Inactivation of the tumour suppressor p53 is the most common defect in cancer 
cells. p53 is a sequence specific transcription factor that is activated in 
response to various forms of genotoxic stress to induce cell cycle arrest and 
apoptosis. Induction of p53 is subjected to complex and strict control through 
several pathways, as it will often determine cellular fate. The p73 protein 
shares strong structural and functional similarities with p53 such as the 
potential to activate p53 responsive genes and the ability to induce apoptosis. 
In addition to alternative splicing at the carboxyl terminus which yields 
several p73 isoforms, a p73 variant lacking the N-terminal transactivation 
domain (Delta Np73) was described in mice. In this study, we report the cloning 
and characterisation of the human Delta Np73 isoforms, their regulation by p53 
and their possible role in carcinogenesis. As in mice, human Delta Np73 lacks 
the transactivation domain and starts with an alternative exon (exon 3'). Its 
expression is driven by a second promoter located in a genomic region upstream 
of this exon, supporting the idea of two independently regulated proteins, 
derived from the same gene. As anticipated, Delta Np73 is capable of regulating 
TAp73 and p53 function since it is able to block their transactivation activity 
and their ability to induce apoptosis. Interestingly, expression of the Delta 
Np73 is strongly up-regulated by the TA isoforms and by p53, thus creating a 
feedback loop that tightly regulates the function of TAp73 and more importantly 
of p53. The regulation of Delta Np73 is exerted through a p53 responsive element 
located on the Delta N promoter. Expression of Delta Np73 not only regulates the 
function of p53 and TAp73 but also shuts off its own expression, once again 
finely regulating the whole system. Our data also suggest that increased 
expression of Delta Np73, functionally inactivating p53, could be involved in 
tumorogenesis. An extensive analysis of the expression pattern of Delta Np73 in 
primary tumours would clarify this issue.