p73 has significant homology to p53. However, tumor-associated up-regulation of 
p73 and genetic data from human tumors and p73-deficient mice exclude a 
classical Knudson-type tumor suppressor role. We report that the human TP73 gene 
generates an NH(2) terminally truncated isoform. DeltaNp73 derives from an 
alternative promoter in intron 3 and lacks the transactivation domain of 
full-length TAp73. DeltaNp73 is frequently overexpressed in a variety of human 
cancers, but not in normal tissues. DeltaNp73 acts as a potent transdominant 
inhibitor of wild-type p53 and transactivation-competent TAp73. DeltaNp73 
efficiently counteracts transactivation function, apoptosis, and growth 
suppression mediated by wild-type p53 and TAp73, and confers drug resistance to 
wild-type p53 harboring tumor cells. Conversely, down-regulation of endogenous 
DeltaNp73 levels by antisense methods alleviates its suppressive action and 
enhances p53- and TAp73-mediated apoptosis. DeltaNp73 is complexed with 
wild-type p53, as demonstrated by coimmunoprecipitation from cultured cells and 
primary tumors. Thus, DeltaNp73 mediates a novel inactivation mechanism of p53 
and TAp73 via a dominant-negative family network. Deregulated expression of 
DeltaNp73 can bestow oncogenic activity upon the TP73 gene by functionally 
inactivating the suppressor action of p53 and TAp73. This trait might be 
selected for in human cancers.