title: RNA splicing factors regulated by HPV16 during cervical tumour progression.
abstract: 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 key 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.
authors.affiliation: Division of Infection and Immunity, Faculty of Biomedical and Life Sciences, University of Glasgow, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Mole
authors.forename: Melanie
authors.initials: M
authors.lastname: McFarlane
authors.forename: Thanaporn
authors.initials: T
authors.lastname: Chuen-Im
authors.forename: Steven G
authors.initials: SG
authors.lastname: Milligan
authors.forename: David
authors.initials: D
authors.lastname: Millan
authors.forename: Sheila V
authors.initials: SV
authors.lastname: Graham
mesh_terms: D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D015967:Gene Expression Regulation, Viral; D052162:Human papillomavirus 16 / Q000502:physiology*; D006801:Humans; D007124:Immunoenzyme Techniques; D009363:Neoplasm Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D030361:Papillomavirus Infections / Q000150:complications* / Q000821:virology; D012326:RNA Splicing / Q000235:genetics*; D012334:RNA, Neoplasm / Q000235:genetics; D016601:RNA-Binding Proteins / Q000378:metabolism; D000068103:Serine-Arginine Splicing Factors; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000821:virology*
chemical_list: D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D012334:RNA, Neoplasm; D016601:RNA-Binding Proteins; D000068103:Serine-Arginine Splicing Factors