Notch1 intracellular domain suppresses APP intracellular domain-Tip60-Fe65 complex mediated signaling through physical interaction.

The amyloid beta-precursor protein (APP) and the Notch receptor are both type 1 integral transmembrane proteins, and both are cleaved by presenilin-dependent gamma-secretase activity. In this study, we have demonstrated that the Notch intracellular domain (Notch1-IC) suppresses APP-intracellular domain (AICD)-mediated ROS generation and cell death after being processed by gamma ...
secretase. Notch1-IC physically interacts with AICD, Fe65, and Tip60, thereby disrupting the association of the AICD-Fe65-Tip60 trimeric transcription activator complex in AICD signaling. AICD-Fe65-Tip60 mediated reactive oxygen species generation was found to be suppressed by Notch1-IC. Furthermore, AICD-Fe65-Tip60 was shown to mediate cell death in human neuroblastoma cells, and the overexpression of Notch1-IC inhibited cell death induced by AICD-Fe65-Tip60. Collectively, our findings indicate that Notch1-IC plays the role of a negative regulator in AICD signaling via the disruption of the AICD-Fe65-Tip60 trimeric complex.
Mesh Terms:
Amyloid Precursor Protein Secretases, Amyloid beta-Protein Precursor, Animals, Cell Line, Tumor, Histone Acetyltransferases, Humans, Mice, Multiprotein Complexes, NIH 3T3 Cells, Nerve Tissue Proteins, Nuclear Proteins, Presenilins, Protease Nexins, Protein Binding, Protein Structure, Tertiary, Reactive Oxygen Species, Receptor, Notch1, Receptors, Cell Surface, Signal Transduction
Biochim. Biophys. Acta
Date: Jun. 01, 2007
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