p53 inhibition by the LANA protein of KSHV protects against cell death

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Abstract

Kaposi's sarcoma-associated herpesvirus (KSHV), or human herpesvirus 8, has been implicated in the development of Kaposi's sarcoma (KS) and several B-cell lymphoproliferative diseases1,2,3. Most cells in lesions derived from these malignancies are latently infected, and different viral gene products have been identified in association with lytic or latent infection by KSHV4,5. The latency-associated nuclear antigen (LANA), encoded by open reading frame 73 of the KSHV genome, is a highly immunogenic protein that is expressed predominantly during viral latency, in most KS spindle cells and in cell lines established from body-cavity-based lymphomas6,7. Antibodies to LANA can be detected in a high percentage of HIV-infected individuals who subsequently develop KS8,9, although its role in disease pathogenesis is not completely understood. p53 is a potent transcriptional regulator of cell growth whose induction leads either to cell-cycle arrest or apoptosis. Loss of p53 function correlates with cell transformation and oncogenesis10,11, and several viral oncoproteins interact with p53 and modulate its biological activity12,13. Here we show that LANA interacts with the tumour suppressor protein p53 and represses its transcriptional activity. This viral gene product further inhibits the ability of p53 to induce cell death. We propose that LANA contributes to viral persistence and oncogenesis in KS through its ability to promote cell survival by altering p53 function.

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Figure 1: Orf73 of the KSHV genome encodes the 222–234K LANA.
Figure 2: Inhibition of p53 transcriptional activity by orf73/LANA.
Figure 3: In vitro and in vivo interaction of transfected or endogenous orf73/LANA and p53.
Figure 4: Repression of p53-mediated cell death by orf73/LANA.
Figure 5: Inhibition of p53-mediated apoptosis in cell lines expressing LANA.

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Acknowledgements

We thank D. Gschwend and N. Barrett for manuscript preparation, E. S. Robertson and R. Mosavin for helpful discussions, B. Chandran for providing a polyclonal antibody to LANA and members of the Nabel Lab for helpful comments. J.F. is supported by a fellowship from the Medical Research Council of Canada. M.O.H. is supported by the Kanton of Zurich. This work was supported in part by the Howard Hughes Medical Institute.

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Correspondence to Gary J. Nabel.

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Friborg, J., Kong, W., Hottiger, M. et al. p53 inhibition by the LANA protein of KSHV protects against cell death. Nature 402, 889–894 (1999) doi:10.1038/47266

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