Abstract
We propose a biochemical mechanism for the negative role of Notch signaling on p53 transactivation function. 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. Furthermore, Notch1-IC expression inhibits the phosphorylation of ectopically expressed p53 in HCT116 p53-/- cells as well as the phosphorylation of endogenous p53 in UV-treated HCT116 p53+/+ cells. Transcriptional downregulation of p53-responsive genes by Notch1-IC was confirmed both by chromatin immunoprecipitation assay and Northern blot analysis. We found the intracellular interaction between Notch1-IC and p53 in HCT116 p53+/+ cells and suggest 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.
| Original language | English |
|---|---|
| Pages (from-to) | 982-991 |
| Number of pages | 10 |
| Journal | Cell Death and Differentiation |
| Volume | 14 |
| Issue number | 5 |
| DOIs | |
| State | Published - May 2007 |
Funding
Acknowledgements. We are grateful to Dr. J Aster (Bringham and Women’s Hospital, USA) for providing pcDNA3-Notch1-IC expression plasmid. This study was supported in part by grants from the Korean National Cancer Control Program, Ministry of Health and Welfare (0220150-3); the Korea Science and Engineering Foundation (2004-01885); and the Korea Research Foundation (KRF-2003-015-C00534 and KRF-2005-070-C00105).