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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
47
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pubmed:dateCreated |
2004-11-15
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pubmed:abstractText |
The deposition of the amyloid beta (Abeta) peptide in neuritic plaques plays a critical role in the pathogenesis of Alzheimer's disease (AD). Abeta is generated through the proteolysis of amyloid precursor protein (APP) by the sequential actions of beta- and gamma-secretases. Although recent evidence has unveiled much about the biochemical identity and characteristics of gamma-secretase, the mechanism regulating endogenous gamma-secretase activity remains elusive. To identify possible extracellular signals and associated signaling cascades that could regulate APP proteolysis by gamma-secretase activity, we have developed a cell-based reporter gene assay by stably cotransfecting HEK293 cells with the Gal4-driven luciferase reporter gene and the Gal4/VP16-tagged C-terminal fragment of APP (C99-GV), the immediate substrate of gamma-secretase. The cleavage of C99-GV by gamma-secretase releases the transcription factor that activates luciferase expression, providing a quantitative measurement of gamma-secretase activity. Using this reporter assay, we have demonstrated that interferon-gamma, interleukin-1beta, and tumor necrosis factor-alpha can specifically stimulate gamma-secretase activity, concomitant with increased production of Abeta and the intracellular domain of APP (AICD). The gamma-secretase-dependent cleavage of Notch is also enhanced upon the stimulation of these cytokines. The cytokine-enhanced gamma-secretase activity can be suppressed by a potent inhibitor of c-Jun N-terminal kinase (JNK). Furthermore, cells transfected with dominant-positive MEKK1, one of the most potent activators of the JNK cascade, exhibit increased gamma-secretase activity, suggesting that the JNK-dependent mitogen-activated protein kinase pathway could mediate the cytokine-elicited regulation of gamma-secretase. Our studies provide direct evidence that cytokine-elicited signaling cascades control Abeta production by modulating gamma-secretase activity.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Amyloid Precursor Protein Secretases,
http://linkedlifedata.com/resource/pubmed/chemical/Amyloid beta-Protein Precursor,
http://linkedlifedata.com/resource/pubmed/chemical/Aspartic Acid Endopeptidases,
http://linkedlifedata.com/resource/pubmed/chemical/BACE1 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Culture Media, Serum-Free,
http://linkedlifedata.com/resource/pubmed/chemical/DNA,
http://linkedlifedata.com/resource/pubmed/chemical/Endopeptidases,
http://linkedlifedata.com/resource/pubmed/chemical/Interferon-gamma,
http://linkedlifedata.com/resource/pubmed/chemical/Interleukin-1,
http://linkedlifedata.com/resource/pubmed/chemical/JNK Mitogen-Activated Protein...,
http://linkedlifedata.com/resource/pubmed/chemical/Luciferases,
http://linkedlifedata.com/resource/pubmed/chemical/MAP Kinase Kinase 4,
http://linkedlifedata.com/resource/pubmed/chemical/Membrane Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Mitogen-Activated Protein Kinase...,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Notch,
http://linkedlifedata.com/resource/pubmed/chemical/Tumor Necrosis Factor-alpha
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pubmed:status |
MEDLINE
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pubmed:month |
Nov
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pubmed:issn |
0021-9258
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
19
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pubmed:volume |
279
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
49523-32
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pubmed:dateRevised |
2009-11-19
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pubmed:meshHeading |
pubmed-meshheading:15347683-Amyloid Precursor Protein Secretases,
pubmed-meshheading:15347683-Amyloid beta-Protein Precursor,
pubmed-meshheading:15347683-Animals,
pubmed-meshheading:15347683-Aspartic Acid Endopeptidases,
pubmed-meshheading:15347683-Blotting, Western,
pubmed-meshheading:15347683-COS Cells,
pubmed-meshheading:15347683-Cell Line,
pubmed-meshheading:15347683-Culture Media, Serum-Free,
pubmed-meshheading:15347683-DNA,
pubmed-meshheading:15347683-Dose-Response Relationship, Drug,
pubmed-meshheading:15347683-Electrophoresis, Polyacrylamide Gel,
pubmed-meshheading:15347683-Endopeptidases,
pubmed-meshheading:15347683-Enzyme-Linked Immunosorbent Assay,
pubmed-meshheading:15347683-Genes, Dominant,
pubmed-meshheading:15347683-Genes, Reporter,
pubmed-meshheading:15347683-Humans,
pubmed-meshheading:15347683-Interferon-gamma,
pubmed-meshheading:15347683-Interleukin-1,
pubmed-meshheading:15347683-JNK Mitogen-Activated Protein Kinases,
pubmed-meshheading:15347683-Luciferases,
pubmed-meshheading:15347683-MAP Kinase Kinase 4,
pubmed-meshheading:15347683-MAP Kinase Signaling System,
pubmed-meshheading:15347683-Membrane Proteins,
pubmed-meshheading:15347683-Mitogen-Activated Protein Kinase Kinases,
pubmed-meshheading:15347683-Mutation,
pubmed-meshheading:15347683-Protein Structure, Tertiary,
pubmed-meshheading:15347683-Receptors, Notch,
pubmed-meshheading:15347683-Signal Transduction,
pubmed-meshheading:15347683-Transfection,
pubmed-meshheading:15347683-Tumor Necrosis Factor-alpha
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pubmed:year |
2004
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pubmed:articleTitle |
Tumor necrosis factor-alpha, interleukin-1beta, and interferon-gamma stimulate gamma-secretase-mediated cleavage of amyloid precursor protein through a JNK-dependent MAPK pathway.
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pubmed:affiliation |
Laboratory of Molecular Neurobiology, Institute of Zoology, Academia Sinica, Taipei 115, Taiwan. yliao@sinica.edu.tw
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pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, P.H.S.,
Research Support, Non-U.S. Gov't
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