used primary keratinocyte-based models of HPV16 and 18 life cycles to investigate the expression of PDZ targets and the functional role of PBM phosphorylation.
The data indicate that changes in total levels of major E6 PDZ targets are not associated with E6-PBM activity. Interestingly, transcription profiles of E6-PBM targets DLG1, PATJ and PTPN13 are dramatically changed in the presence of HPV16 and 18, whilst others remain unaffected. Further analysis of transcriptional changes of DLG1 revealed upregulation of specific alternatively spliced isoforms, including a novel isoform containing an exon previously thought to be intronic.
This investigation revealed that phosphorylation of the PBM is linked to oncoprotein stability, presenting a potential regulatory mechanism of E6 PDZ interactions during the virus life cycle.
Together, these data offer interesting new perspectives on interactions between oncogenic HPV types and PDZ domain-containing targets and indicate that deregulation of their function by the virus may occur through multiple mechanisms.

Type of Work: Thesis (Doctorates > Ph.D.)
Award Type: Doctorates > Ph.D.
College/Faculty: Colleges (2008 onwards) > College of Medical & Dental Sciences
School or Department: Institute of Cancer Studies
Funders: Medical Research Council, Wellcome Trust
Subjects: Q Science > QR Microbiology > QR355 Virology
URI: http://etheses.bham.ac.uk/id/eprint/6127


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