APOPTOSIS IS ANTAGONIZED BY LARGE T-ANTIGENS IN THE PATHWAY TO IMMORTALIZATION BY POLYOMAVIRUSES

The viability of rat embryo cells immortalized by thermosensitive muta nts of SV40 or polyoma Large T antigen is impaired at the non-permissi ve temperature thus demonstrating that the immortal phenotype is domin antly maintained by Large T antigens. We have observed that exposing t hese cells to the restrictive temperature not only induces growth arre st but also causes apoptotic cell death. We present evidence supportin g the model that polyomaviruses may indeed establish immortality by an tagonizing the lethal effects of tumor suppressor genes via physical i nteractions between their products and Large T antigens. In the case o f SV40-immortalized cells REtsAF, shift-up to 39.5 degrees C dissociat es Large T antigen/p53 complexes releasing wild-type p53 molecules cap able of inducing apoptotic cell death. In polyomavirus-immortalized ce lls, apoptosis may result from an alternative pathway mediated by othe r unidentified negatively acting molecules.