Specific isoforms of p73 control the induction of cell death induced by the viral proteins, E1A or apoptin.
A member of the p53 family, p73, has several isoforms and differentially regulates transcription of genes involved in the control of the cell cycle and apoptosis. We have previously shown efficient and p53-independent, tumor-specific cell death induced by the viral proteins E1A and Apoptin. Here, we demonstrate that the induction of apoptosis by these viral proteins involves activation of TAp73. Both E1A and Apoptin induced expression of endogenous TAp73 and the p53/p73 BH3-only pro-apoptotic target, PUMA, independently of the p53 function. Furthermore, exogenous expression of TAp73 isoforms, particularly TAp73beta, sensitized cells to killing by both E1A and Apoptin, while expression of DeltaNp73alpha blocked this activity. Besides, knockout of the p73 regulator, c-Abl, attenuated E1A-induced apoptosis. In accordance with the role of p73 in apoptosis induced by these viral proteins, overexpression of TAp73beta strongly induced apoptosis in p53-deficient cancer cells in vitro and in HNSCC xenografts. Using a doxycycline-inducible system, we provide evidence for target selectivity and significant differences in protein stability for specific p73 isoforms, suggesting a diverse and pivotal role for p73 in response to various genotoxic agents. Collectively, our data show that in the absence of the p53 function, viral proteins E1A and Apoptin utilize the p73 pathway to induce efficient tumor cell death.
Klanrit
Poramaporn
P
Head and Neck Oncology Group, King's College London Dental Institute, London, United Kingdom.
Flinterman
Marcella B
MB
Odell
Edward W
EW
Melino
Gerry
G
Killick
Richard
R
Norris
James S
JS
Tavassoli
Mahvash
M
D017500:Adenovirus E1A Proteins / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000378:metabolism; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009687:Nuclear Proteins / Q000378:metabolism*; D020033:Protein Isoforms / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D015533:Transcriptional Activation; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D014764:Viral Proteins / Q000378:metabolism*
D017500:Adenovirus E1A Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D020033:Protein Isoforms; D011518:Proto-Oncogene Proteins; C000606460:TP73 protein, human; C000606368:Trp73 protein, mouse; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D014764:Viral Proteins; C454920:delta Np73, mouse