title: AβPP intracellular C-terminal domain function is related to its degradation processes.
abstract: The amyloid-β protein precursor (AβPP) can be processed by either the amyloidogenic or the non-amyloidogenic pathway; both pathways lead to release of the AβPP intracellular C-terminal domain (AICD). AICD involvement in signal transduction within Fe65/Tip60 complex is one of the most discussed mechanisms, and different models have been hypothesized to explain the role of AICD within this complex. The analysis of these models in relation to the degradation processes highlights the discrepancy among AICD localization, function, and degradation, leading to the hypothesis that a signaling mechanism may exist which allows AβPP proteolysis to generate either a transcriptionally active fragment or an inactive one with different involvement of proteasome and IDE (insulin-degrading enzyme). Our work aimed to analyze the functional role of AICD within the Fe65/Tip60 complex considering the AICD degradation processes. Our data suggest a correlation between the role of AICD in gene regulation and its removal operated by proteasome activity. Moreover, treatments with IDE inhibitor underlined the presence of an alternative mechanism involved in AICD removal when the latter is not exerting nuclear activity, thus providing clearer support for the existence of at least two mechanisms as previously suggested.
authors.affiliation: Department of Drug Sciences, Pharmacology Unit, Center of Excellence in Applied Biology, University of Pavia, Pavia, Italy.
authors.forename: Erica
authors.initials: E
authors.lastname: Buoso
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Biundo
authors.forename: Cristina
authors.initials: C
authors.lastname: Lanni
authors.forename: Gennaro
authors.initials: G
authors.lastname: Schettini
authors.forename: Stefano
authors.initials: S
authors.lastname: Govoni
authors.forename: Marco
authors.initials: M
authors.lastname: Racchi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000686:Amyloidosis / Q000235:genetics* / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000235:genetics; D057809:HEK293 Cells; D051548:Histone Acetyltransferases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007339:Insulysin / Q000235:genetics / Q000378:metabolism; D000074443:Lysine Acetyltransferase 5; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D013329:Structure-Activity Relationship; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: C466684:APBB2 protein, human; D048868:Adaptor Proteins, Signal Transducing; D016229:Amyloid beta-Peptides; D046912:Multiprotein Complexes; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D051548:Histone Acetyltransferases; C098489:KAT5 protein, human; D000074443:Lysine Acetyltransferase 5; D007339:Insulysin; D046988:Proteasome Endopeptidase Complex