ORF73 of herpesvirus saimiri, a viral homolog of Kaposi's sarcoma-associated herpesvirus, modulates the two cellular tumor suppressor proteins p53 and pRb.
All known DNA tumor viruses are known to target and inactivate two main cell cycle regulatory proteins, retinoblastoma protein (pRb) and p53. Inactivation of pRb promotes host cell cycle progression into S phase, and inactivation of p53 promotes cell immortalization. The DNA tumor virus Kaposi's sarcoma associated herpesvirus (KSHV)-encoded latency-associated nuclear antigen (LANA) was shown to target and inactivate pRb as well as p53. In this report we provide evidence that these functions are conserved in the homologous protein encoded by the related gammaherpesvirus herpesvirus saimiri (HVS). ORF73, the HVS homologue of LANA, is shown to bind both p53 and pRb in vitro and in vivo, to colocalize with p53 in human T cells infected with HVS, and in cells overexpressing both ORF73 and p53, as well as to adversely influence pRB/E2F and p53 transcriptional regulation. The C terminus of LANA, the region most highly conserved in ORF73, is shown to be responsible for both pRb and p53 interactions, supporting the hypothesis that these functions are conserved in both homologues. Finally, the region of p53 targeted by LANA (and ORF73) maps to the domain required for tetramerization. However, preliminary cross-linking studies do not detect disruption of p53 tetramerization by either LANA or HVS-encoded ORF73, suggesting that p53 inactivation may be by a mechanism independent of tetramer disruption.
Borah
Sumit
S
Department of Microbiology and Abramson Comprehensive Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Verma
Subhash C
SC
Robertson
Erle S
ES
D000956:Antigens, Viral; D002460:Cell Line; D005786:Gene Expression Regulation; D006567:Herpesvirus 2, Saimiriine / Q000235:genetics*; D019288:Herpesvirus 8, Human / Q000235:genetics; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism*; D011485:Protein Binding; D025941:Protein Interaction Mapping; D017434:Protein Structure, Tertiary; D021122:Protein Subunits / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism*; D013601:T-Lymphocytes / Q000737:chemistry / Q000821:virology; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D014764:Viral Proteins / Q000378:metabolism
D000956:Antigens, Viral; D009687:Nuclear Proteins; D021122:Protein Subunits; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D014764:Viral Proteins; C109540:latency-associated nuclear antigen