Accumulation of p53 in response to adenovirus early region 1A sensitizes human cells to tumor necrosis factor alpha-induced apoptosis

Many tumor cells are resistant to tumor necrosis factor alpha (TNFα)-induced apoptosis. Adenovirus early region 1A (AdE1A) sensitizes the otherwise resistant cells to TNFα. AdE1A also stabilizes the p53 protein. The present study demonstrates a correlation between AdE1A-induced sensitization and stabilization of p53 in TNFα-induced apoptosis since the N-terminal and CR2 regions, the binding sites for CBP/p300, Rb and 26S proteasome regulatory components, are required for both these actions of AdE1A. TNFα does not induce apoptosis and AdE1A fails to sensitize TNFα cytotoxicity in p53-negative cells. However, introduction of exogenous p53 overcomes the cellular resistance to TNFα toxicity and enhances AdE1A sensitization, demonstrating that AdE1A sensitizes TNFα-induced apoptosis by its stabilization of p53. A proteasome inhibitor, lactacystin, enhances TNFα cytotoxicity in p53-positive and -negative cells, suggesting that accumulation of cellular proteins other than p53 might also regulate the cellular response to TNFα signaling.