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.