RNA splicing factors regulated by HPV16 during cervical tumour progression

The most prevalent human papillomaviruses (HPVs) causing cervical disease are the 'high-risk' HPV types 16 and 18. All papillomaviruses express a transcription factor, E2, that can regulate viral and cellular gene expression. Recently, we demonstrated high-risk HPV E2-mediated transcriptional transactivation of SF2/ASF. This essential oncoprotein is a Ill member of a family of proteins, the SR proteins, that regulate constitutive and alternative splicing. Tight control of RNA splicing is necessary for the production of wild-type proteins. So, aberrant expression of SR proteins is involved in the aetiology of a range of human diseases, including cancer. Here we demonstrate epithelial differentiation-specific control of SF2/ASF in HPV16-infected keratinocytes in organotypic raft culture and in low-grade cervical lesions (CIN1). Further, we demonstrate HPV16 infection/differentiation-induced up-regulation of a specific subset of SR proteins and present evidence that HPV16 E2 controls expression of SRp20, SC35 and SRp75. Using a series of cell lines that model cervical tumour progression, we show that SF2/ASF, SRp20 and SC35 are specifically up-regulated in a model of cervical tumour progression. These SR proteins are also over-expressed in high-grade cervical lesions, indicating that they may all have oncogenic functions. SR proteins could be useful biomarkers for HPV-associated disease. Copyright (C) 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.