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Human polyomavirus BKV transcriptionally activates DNA methyltransferase 1 through the pRb/E2F pathway

Oncogene volume 25, pages 2727–2735 (2006)Cite this article

Abstract

Many DNA tumor virus oncogenes are capable of activating and highjacking the host cell's DNA replication machinery for its own reproduction purposes through targeting and inactivation of the retinoblastoma pocket protein family. Pocket proteins function to regulate cell cycle progression and DNA synthesis through inhibitory interactions with the E2F transcription factors. The interaction of viral oncogenes with the pocket proteins is crucial for their transforming activity. We recently demonstrated that the DNA methyltransferase 1 (DNMT1) gene is an E2F target gene that is transcriptionally activated in cells lacking the retinoblastoma gene (Rb−/−). Overexpression of DNMT1 is implicated in tumor suppressor gene hypermethylation which is associated with tumorigenesis. Given that viral oncogenes potently stimulate E2F activity, we hypothesized that viral infection might activate DNMT1 and thereby promote transformation. Herein, we demonstrate that DNMT1 is strongly activated by the human polyomavirus BKV large T antigen (TAg) and adenovirus E1a. Viral oncogene mutants incapable of binding the pocket proteins are ineffective at activating DNMT1 compared to their wild-type counterparts. Additionally, mutation of the E2F sites within the DNMT1 promoters dramatically abrogates transcriptional activation. These data suggest that viral induction of DNMT1 through modulation of the pRB/E2F pathway may be involved in viral transformation.

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Acknowledgements

We thank Tyler Jacks, Nephros Therapeutics (Ann Arbor, MI, USA), Erik Knudsen, Elizabeth Moran and Ed Harlow for providing cells, plasmids or antibodies utilized in this study. Grant support: DK61488 from the National Institutes of Health (MLD.), AI060584 from the National Institutes of Health (MJI), and 5T32 CA09676 Cancer Biology Training Fellowship from the National Institutes of Health (MTM).

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Authors and Affiliations

  1. Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, MI, USA

    M T McCabe, M J Imperiale & M L Day

  2. Department of Urology, University of Michigan, Ann Arbor, MI, USA

    M T McCabe & M L Day

  3. Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI, USA

    J A Low & M J Imperiale

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Correspondence to M L Day.

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McCabe, M., Low, J., Imperiale, M. et al. Human polyomavirus BKV transcriptionally activates DNA methyltransferase 1 through the pRb/E2F pathway. Oncogene 25, 2727–2735 (2006). https://doi.org/10.1038/sj.onc.1209266

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