Abstract
Human adenoviruses (HAdV) are used as a model system to investigate tumorigenic processes in mammalian cells where the viral oncoproteins E1A and E1B-55K are absolutely required for oncogenic transformation, because they simultaneously accelerate cell cycle progression and inhibit tumor suppressor proteins such as p53, although the underlying mechanism is still not understood in detail. In our present study, we provide evidence that E1B-55K binding to the PML-NB component Sp100A apparently has an essential role in regulating adenovirus-mediated transformation processes. Specifically, when this E1B-55K/Sp100A complex recruits p53, Sp100A-induced activation of p53 transcriptional activity is effectively abolished. Hence, Sp100A exhibits tumor-suppressive activity, not only by stabilizing p53 transactivation but also by depressing E1A/E1B-55K-mediated transformation. E1B-55K counteracts this suppressive activity, inducing Sp100A SUMOylation and sequestering the modified cellular factor into the insoluble matrix of the nucleus or into cytoplasmic inclusions. These observations provide novel insights into how E1B-55K modulates cellular determinants to maintain growth-promoting activity during oncogenic processes and lytic infection.
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Acknowledgements
We thank Ron Hay, Ellis Jaffray, Roger Everett, Hans Will, Thomas Sternsdorf and Nicole Fischer for providing reagents and scientific discussion. The Heinrich Pette Institute, Leibniz Institute for Experimental Virology is supported by the Freie und Hansestadt Hamburg and the Bundesministerium für Gesundheit (BMG). JB was supported by grant from the Deutsche Forschungsgemeinschaft (DFG) to TD (DO 343/7-1). MT was supported by the Dräger Stiftung. TD is supported by the DFG and the Wilhelm Sander-Stiftung. SS was supported by the Else Kröner-Fresenius-Stiftung and the Deutsche Krebshilfe e. V. Part of this work was supported by the B. Braun Stiftung and the Fonds der Chemischen Industrie.
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Berscheminski, J., Brun, J., Speiseder, T. et al. Sp100A is a tumor suppressor that activates p53-dependent transcription and counteracts E1A/E1B-55K-mediated transformation. Oncogene 35, 3178–3189 (2016). https://doi.org/10.1038/onc.2015.378
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DOI: https://doi.org/10.1038/onc.2015.378
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