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Amyloid precursor protein promotes endoplasmic reticulum stress‐induced cell death via C/EBP homologous protein‐mediated pathway
Author(s) -
Takahashi Keita,
Niidome Tetsuhiro,
Akaike Akinori,
Kihara Takeshi,
Sugimoto Hachiro
Publication year - 2009
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2009.06067.x
Subject(s) - unfolded protein response , tunicamycin , endoplasmic reticulum , chop , viability assay , amyloid precursor protein , microbiology and biotechnology , chemistry , gene knockdown , programmed cell death , apoptosis , biology , biochemistry , medicine , disease , alzheimer's disease
The accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER) is known to activate the ER, which is termed ER stress. Here, we demonstrated that amyloid precursor protein (APP) is a novel mediator of ER stress‐induced apoptosis through the C/EBP homologous protein (CHOP) pathway. Expression of APP mRNA was elevated by tunicamycin‐ or dithiothreitol‐induced ER stress. The levels of C83 and APP intracellular domain (AICD) fragments, which are cleaved from APP, were significantly increased under ER stress, although the protein level of full‐length APP was decreased. Cellular viability was reduced in APP‐over‐expressing cells, which was attenuated by treatment with a γ‐secretase inhibitor, N ‐[ N ‐(3,5‐difluorophenacetyl)‐L‐alanyl]‐ S ‐phenylglycine t ‐butyl ester (DAPT). Cellular viability was also reduced in AICD‐FLAG‐over‐expressing cells. The mRNA and protein levels of CHOP, an ER stress‐responsive gene, were remarkably increased by APP over‐expression, which was attenuated by treatment with DAPT. CHOP mRNA induction was also found in AICD‐FLAG‐over‐expressing cells. Cell death and CHOP up‐regulation by ER stress were attenuated by APP knockdown. Data obtained with a luciferase assay and chromatin immunoprecipitation assay indicated that AICD associates with the promoter region of the CHOP gene. In conclusion, ER stress‐induced APP undergoes α‐ and γ‐secretase cleavage and subsequently induces CHOP‐mediated cell death.