Notch1-mediated repression of p53 transactivation

Abstract

A biochemical mechanism for the negative role of Notch signaling on p53 transactivation function was proposed. Expression of the intracellular domain of human Notch1 (Notch1-IC) inhibits the expression of p53-responsive genes p21, mdm2, and bax in $HCT116 p53^{-/-}$ cells. In addition, Notch1-IC expression inhibits the phosphorylation of ectopically expressed p53 in $HCT116 p53^{-/-}$ cells as well as the phosphorylation of endogenous p53 in ultraviolet treated $HCT116 p53^{+/+}$ cells. It was confirmed that transcriptional downregulation of p53-responsive genes by Notch1-IC both by chromatin immunoprecipitation and Northern blot analyses. The intracellular interaction between Notch1-IC and p53 in $HCT116 p53^{+/+}$ cells was observed, suggesting that activated Notch1 interaction with p53 is an important cellular event for the inhibition of p53-dependent transactivation. The N-terminal fragment of Notch1-IC, which can interacts with p53, inhibits p53 phosphorylation and represses p53 transactivation. In addition, Notch signaling downregulated p53-dependent apoptosis induced by UV irradiation.