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PML isoforms IV and V contribute to adenovirus-mediated oncogenic transformation by functionally inhibiting the tumor-suppressor p53

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Abstract

Although modulation of the cellular tumor-suppressor p53 is considered to have the major role in E1A/E1B-55K-mediated tumorigenesis, other promyelocytic leukemia nuclear body (PML-NB)/PML oncogenic domain (POD)-associated factors including SUMO, Mre11, Daxx, as well as the integrity of these nuclear bodies contribute to the transformation process. However, the biochemical consequences and oncogenic alterations of PML-associated E1B-55K by SUMO-dependent PML-IV and PML-V interaction have so far remained elusive. We performed mutational analysis to define a PML interaction motif within the E1B-55K polypeptide. Our results showed that E1B-55K/PML binding is not required for p53, Mre11 and Daxx interaction. We also observed that E1B-55K lacking subnuclear PML localization because of either PML-IV or PML-V-binding deficiency was no longer capable of mediating E1B-55K-dependent SUMOylation of p53, inhibition of p53-mediated transactivation or efficiently transforming primary rodent cells. These results together with the observation that E1B-55K-dependent SUMOylation of p53 is required for efficient cell transformation, provides evidence for the idea that the SUMO ligase activity of the E1B-55K viral oncoprotein is intimately linked to its growth-promoting oncogenic activities.

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Acknowledgements

We thank Roger D Everett for providing reagents, and greatly appreciate the critical comments and very helpful advise from Thomas Sternsdorf. We thank Ellis Jaffray, Gabriele Dobner and Thomas Speiseder for technical support and Hannah Staege for animal work. The Heinrich Pette Institute, Leibniz Institute for Experimental Virology is supported by the Freie und Hansestadt Hamburg and the Bundesministerium für Gesundheit (BMG). SS was supported by the Peter und Traudl Engelhorn Stiftung and additional grants from the Erich und Gertrud Roggenbuck Stiftung, the Else Kröner-Fresenius-Stiftung and the Deutsche Krebshilfe e. V. TD is supported by the Deutsche Forschungsgemeinschaft (DFG) and the Wilhelm Sander-Stiftung. Part of this work was supported by the B Braun Stiftung, the Dräger Stiftung and the Fonds der Chemischen Industrie. PB and PEB were supported by grants from the Canadian Institutes of Health Research. Image collection for the manuscript was performed in the McGill University Life Sciences Complex Imaging Facility. Purchase of equipment in the facility was made possible with funding from the Canadian Foundation for Innovation (CFI) and the Ministère du Développement économique, innovation et exportation Québec (MDEIE).

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Author notes

  1. P Wimmer and J Berscheminski: These authors contributed equally to this work and should be considered co-first authors.

  2. T Dobner and S Schreiner: These authors contributed equally to this work and should be considered co-last authors.

  3. Present address: Institute of Virology, Technische Universität München/ Helmholtz Zentrum München, Munich, Germany.

Authors and Affiliations

  1. Department of Viral Transformation, Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany

    P Wimmer, J Berscheminski, P Groitl, T Dobner & S Schreiner

  2. Department of Biochemistry, McGill University, Montreal, Quebec, Canada,

    P Blanchette & P E Branton

  3. Department of Oncology, McGill University, Montreal, Quebec, Canada,

    P E Branton

  4. Department of Goodman Cancer Center, McGill University, Montreal, Quebec, Canada,

    P E Branton

  5. Wellcome Trust Centre for Gene Regulation and Expression, College of Life Sciences, University of Dundee, Dundee, UK

    R T Hay

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  1. P Wimmer
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Correspondence to S Schreiner.

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PW is currently an employee of Novartis. The remaining authors declare no conflict of interest.

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Wimmer, P., Berscheminski, J., Blanchette, P. et al. PML isoforms IV and V contribute to adenovirus-mediated oncogenic transformation by functionally inhibiting the tumor-suppressor p53. Oncogene 35, 69–82 (2016). https://doi.org/10.1038/onc.2015.63

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