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

Many tumor cells are resistant to tumor necrosis factor alpha (TNF alpha)-induced apoptosis. Adenovirus early region 1A (AdE1A) sensitizes the otherwise resistant cells to TNF alpha AdE1A also stabilizes the p53 protein. The present study demonstrates a correlation between AdE1A-induced sensitization and stabilization of p53 in TNF alpha-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. TNF alpha does not induce apoptosis and AdE1A fails to sensitize TNF alpha cytotoxicity in p53-negative cells. However, introduction of exogenous p53 overcomes the cellular resistance to TNFa. toxicity and enhances AdE1A sensitization, demonstrating that AdE1A sensitizes TNF alpha-induced apoptosis by its stabilization of p53. A proteasome inhibitor, lactacystin, enhances TNF alpha cytotoxicity in p53-positive and -negative cells, suggesting that accumulation of cellular proteins other than p53 might also regulate the cellular response to TNF alpha signaling. (c) 2005 Elsevier Inc. All rights reserved.