REGULATION OF APOPTOSIS IN TRANSGENIC MICE BY SIMIAN-VIRUS-40 T-ANTIGEN-MEDIATED INACTIVATION OF P53

Several proteins encoded by DNA tumor viruses are thought to disrupt c ellular growth control by interacting with key cellular proteins, such as p53 and pRB, that normally function to regulate cell growth. Howev er, the biological consequences of intracellular complexing between th e viral oncoproteins and cellular proteins have remained unclear. Such complexes could either facilitate functional inactivation of the cell ular proteins, leading to a loss of-function phenotype, or could activ ate new functions, leading to a gain-of-function phenotype. Here we de monstrate that the simian virus 40 large tumor (T) antigen produces a loss-of-p53-function phenotype when introduced into the thymocytes of transgenic mice. Like thymocytes from the recently characterized p53-n ull mice, thymocytes from transgenic mice expressing a T-antigen varia nt capable of binding to p53 are resistant to irradiation-induced apop tosis. Thymocytes from transgenic mice expressing a mutant T antigen t hat is unable to complex p53, but retains the ability to complex the p RB and p107 proteins, retain sensitivity to irradiation. We further de monstrate that although irradiation-induced apoptosis is impaired by T antigen, clonal deletion of autoreactive thymocytes via p53-independe nt apoptosis is not perturbed by T antigen. These results provide conv incing evidence that T antigen inactivates p53 in thymocytes in vivo a nd suggest a mechanism by which T antigen predisposes thymocytes to tu morigenesis in T antigen-transgenic mice.