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

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

Authors

  • von Rotz RC
  • Kohli BM
  • Bosset J
  • Meier M
  • Suzuki T
  • Nitsch RM
  • Konietzko U

Journal

Journal of cell science

Publication Data

September 1, 2004

Associated Grants

None

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