RNA splicing factors regulated by HPV16 during cervical tumour progression

Mole, S., McFarlane, M. , Chuen-Im, T., Milligan, S.G., Millan, D. and Graham, S.V. (2009) RNA splicing factors regulated by HPV16 during cervical tumour progression. Journal of Pathology, 219(3), pp. 383-391. (doi: 10.1002/path.2608) (PMID:19718710) (PMCID:PMC2779514)

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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Graham, Professor Sheila and Mcdonald, Dr Melanie and Milligan, Mr Steve
• Authors: Mole, S., McFarlane, M., Chuen-Im, T., Milligan, S.G., Millan, D., and Graham, S.V.
• Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity; College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Virus Research
• Journal Name: Journal of Pathology
• Journal Abbr.: J. pathol.
• ISSN: 0022-3417
• ISSN (Online): 1096-9896
• Published Online: 04 August 2009

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
36993	1	Testing a novel marker in prognosis of HPV-associated cervical lesions	Sheila Graham	Scottish Executive Health Department (SEHHD-CSO)	CZG/1/100	Centre for Virus Research