The tightly regulated expression of p53 contributes to genomic stability and transcription of the p53 gene is induced prior to cells entering S-phase, possibly as a mechanism to insure a rapid p53 response in the event of DNA damage. We have previously described the cloning of an additional 1000 bp of upstream p53 sequences that play a role in the regulated expression of p53, and identified that C/EBPβ-2 participates in inducing p53 gene expression in a cell cycle regulated fashion. This report deals with the transcriptional regulator, RBP-Jκ, an essential target of the Notch receptor signaling pathway. It binds to the p53 promoter in a cell cycle regulation fashion and also serves to repress p53 gene expression. We conclude from these findings that the coordinate expression of C/EBPβ-2 and RBP-Jκ may be linked to p53 transcription during G0 and as cells move into S-phase. Because defects in the Notch signaling pathway have been implicated in carcinogenesis, aberrant RBP-Jκ expression and deregulated regulation of the p53 tumor suppressor could be an important step in some forms of cancers.