Inhibition of cellular transformation by the adeno-associated virus rep gene

The replication, or rep, gene of the human parvovirus, adeno-associated virus (AAV), is a pleiotropic effector of numerous viral functions. The rep gene trans-regulates viral DNA replication, mRNA transcription, and assembly of the infectious virion. In addition to its roles in the virus life cycle the rep gene also represses gene expression from viral or cellular transcription promoters in both transient and long-term assays. In this report we have investigated the ability of the rep gene to inhibit cellular transformation mediated by SV40 DNA or the adenovirus E1a and human ras oncogene pair. In DNA transfection assays, the complete AAV rep gene inhibited SV40 DNA and E1a/ras gene-mediated transformation of mouse fibroblasts. AAV DNA plasmids that expressed the Rep68/40 or Rep52/40 proteins alone did not suppress transformation. AAV DNA replication was not required for suppression. Due to the antiproliferative effect of the AAV rep gene, we propose that it acts a viral analogue of cellular anti-oncogenes and is a useful model system for studying the regulation of cellular proliferation.