Induction of genomic instability in SV40 transformed human cells: sufficiency of the N-terminal 147 amino acids of large T antigen and role of pRB and p53.

Genomic instability is an early event in the transformation of human cells by SV40 and may contribute, as a mutagenic process, to the generation of the rare cells which survive crisis and yield immortal populations. We have previously reported that expression of large T antigen is responsible for induction of chromosome aberrations and aneuploidy. In the present study we have demonstrated that the amino terminal 147 amino acids of the protein are as proficient as full length T antigen for this destabilization of the cell genome. Analysis of mutants within this region indicated that T antigens defective for binding to pRB or lacking the first 127 amino acids are significantly reduced in their ability to induce aneuploidy and/or aberrations, whereas a cytoplasmic T antigen is less severely impaired. In addition, we have shown that binding of T antigen to p53 is dispensable for genome destabilization but may be required for continued proliferation of genetically aberrant cells.