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 etiopathoge nesis of Kaposi sarcoma and certain lymphoproliferative disorders. Open rea ding frame (ORF) 73 encodes the main immunogenic latent nuclear antigen (LN A-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 rep resses its transcriptional activity. Here we show that LNA-1 also interacts with the retinoblastoma protein. LNA-1 transactivated an artificial promot er carrying the cell cycle transcription factor E2F DNA-binding sequences a nd also upregulated the cyclin E (CCNE1) promoter, but not the B-myb (MYBL2 ) promoter. LNA-1 overcame the flat-cell phenotype induced by retinoblastom a protein in Saos2 cells. In cooperation with the cellular oncogene Harvey rat sarcoma viral oncogene homolog (Hras), LNA-I transformed primary rat em bryo fibroblasts and rendered them tumorigenic. These findings indicate tha t LNA-I acts as a transcription co-factor and may contribute to KSHV-induce d oncogenesis by targeting the retinoblastoma protein-E2F transcriptional r egulatory pathway.