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Polyoma Virus Middle T and Small t Antigens Cooperate to Antagonize p53-induced Cell Cycle Arrest and Apoptosis¹

Microbiology and Tumor Biology Center, Karolinska Institute, S-171 77 Stockholm, Sweden

Abstract

Wild-type p53 triggers two distinct biological responses, cell cycle arrest and apoptosis. Several small DNA tumor viruses encode proteins that bind p53 and thus block the function of p53. This probably reflects the need of these viruses to prevent p53-induced cell cycle arrest and apoptosis to allow viral DNA replication. Unlike SV40 large T, polyoma virus large T does not bind p53, and it is still unclear how polyoma virus blocks p53 function. To address this question, we transfected polyoma virus middle T or small t alone or middle T and small t together into J3D mouse T-lymphoma cells carrying temperature-sensitive p53 (ts p53). Induction of wild-type p53 by temperature shift to 32°C triggered both G₁ cell cycle arrest and apoptosis in parental J3D-ts p53 cells. In contrast, J3D-ts p53 cells coexpressing middle T and small t showed only a weak G₁ cell cycle arrest response after induction of wild-type p53 at 32°C. Fluorescence-activated cell sorter analysis revealed that nearly half of the middle T-expressing cells, 30% of the small t-expressing cells, and a majority of the cells coexpressing middle T and small t were resistant to p53-induced apoptosis. The phosphatidylinositol 3-kinase inhibitor wortmannin partially abrogated the protective effect of middle T but not small t on p53-induced apoptosis, indicating that middle T prevents p53-induced apoptosis through the phosphatidylinositol 3-kinase signal transduction pathway. Our results thus establish a mechanism for polyoma virus-mediated inhibition of p53 function.

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