USE OF TRANSGENIC MICE REVEALS CELL-SPECIFIC TRANSFORMATION BY A SIMIAN VIRUS-40 T-ANTIGEN AMINO-TERMINAL MUTANT

We have used the multifunctional transforming protein, simian virus 40 T antigen, as a probe to study the mechanisms of cell growth regulati on in the intact organism. T antigen appears to perturb cell growth, a t least in part, by stably interacting with specific cellular proteins that function to maintain normal cell growth properties. Experiments in cultured cells indicate that at least three distinct regions of sim ian virus 40 T antigen have roles in transformation. Two regions corre late with the binding of known cellular proteins, p53, pRB, and p107. A third activity, located near the amino terminus, has been defined ge netically but not biochemically. By targeting expression of wild-type and mutant forms of T antigen to distinct cell types in transgenic mic e, we have begun to systematically determine which activities play a r ole in tumorigenesis of each cell type. In this study, we sought to de termine the role of the amino-terminal transformation function with su ch an analysis of the T-antigen mutant dl1135. This protein, which lac ks amino acids 17 to 27, retains the p53-, pRB-, and p107-binding acti vities yet fails to transform cells in culture. To direct expression i n transgenic mice, we used the lymphotropic papovavirus transcriptiona l signals that are specific for B and T lymphocytes and the choroid pl exus epithelium of the brain. We show here that although defective in cell culture, dl1135 specifically induced the development of thymic ly mphomas in the mouse. Expression of the protein was routinely observed in B- and T-lymphoid cells, although B-cell abnormalities were not ob served. Choroid plexus tumors were observed only infrequently; however , dl1135 was not consistently expressed in this tissue. Within a given transgenic line, the penetrance of T-cell tumorigenesis was 100% but appeared to require secondary events, as judged from the clonal nature of the tumors. These experiments suggest that the amino-terminal regi on of T antigen has a role in the transformation of certain cell types (such as fibroblasts in culture and B lymphocytes) but is dispensable for the transformation of T lymphocytes.