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Oncogenic transformation by human adenoviruses requires early regions 1A and 1B (E1A and E1B) and provides a model of multistep carcinogenesis. This study shows that the metabolic stabilization of p53 observed in adenovirus 5 (Ad5)-transformed cells can occur in untransformed cells expressing E1A alone. Stabilized p53 was localized to the nucleus and was indistinguishable from wild-type p53 with respect to its interactions with hsc70, PAb420, Ad5 p55E1B, and SV40 large T antigen. Moreover, binding of Ad5 p55E1B or SV40 large T antigen had no additional effect on p53 levels or turnover. Higher levels of p53 were also induced in a variety of cell types within 40 hr after transferring E1A genes. E1A also caused cells to lose viability by a process resembling apoptosis. The apoptosis appeared to involve p53, because p53 levels reverted to normal in surviving cells that had lost E1A, and E1B protected cells from the toxic effects of E1A. These results suggest that (1) the involvement of p53 in tumor suppression and/or apoptosis can be regulated at the level of protein turnover, and (2) a major oncogenic role for E1B is to counter cellular responses to E1A (i.e., stabilization of p53 and associated apoptosis) that preclude transformation by E1A alone. This represents the first physiological setting in which high levels of endogenous p53 are induced in response to an oncogenic challenge, with the apparent consequence of suppressing transformation.