THE AMINO-TERMINAL REGION OF SV40 LARGE T-ANTIGEN IS SUFFICIENT TO INDUCE HEPATIC-TUMORS IN MICE

The transforming activity of SV40 large T-antigen (Tag) depends on its binding to cellular proteins involved in the control of the cell cycl e (p53, pRb, p300..) and on the J-domain region in the amino-terminus. We established transgenic lines expressing wild-type or Tag mutant pr oteins lacking one of the three transforming domains, to determine the respective contributions of these domains to hepatic tumour formation . Tag mutants with no pRb-binding domain or N-terminal fragment did no t cause neoplastic liver abnormalities. The dl1137 Tag mutant protein, which inhibits pRb function without affecting p53, induced hepatic tu mours, These tumours grew significantly faster than those induced by w ild-type Tag. Our results demonstrate different requirements for each of the inactivating functions of SV40 Tag in hepatocyte transformation and show that the loss of p53 function has only a moderate effect on hepatic tumour formation.