Activated Notch1 interacts with p53 to inhibit its phosphorylation and transactivation.
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.
Kim
S B
SB
Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, South Korea.
Chae
G W
GW
Lee
J
J
Park
J
J
Tak
H
H
Chung
J H
JH
Park
T G
TG
Ahn
J K
JK
Joe
C O
CO
D017209:Apoptosis / Q000528:radiation effects; D004247:DNA / Q000378:metabolism; D015536:Down-Regulation / Q000528:radiation effects; D045325:HCT116 Cells; D006801:Humans; D010766:Phosphorylation / Q000528:radiation effects; D011485:Protein Binding / Q000528:radiation effects; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000528:radiation effects; D014158:Transcription, Genetic / Q000528:radiation effects; D015533:Transcriptional Activation / Q000235:genetics* / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D014466:Ultraviolet Rays
C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53; D004247:DNA