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The latent nuclear antigen of Kaposi sarcoma-associated herpesvirus targets the retinoblastoma–E2F pathway and with the oncogene Hras transforms primary rat cells

Kaposi sarcoma-associated herpesvirus (KSHV) is involved in the etiopathogenesis of Kaposi sarcoma and certain lymphoproliferative disorders. Open reading frame (ORF) 73 encodes the main immunogenic latent nuclear antigen (LNA-1) of KSHV. LNA-1 maintains the KSHV episome and tethers the viral genome to chromatin during mitosis. In addition, LNA-1 interacts with p53 and represses its transcriptional activity. Here we show that LNA-1 also interacts with the retinoblastoma protein. LNA-1 transactivated an artificial promoter carrying the cell cycle transcription factor E2F DNA-binding sequences and also upregulated the cyclin E (CCNE1) promoter, but not the B-myb (MYBL2) promoter. LNA-1 overcame the flat-cell phenotype induced by retinoblastoma protein in Saos2 cells. In cooperation with the cellular oncogene Harvey rat sarcoma viral oncogene homolog (Hras), LNA-1 transformed primary rat embryo fibroblasts and rendered them tumorigenic. These findings indicate that LNA-1 acts as a transcription co-factor and may contribute to KSHV-induced oncogenesis by targeting the retinoblastoma protein–E2F transcriptional regulatory pathway

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Figure 1: Effect of LNA-1 on E2F-regulated promoters.
Figure 2: LNA-1 and RB1 associate in vivo.
Figure 3: LNA-1 interacts with Rb in vitro.
Figure 4: LNA-1 can ‘rescue’ the RB1-induced flat-cell phenotype in Saos2 cells.
Figure 5: LNA-1 ‘cooperates’ with HRAS to transform primary REF cells.

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Acknowledgements

This work was supported by The Cancer Research Campaign, The UK Medical Research Council and Glaxo Wellcome. We thank T. Sharp and J.-B. Rascle for discussions, R. Weiss for critical reading of the manuscript, and D. Bourboulia, M.-Q. Du and N. Phillips for technical assistance.

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Correspondence to Chris Boshoff.

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Radkov, S., Kellam, P. & Boshoff, C. The latent nuclear antigen of Kaposi sarcoma-associated herpesvirus targets the retinoblastoma–E2F pathway and with the oncogene Hras transforms primary rat cells. Nat Med 6, 1121–1127 (2000). https://doi.org/10.1038/80459

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