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Polypyrimidine tract binding protein induces human papillomavirus type 16 late gene expression by interfering with splicing inhibitory elements at the major late 5' splice site, SD3632
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
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2008 (English)In: Journal of Virology, ISSN 0022-538X, Vol. 82, no 7, 3665-3678 p.Article in journal (Refereed) Published
Abstract [en]

We have initiated a screen for cellular factors that can induce human papillomavirus type 16 (HPV-16) late gene expression in human cancer cells. We report that the overexpression of polypyrimidine tract binding protein (PTB), also known as heterologous nuclear ribonucleoprotein I (hnRNP I), induces HPV-16 late gene expression in cells transfected with subgenomic HPV-16 plasmids or with full-length HPV-16 genomes and in persistently HPV-16-infected cells. In contrast, other hnRNPs such as hnRNP B1/A2, hnRNP F, and hnRNP Q do not induce HPV-16 late gene expression. PTB activates SD3632, the only 5' splice site on the HPV-16 genome that is used exclusively by late mRNAs. PTB interferes with splicing inhibitory sequences located immediately upstream and downstream of SD3632, thereby activating late gene expression. One AU-rich PTB-responsive element was mapped to a 198-nucleotide sequence located downstream of SD3632. The deletion of this element induced HPV-16 late gene expression in the absence of PTB. Our results suggest that the overexpression of PTB interferes with cellular factors that interact with the inhibitory sequences. One may speculate that an increase in PTB levels or a reduction in the concentration of a PTB antagonist is required for the activation of HPV-16 late gene expression during the viral life cycle.

Place, publisher, year, edition, pages
2008. Vol. 82, no 7, 3665-3678 p.
National Category
Microbiology in the medical area
Identifiers
URN: urn:nbn:se:uu:diva-99656DOI: 10.1128/JVI.02140-07ISI: 000254139800045PubMedID: 18216120OAI: oai:DiVA.org:uu-99656DiVA: diva2:208524
Available from: 2009-03-18 Created: 2009-03-18 Last updated: 2011-07-01Bibliographically approved
In thesis
1. Cellular and Viral Factors that Control Human Papillomavirus Type 16 Late Gene Expression
Open this publication in new window or tab >>Cellular and Viral Factors that Control Human Papillomavirus Type 16 Late Gene Expression
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Human papillomavirus type 16 (HPV-16) is the major cause of cervical cancer. We speculate that inhibition of HPV-16 late gene expression is a prerequisite for establishment of persistence and progression to cervical cancer. This is based on the findings that the late proteins are found only in the nuclei of terminally differentiated epithelium, and are never detected in human papillomavirus infected cervical cancer cells. It is therefore of great importance to understand how HPV-16 controls the onset of the immunogenic proteins L1 and L2 in an infected cancer cell. HPV-16 late gene expression is tightly regulated by differentiation-dependent transcription as well as by post-transcriptional mechanisms.

The long-term goal of these studies was to understand how HPV late gene expression is regulated. The specific aim of this thesis was to identify cellular and viral factors that force the virus to switch on the late genes, and to determine the mechanism of action of these factors. This will help us to understand under which circumstances HPV establish persistent infections that could progress to cancer.

We found three cellular factors; PTB, ASF/SF2 and SRp30c, and one viral factor; AdE4orf4, that in four distinctive ways were involved in the regulation of HPV-16 late gene expression. Interestingly, over-expression of PTB, AdE4orf4 or SRp30c produced different types of spliced late mRNAs. PTB induced the unspliced L2/L1 mRNA, while AdE4orf4 and SRp30c induced the spliced L1 and L1i mRNA, respectively. The three proteins had different mechanisms of action and different target sites within the HPV-16 genome, which revealed the many and complex pathways in HPV-16 gene regulation. These findings have contributed to a broader understanding of how the expression of HPV-16 late genes is controlled.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2011. 63 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 670
National Category
Microbiology in the medical area
Research subject
Medical Virology
Identifiers
urn:nbn:se:uu:diva-150706 (URN)978-91-554-8069-1 (ISBN)
Public defence
2011-05-31, BMC, C10:305, Husargatan 3, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2011-05-10 Created: 2011-04-04 Last updated: 2011-07-01Bibliographically approved

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