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Functional effects of sequence variations in the E6 and E2 genes of human papillomavirus 16 European and Asian variants

Authors

  • Dong Hang,

    1. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Laboratory of Genetics, Peking University Cancer Hospital & Institute, Beijing, China
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  • Lei Gao,

    1. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Laboratory of Genetics, Peking University Cancer Hospital & Institute, Beijing, China
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  • Min Sun,

    1. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Laboratory of Genetics, Peking University Cancer Hospital & Institute, Beijing, China
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  • Ying Liu,

    1. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Laboratory of Genetics, Peking University Cancer Hospital & Institute, Beijing, China
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  • Yang Ke

    Corresponding author
    1. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Laboratory of Genetics, Peking University Cancer Hospital & Institute, Beijing, China
    • Correspondence to: Yang Ke, MD, Laboratory of Genetics, Peking University Cancer Hospital & Institute, No. 52 Fucheng Road, Haidian District, Beijing 100142, China.

      E-mail: keyang@bjmu.edu.cn

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  • Conflicts of Interest: The authors declare that there is no conflict of interest.

Abstract

Sequence variations within the genome of human papillomavirus (HPV) type 16 have been reported in different ethnic populations, with some evidence suggesting that non-European variants may confer higher oncogenic potential. HPV16 European (EUR) and Asian (As) variants were identified previously as two major variants in cervical cancer from Anyang, China. The evolutionary analysis of these variants revealed that several important sequence variations in the E6 and E2 genes were under positive selection pressure. The aim of this study was to evaluate the effects of these variations on E6 and E2 functions regarding p53 degradation and transcription regulation of the long control region (LCR). By Western blot analysis, a similar ability to degrade p53 was observed among EUR E6, As E6, EUR E6-L83V and As E6-E113D. A rare variation, EUR E6-R10G, was found to shorten the half-life of p53 more efficiently than the other variations. Unlike EUR E2 acting as a transcriptional activator or a repressor at different concentrations, As E2 showed a dose-dependent repression of LCR activity, about twofold stronger than EUR E2 in the luciferase reporter assays. Furthermore, the site-directed mutagenesis revealed that E232K, which is a linked variation in the hinge region of As E2, was responsible for its enhanced repression ability. Collectively, these data indicate the altered functions of HPV16 E6 and E2 by certain variations, which may influence the potential of viral carcinogenesis. J. Med. Virol. 86:618–626, 2014. © 2013 Wiley Periodicals, Inc.

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