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Journal of Virology, January 2009, p. 357-367, Vol. 83, No. 1
0022-538X/09/$08.00+0     doi:10.1128/JVI.01414-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Human Papillomavirus Type 16 E2 Protein Transcriptionally Activates the Promoter of a Key Cellular Splicing Factor, SF2/ASF{triangledown}

Sarah Mole, Steven G. Milligan, and Sheila V. Graham*

Division of Infection and Immunity, Faculty of Biomedical and Life Sciences, University of Glasgow, Glasgow G12 8TA, Scotland, United Kingdom

Received 8 July 2008/ Accepted 16 October 2008

Human papillomavirus (HPV) gene expression is regulated in concert with the epithelial differentiation program. In particular, expression of the virus capsid proteins L1 and L2 is tightly restricted to differentiated epithelial cells. For HPV16, the capsid proteins are encoded by 13 structurally different mRNAs that are produced by extensive alternative splicing. Previously, we demonstrated that upon epithelial differentiation, HPV16 infection upregulates hnRNP A1 and SF2/ASF, both key factors in alternative splicing regulation. Here we cloned a 1-kb region upstream of and including the transcriptional start site of the SF2ASF gene and used it in in vivo transcription assays to demonstrate that the HPV16 E2 transcription factor transactivates the SF2/ASF promoter. The transactivation domain but not the DNA binding domain of the protein is necessary for this. Active E2 association with the promoter was demonstrated using chromatin immunoprecipitation assays. Electrophoretic mobility shift assays indicated that E2 interacted with a region 482 to 684 bp upstream of the transcription initiation site in vitro. This is the first time that HPV16 E2 has been shown to regulate cellular gene expression and the first report of viral regulation of expression of an RNA processing factor. Such E2-mediated control during differentiation of infected epithelial cells may facilitate late capsid protein expression and completion of the virus life cycle.

* Corresponding author. Mailing address: Room 312, Jarrett Building, Institute of Comparative Medicine, University of Glasgow, Garscube Estate, Glasgow G61 1QH, Scotland, UK. Phone: 44 141 330 6256. Fax: 44 141 330 5602. E-mail: s.v.graham{at}bio.gla.ac.uk

{triangledown} Published ahead of print on 22 October 2008.

Journal of Virology, January 2009, p. 357-367, Vol. 83, No. 1
0022-538X/09/$08.00+0     doi:10.1128/JVI.01414-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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