p73, an important developmental gene, shares a high sequence homology with p53 
and induces both G(1) cell cycle arrest and apoptosis. However, the molecular 
mechanisms through which p73 induces apoptosis are unclear. We found that 
p73-induced apoptosis is mediated by PUMA (p53 up-regulated modulator of 
apoptosis) induction, which, in turn, causes Bax mitochondrial translocation and 
cytochrome c release. Overexpression of p73 isoforms promotes cell death and bax 
promoter transactivation in a time-dependent manner. However, the kinetics of 
apoptosis do not correlate with the increase of Bax protein levels. Instead, 
p73-induced mitochondrial translocation of Bax is kinetically compatible with 
the induction of cell death. p73 is localized in the nucleus and remains nuclear 
during the induction of cell death, indicating that the effect of p73 on Bax 
translocation is indirect. The ability of p73 to directly transactivate PUMA and 
the direct effect of PUMA on Bax conformation and mitochondrial relocalization 
suggest a molecular link between p73 and the mitochondrial apoptotic pathway. 
Our data therefore indicate that PUMA-mediated Bax mitochondrial translocation, 
rather than its direct transactivation, correlates with cell death. Finally, 
human DeltaNp73, an isoform lacking the amino-terminal transactivation domain, 
inhibits TAp73-induced as well as p53-induced apoptosis. The DeltaNp73 isoforms 
seem therefore to act as dominant negatives, repressing the PUMA/Bax system and, 
thus, finely tuning p73-induced apoptosis. Our findings demonstrate that p73 
elicits apoptosis via the mitochondrial pathway using PUMA and Bax as mediators.