The transcriptional activity of the APP intracellular domain-Fe65 complex is inhibited by activation of the NF-kappaB pathway.
The beta-amyloid precursor protein (APP) is an integral membrane protein that is the subject of proteolytic processing. Sequential cleavage of APP by beta-secretase and subsequently gamma-secretase generates the beta-amyloid peptide as well as a cytoplasmic intracellular domain (AICD). AICD binds to the transcriptional coactivator Fe65, and this complex has been shown to display transcriptional activity. The regulation of this complex is poorly understood. We show here that activation of the NF-kappaB pathway, either by overexpression of NF-kappaB-inducing kinase (NIK) or by treatment with the proinflammatory cytokine IL-1beta, downregulates the transcriptional activity of the AICD-Fe65 complex. This therefore provides a mechanism by which the activity of AICD might be modulated by extracellular stimuli. These results also identify an intracellular signal transduction pathway influenced by the NF-kappaB signaling pathway.
Zhao
Quan
Q
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Lee
Frank S
FS
D016564:Amyloid beta-Protein Precursor / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D019556:COS Cells; D006367:HeLa Cells; D006801:Humans; D066298:In Vitro Techniques; D046911:Macromolecular Substances; D016328:NF-kappa B / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic
C091042:APBB1 protein, human; D016564:Amyloid beta-Protein Precursor; D046911:Macromolecular Substances; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D011994:Recombinant Proteins