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The APP intracellular domain forms nuclear multiprotein complexes and regulates the transcription of its own precursor.

Journal of cell science | Sep 1, 2004

http://www.ncbi.nlm.nih.gov/pubmed/15331662

The physiological functions of the beta-amyloid precursor protein (APP) may include nuclear signaling. To characterize the role of the APP adaptor proteins Fe65, Jip1b, X11alpha (MINT1) and the chromatin-associated protein Tip60, we analyzed their interactions by confocal microscopy and co-immunoprecipitations. AICD corresponding to S3-cleaved APP bound to Fe65 that transported it to nuclei and docked it to Tip60. These proteins formed AICD-Fe65-Tip60 (AFT) complexes that were concentrated in spherical nuclear spots. gamma-Secretase inhibitors prevented AFT-complex formation with AICD derived from full-length APP. The APP adaptor protein Jip1b also transported AICD to nuclei and docked it to Tip60, but AICD-Jip1b-Tip60 (AJT) complexes had different, speckle-like morphology. By contrast, X11alpha trapped AICD in the cytosol. Induced AICD expression identified the APP-effector genes APP, BACE, Tip60, GSK3beta and KAI1, but not the Notch-effector gene Hes1 as transcriptional targets. These data establish a role for APP in nuclear signaling, and they suggest that therapeutic strategies designed to modulate the cleavage of APP affect AICD-dependent signaling.

Pubmed ID: 15331662 RIS Download

Mesh terms: Acetyltransferases | Active Transport, Cell Nucleus | Adaptor Proteins, Signal Transducing | Amyloid beta-Protein Precursor | Antigens, CD | Antigens, CD82 | Basic Helix-Loop-Helix Transcription Factors | Cell Nucleus | Cells, Cultured | Fluorescence Resonance Energy Transfer | Histone Acetyltransferases | Homeodomain Proteins | Humans | Membrane Glycoproteins | Multiprotein Complexes | Nerve Tissue Proteins | Nuclear Proteins | Protein Binding | Proto-Oncogene Proteins | Transcription, Genetic

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