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

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  • 2004-08-28
Published in:
  • Journal of cell science. - 2004
Acetyltransferases
Active Transport, Cell Nucleus
Adaptor Proteins, Signal Transducing
Amyloid beta-Protein Precursor
Antigens, CD
Basic Helix-Loop-Helix Transcription Factors
Cell Nucleus
Cells, Cultured
Fluorescence Resonance Energy Transfer
Histone Acetyltransferases
Homeodomain Proteins
Humans
Kangai-1 Protein
Lysine Acetyltransferase 5
Membrane Glycoproteins
Multiprotein Complexes
Nerve Tissue Proteins
Nuclear Proteins
Protein Binding
Proto-Oncogene Proteins
Transcription Factor HES-1
Transcription, Genetic
English 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.
Language
  • English
Open access status
hybrid
Identifiers
Persistent URL
https://folia.unifr.ch/global/documents/210792
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