TP73, despite significant homology to TP53, is not a classic tumor suppressor 
gene, since it exhibits upregulation of nonmutated products in human tumors and 
lacks a tumor phenotype in p73-deficient mice. We recently reported that an 
N-terminally truncated isoform, DeltaNp73, is upregulated in breast and 
gynecological cancers. We further showed that DeltaNp73 is a potent 
transdominant inhibitor of wild-type p53 and TAp73 in cultured human tumor cells 
by efficiently counteracting their target gene transactivations, apoptosis, and 
growth suppression functions (A. I. Zaika et al., J. Exp. Med. 6:765-780, 2002). 
Although these data strongly suggest oncogenic properties of DeltaNp73, this can 
only be directly shown in primary cells. We report here that DeltaNp73 confers 
resistance to spontaneous replicative senescence of primary mouse embryo 
fibroblasts (MEFs) and immortalizes MEFs at a 1,000-fold-higher frequency than 
occurs spontaneously. DeltaNp73 cooperates with cMyc and E1A in promoting 
primary cell proliferation and colony formation and compromises p53-dependent 
MEF apoptosis. Importantly, DeltaNp73 rescues Ras-induced senescence. Moreover, 
DeltaNp73 cooperates with oncogenic Ras in transforming primary fibroblasts in 
vitro and in inducing MEF-derived fibrosarcomas in vivo in nude mice. Wild-type 
p53 is likely a major target of DeltaNp73 inhibition in primary fibroblasts 
since deletion of p53 or its requisite upstream activator ARF abrogates the 
growth-promoting effect of DeltaNp73. Taken together, DeltaNp73 behaves as an 
oncogene that targets p53 that might explain why DeltaNp73 upregulation may be 
selected for during tumorigenesis of human cancers.