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 (TNFalpha)-induced apoptosis. Adenovirus early region 1A (AdE1A) sensitizes the otherwise resistant cells to TNFalpha. AdE1A also stabilizes the p53 protein. The present study demonstrates a correlation between AdE1A-induced sensitization and stabilization of p53 in TNFalpha-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. TNFalpha does not induce apoptosis and AdE1A fails to sensitize TNFalpha cytotoxicity in p53-negative cells. However, introduction of exogenous p53 overcomes the cellular resistance to TNFalpha toxicity and enhances AdE1A sensitization, demonstrating that AdE1A sensitizes TNFalpha-induced apoptosis by its stabilization of p53. A proteasome inhibitor, lactacystin, enhances TNFalpha cytotoxicity in p53-positive and -negative cells, suggesting that accumulation of cellular proteins other than p53 might also regulate the cellular response to TNFalpha signaling.
Zhang
Xian
X
Cancer Research UK Institute for Cancer Studies, The Medical School, University of Birmingham, UK. x.zhang.2@bham.ac.uk
Hussain
Rahel
R
Turnell
Andrew S
AS
Mymryk
Joe S
JS
Gallimore
Phillip H
PH
Grand
Roger J A
RJ
D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D017500:Adenovirus E1A Proteins / Q000235:genetics* / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002289:Carcinoma, Non-Small-Cell Lung; D045744:Cell Line, Tumor; D006801:Humans; D008175:Lung Neoplasms; D011994:Recombinant Proteins / Q000378:metabolism; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology* / Q000633:toxicity; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
D017500:Adenovirus E1A Proteins; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; C067713:lactacystin; D000111:Acetylcysteine