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Deregulation of c-Myc in primary effusion lymphoma by Kaposi's sarcoma herpesvirus latency-associated nuclear antigen

Oncogene volume 26, pages 4979–4986 (2007)Cite this article

Abstract

Primary effusion lymphoma (PEL) is a rare subtype of non-Hodgkin's lymphoma, which is associated with infection by Kaposi's sarcoma herpesvirus (KSHV)/human herpesvirus-8. The c-Myc transcription factor plays an important role in cellular proliferation, differentiation and apoptosis. Lymphomas frequently have deregulated c-Myc expression owing to chromosomal translocations, amplifications or abnormal stabilization. However, no structural abnormalities were found in the c-myc oncogene in PEL. Given that c-Myc is often involved in lymphomagenesis, we hypothesized that it is deregulated in PEL. We report that PEL cells have abnormally stable c-Myc protein. The turnover of c-Myc protein is stringently regulated by post-transcriptional modifications, including phosphorylation of c-Myc threonine 58 (T58) by glycogen synthase kinase-3β (GSK-3β). Our data show that the impaired c-Myc degradation in PEL cells is associated with a significant underphosphorylation of c-Myc T58. The KSHV latency-associated nuclear antigen (LANA) is responsible for this deregulation. Overexpression of LANA in human embryonic kidney 293 or peripheral blood B cells leads to post-transcriptional deregulation of c-Myc protein. Conversely, when LANA is eliminated from PEL cells using RNA interference, GSK-3β-mediated c-Myc T58 phosphorylation is restored. The presence of c-Myc and LANA in GSK-3β-containing complexes in PEL cells further confirms the significance of these interactions in naturally KSHV-infected cells.

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Acknowledgements

We thank Rosalie Sears for invaluable advice about the details of c-Myc experiments. This work was supported by NIH Grant R01 CA068939, by a Leukemia and Lymphoma Society Translational Research Program Grant and by an Irma T Hirschl/Monique Weill-Caulier Career Scientist Award to EC.

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Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, Weill Graduate School of Medical Sciences of Cornell University, New York, NY, USA

    D Bubman

  2. Department of Pathology and Laboratory Medicine, Weill Graduate School of Medical Sciences of Cornell University, New York, NY, USA

    I Guasparri

  3. Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University, New York, NY, USA

    E Cesarman

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  1. D Bubman
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Correspondence to E Cesarman.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Bubman, D., Guasparri, I. & Cesarman, E. Deregulation of c-Myc in primary effusion lymphoma by Kaposi's sarcoma herpesvirus latency-associated nuclear antigen. Oncogene 26, 4979–4986 (2007). https://doi.org/10.1038/sj.onc.1210299

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