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Recruitment of the tumour suppressor protein p73 by Kaposi’s Sarcoma Herpesvirus latent nuclear antigen contributes to the survival of primary effusion lymphoma cells

Oncogene volume 32, pages 3676–3685 (2013)Cite this article

Abstract

Kaposi’s Sarcoma Herpesvirus (KSHV) is the causative agent of Kaposi’s Sarcoma (KS) and two rare lymphoproliferative disorders, primary effusion lymphoma (PEL) and the plasmablastic variant of multicentric Castleman’s disease (MCD). The KSHV latency-associated nuclear antigen-1 (LANA), required for the replication and maintenance of latent viral episomal DNA, is involved in the transcriptional regulation of viral and cellular genes and interacts with different cellular proteins, including the tumour suppressor p53. Here, we report that LANA also recruits the p53-related nuclear transcription factor p73, which influences cellular processes like DNA damage response, cell cycle progression and apoptosis. Both the full-length isoform TAp73α, as well as its dominant negative regulator ΔNp73α, interact with LANA. LANA affects TAp73α stability and sub-nuclear localisation, as well as TAp73α-mediated transcriptional activation of target genes. We observed that the small-molecule inhibitor Nutlin-3, which disrupts the interaction of p53 and p73 with MDM2, induces apoptotic cell death in p53 wild-type, as well as p53-mutant PEL cell lines, suggesting a possible involvement of p73. The small-molecule RETRA, which activates p73 in the context of mutant p53, leads to the induction of apoptosis in p53-mutant PEL cell lines. RNAi-mediated knockdown of p73 confirmed that these effects depend on the presence of the p73 protein. Furthermore, both Nutlin-3 and RETRA disrupt the LANA–p73 interaction in different PEL cell lines. These results suggest that LANA modulates p73 function and that the LANA–p73 interaction may represent a therapeutic target to interfere with the survival of latently KSHV-infected cells.

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Acknowledgements

We thank Magdalena Weidner-Glunde for cloning of the GST fusion construct LANA N, as well as Eva Gellermann for cloning the GST fusion constructs C8a and C8b. This work was supported by the DFG IRTG 1273, the EU Integrated Project INCA (LSHC-CT-18730) and the collaborative research centre (CRC) 900 of the Deutsche Forschungsgemeinschaft.

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Authors and Affiliations

  1. Institute of Virology, Hannover Medical School, Hannover, Germany

    S Santag, W Jäger, C B Karsten, S Kati, M Pietrek & T F Schulz

  2. Institute of Cell and Molecular Pathology, Hannover Medical School, Hannover, Germany

    D Steinemann

  3. Institute of Biotechnology and Research Programs Unit, Genome-Scale Biology Biomedicum Helsinki, University of Helsinki, Helsinki, Finland

    G Sarek & P M Ojala

  4. Foundation for the Finnish Cancer Institute,

    P M Ojala

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Santag, S., Jäger, W., Karsten, C. et al. Recruitment of the tumour suppressor protein p73 by Kaposi’s Sarcoma Herpesvirus latent nuclear antigen contributes to the survival of primary effusion lymphoma cells. Oncogene 32, 3676–3685 (2013). https://doi.org/10.1038/onc.2012.385

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