p73, like Notch, has been implicated in neurodevelopment and in the maintenance 
of the mature central nervous system. In this study, by the use of reporter-gene 
assays, we demonstrate that C-promoter binding factor-1 (CBF-1)-dependent gene 
transcription driven by the Notch-1 intracellular domain (N1(ICD)) is potently 
antagonized by exogenously expressed transactivating (TA) p73 splice variants in 
SH-SY5Y neuroblastomas and in primary neurones. Time course analysis indicated 
that the inhibitory effects of TAp73 are direct and are not mediated via the 
product of a downstream target gene. We found that endogenous TAp73 stabilized 
by either c-Abl or cisplatin treatment also potently antagonized 
N1(ICD)/CBF-1-dependent gene transcription. Furthermore, western blotting 
revealed that exogenous TAp73 suppressed endogenous hairy and enhancer of 
split-1 (HES-1) protein levels and antagonized the increase in HES-1 protein 
induced by exogenous N1(ICD) expression. Evidence of a direct physical 
interaction between N1(ICD) and TAp73alpha was demonstrated by 
co-immunoprecipitation. Using Notch deletion constructs, we demonstrate that 
TAp73alpha binds the N1(ICD) in a region C-terminal of aa 2094. Interestingly, 
DeltaNp73alpha and TAp73alpha(R292H) also co-purified with N1(ICD), but neither 
inhibited N1(ICD)/CBF-1-dependent transcription. This suggests that an intact 
transactivation (TA) domain and the ability to bind DNA are necessary for TAp73 
to antagonize Notch signalling. Finally we found that TAp73alpha reversed the 
N1(ICD)-mediated repression of retinoic acid-induced differentiation of SH-SY5Y 
neuroblastomas, providing functional evidence for an inhibitory effect of 
TAp73alpha on notch signalling. Collectively, these findings may have 
ramifications for neurodevelopment, neurodegeneration and oncogenesis.