IDENTIFICATION OF A NOVEL ANTIAPOPTOTIC FUNCTIONAL DOMAIN IN SIMIAN-VIRUS-40 LARGE T-ANTIGEN

The ability of DNA tumor virus proteins to trigger apoptosis in mammal ian cells is well established. For example, transgenic expression of a simian virus 40 (SV40) T-antigen N-terminal fragment (N-termTag) is k nown to induce apoptosis in choroid plexus epithelial cells. SV IO T-a ntigen-induced apoptosis has generally been considered to be a p53-dep endent event because cell death in the brain is greatly diminished in a p53(-/-) background strain and is abrogated by expression of wild-ty pe (p53-binding) SV40 T antigen. We now show that while N-termTags tri ggered apoptosis in rat embryo fibroblasts cultured in low serum, expr ession of full-length T antigens unable to bind p53 [mut((p53-))Tags] protected against apoptosis without causing transformation. One domain essential for blocking apoptosis by T antigen was mapped to amino aci ds 525 to 541. This domain has >60% homology with a domain of adenovir us type 5 E1B 19K required to prevent EIA-induced apoptosis. In the co ntext of both wild-type T antigen and mut((p53-))Tags, mutation of two conserved amino acids in this region eliminated T antigen's antiapopt otic activity in REF-52 cells. These data suggest that SV40 T antigen contains a novel functional domain involved in preventing apoptosis in dependently of inactivation of p53.