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Epstein–Barr virus encoded LMP1 downregulates TCL1 oncogene through miR-29b

Oncogene volume 29, pages 1316–1328 (2010)Cite this article

Abstract

Epstein–Barr virus (EBV) encoded latent membrane protein 1 (LMP1) is noted for its transforming potential. Yet, it also acts as a cytostatic and growth-relenting factor in Burkitt's lymphoma (BL) cells. The underlying molecular mechanisms of the growth inhibitory property of LMP1 have remained largely unknown. In this study, we show that LMP1 negatively regulates a major oncogene, TCL1, in diffuse large B-cell lymphoma (DLBCL) and BL cells. MicroRNA (miR) profiling of LMP1 transfectants showed that among others, miR-29b, is upregulated. LMP1 diminished TCL1 by inducing miR-29b through C-terminus activation region 1 (CTAR1) and CTAR2. miR-29b locked nucleic acid (LNA) antisense oligonucleotide transfection into LMP1-expressing cells reduced miR-29b expression and consequently reconstituted TCL1, suggesting that LMP1 negatively regulates TCL1 through miR-29b upregulation. The miR-29b increase by LMP1 was due to an increase in the cluster pri-miR-29b1-a transcription, derived from human chromosome 7. Using pharmacological inhibitors, we found that p38 mitogen-activated protein kinase-activating function of LMP1 is important for this effect. The ability of LMP1 to negatively regulate TCL1 through miR-29b might underlie its B-cell lymphoma growth antagonistic property. As LMP1 is also important for B-cell transformation, we suggest that the functional dichotomy of this viral protein may depend on a combination of levels of its expression, lineage and differentiation of the target cells and regulation of miRs, which then directs the outcome of the cellular response.

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Acknowledgements

We thank V Licursi, V Del Vescovo and Dr R Negri's group members for help with microarray scanning facility and statistical analysis. We thank Dr Martin Rowe (Birmingham University, UK) for providing mutant LMP1 plasmids and comments. Dr Michael Teitell (UCLA, Los Angeles) and Dr Stefanie Gofflot (University of Liege, Belgium) are acknowledged for supplying TCL1 promoter reporter constructs and SUDH4 DLBCL cell line, respectively. This work was supported by grants from MIUR and Associazione Italiana per la ricerca sul Cancro (AIRC), progetto strategico ISS 9ACF/1 of Ministero della Salute, Pasteur Cenci-Bolognetti Foundation, Fondazione Italiana per la sclerosi multipla (FISM), Sixth Research Framework Programme of the European Union, Project RIGHT (LSHB-CT-2004 005276) and SIROCCO (037900).

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  1. Department of Experimental Medicine and Pathology, Istituto Pasteur-Fondazione Cenci-Bolognetti, La Sapienza University, Rome, Italy

    E Anastasiadou, F Boccellato, P Rosato, L Frati, A Faggioni & P Trivedi

  2. Department of Genetics and Molecular Biology, La Sapienza University, Rome, Italy

    S Vincenti, I Bozzoni & C Presutti

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  1. E Anastasiadou
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Correspondence to P Trivedi.

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Anastasiadou, E., Boccellato, F., Vincenti, S. et al. Epstein–Barr virus encoded LMP1 downregulates TCL1 oncogene through miR-29b. Oncogene 29, 1316–1328 (2010). https://doi.org/10.1038/onc.2009.439

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