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 c ells by SV40 and may contribute, as a mutagenic process, to the genera tion of the rare cells which survive crisis and yield immortal populat ions. We have previously reported that expression of large T antigen i s 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 withi n this region indicated that T antigens defective for binding to pRB o r lacking the first 127 amino acids are significantly reduced in their ability to induce aneuploidy and/or aberrations, whereas a cytoplasmi c 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 aberra nt cells.