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

• Published in: Virology (New York, N.Y.) Vol. 340; no. 2; pp. 285 - 295
• Main Authors: Zhang, Xian, Hussain, Rahel, Turnell, Andrew S., Mymryk, Joe S., Gallimore, Phillip H., Grand, Roger J.A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 30-09-2005
• Subjects: 26S proteasome; Acetylcysteine - analogs & derivatives; Acetylcysteine - pharmacology; AdE1A; Adenovirus; Adenovirus E1A Proteins - genetics; Adenovirus E1A Proteins - metabolism; Apoptosis; Apoptosis - drug effects; Apoptosis - physiology; Carcinoma, Non-Small-Cell Lung; CBP/p300; Cell Line, Tumor; Humans; Lung Neoplasms; p53; Recombinant Proteins - metabolism; TNFα; Transfection; Tumor Necrosis Factor-alpha - pharmacology; Tumor Necrosis Factor-alpha - toxicity; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; AdE1A; Rb; TNFα; 26S proteasome; Adenovirus; CBP/p300; p53; Apoptosis
• ISSN: 0042-6822; 1096-0341
• DOI: 10.1016/j.virol.2005.06.020

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.