Document Detail


Amyloid precursor protein promotes endoplasmic reticulum stress-induced cell death via C/EBP homologous protein-mediated pathway.
MedLine Citation:
PMID:  19476545     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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 gamma-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 alpha- and gamma-secretase cleavage and subsequently induces CHOP-mediated cell death.
Authors:
Keita Takahashi; Tetsuhiro Niidome; Akinori Akaike; Takeshi Kihara; Hachiro Sugimoto
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Publication Detail:
Type:  Journal Article     Date:  2009-03-26
Journal Detail:
Title:  Journal of neurochemistry     Volume:  109     ISSN:  1471-4159     ISO Abbreviation:  J. Neurochem.     Publication Date:  2009 Jun 
Date Detail:
Created Date:  2009-05-29     Completed Date:  2009-06-15     Revised Date:  2010-04-08    
Medline Journal Info:
Nlm Unique ID:  2985190R     Medline TA:  J Neurochem     Country:  England    
Other Details:
Languages:  eng     Pagination:  1324-37     Citation Subset:  IM    
Affiliation:
Department of Neuroscience for Drug Discovery, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.
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MeSH Terms
Descriptor/Qualifier:
Amyloid beta-Protein / metabolism
Amyloid beta-Protein Precursor / genetics,  metabolism*
Cell Death / drug effects
Cell Line / ultrastructure
Chromatin Immunoprecipitation / methods
Dipeptides / pharmacology
Dithiothreitol / pharmacology
Endoplasmic Reticulum / drug effects,  metabolism*
Enzyme Inhibitors / pharmacology
Humans
L-Lactate Dehydrogenase / metabolism
Neuroblastoma
Prostanoic Acids / metabolism
Protein Structure, Tertiary / physiology
RNA, Messenger / metabolism
RNA, Small Interfering / pharmacology
Signal Transduction / drug effects,  physiology*
Stress, Physiological / drug effects*
Time Factors
Transcription Factor CHOP / metabolism*
Transfection
Tunicamycin / pharmacology
Tyrosine / metabolism
Chemical
Reg. No./Substance:
0/Amyloid beta-Protein; 0/Amyloid beta-Protein Precursor; 0/DDIT3 protein, human; 0/Dipeptides; 0/Enzyme Inhibitors; 0/N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester; 0/Prostanoic Acids; 0/RNA, Messenger; 0/RNA, Small Interfering; 11089-65-9/Tunicamycin; 147336-12-7/Transcription Factor CHOP; 3483-12-3/Dithiothreitol; 55520-40-6/Tyrosine; 82598-17-2/9-hydroxy-19,20-bisnorprostanoic acid; EC 1.1.1.27/L-Lactate Dehydrogenase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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