Aberrant Notch signaling contributes to more than half of all human T-cell leukemias. Accumulating evidence indicates Notch involvement in other human neoplasms. To investigate the possible role of Notch in the regulation of p63, one of the p53 family proteins, which induces the expression of several target proteins involved in cell cycle arrest and apoptosis, I examined the effect of Notch signaling on the transactivation functions of p63. Ectopic expression of activated human Notchl (Nl-IC) represses p63 transactivation. Data show that p63 protein levels are reduced by the expression of N1-IC in HCT116 p53-/- cells. Data further suggest that proteasomedependent degradation of protein did not result in the decrease of p63 protein levels by Nl-IC. The transactivation of NI-IC is attributable to the decrease of p63 protein levels since Notchl-ARAM mutant which lacks the ability of Nl-IC to transactivate its target genes did not reduce levels of p63 protein. I showed that Notchl suppresses transcription of p63 in RT-PCR analysis. Therefore, this study concludes that Nl-IC mediates suppression of p63 transactivation by inhibiting transcription of p63.