Linked Life Data

12032152

Source:http://linkedlifedata.com/resource/pubmed/id/12032152

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
32
pubmed:dateCreated
2002-8-5
pubmed:abstractText
The amyloid precursor protein (APP), a large glycoprotein highly expressed in neurons, is cleaved in its intramembranous domain by gamma secretase to generate amyloid-beta and a free carboxyl-terminal intracellular fragment (APP-CT), which has previously been suggested to interact with the adapter protein Fe65 and the histone acetyltransferase Tip60. An identical gamma secretase activity mediates cleavage of Notch, releasing an intracellular signaling domain that translocates to the nucleus. We examined the effect of an ectopically expressed 58-amino acid APP-CT fragment (APP-C58) on human H4 neuroglioma cells. We demonstrate by confocal microscopy and fluorescence resonance energy transfer analysis that APP-C58 translocates to the nucleus and forms a complex in the nucleus with the Tip60, independent of interactions with Fe65. APP-C58 transfected H4 cells undergo apoptosis within 48-72 h, marked by nuclear blebbing, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining, and blockade by a caspase inhibitor. When nuclear access of APP-C58 is prevented by fusing with a strong membrane-targeting farnesylation domain, apoptosis is blocked. APP-C58-induced apoptosis was markedly enhanced by co-transfection with wild type Tip60 and decreased by mutant Tip60 lacking histone acetyltransferase activity, suggesting that Tip60 mediates APP-CT-induced cell death. Thus, gamma secretase cleavage of APP may contribute to Alzheimer's disease-related neurodegeneration in two ways: release of amyloid-beta and liberation of a bioactive carboxyl-terminal domain from membrane-bound APP.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Aug
pubmed:issn
0021-9258
pubmed:author
pubmed:issnType
Print
pubmed:day
9
pubmed:volume
277
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
28530-6
pubmed:dateRevised
2011-9-28
pubmed:meshHeading
pubmed-meshheading:12032152-Acetyltransferases, pubmed-meshheading:12032152-Alzheimer Disease, pubmed-meshheading:12032152-Amyloid Precursor Protein Secretases, pubmed-meshheading:12032152-Amyloid beta-Protein Precursor, pubmed-meshheading:12032152-Animals, pubmed-meshheading:12032152-Apoptosis, pubmed-meshheading:12032152-Aspartic Acid Endopeptidases, pubmed-meshheading:12032152-Cell Nucleus, pubmed-meshheading:12032152-Dimerization, pubmed-meshheading:12032152-Endopeptidases, pubmed-meshheading:12032152-Energy Transfer, pubmed-meshheading:12032152-Genetic Vectors, pubmed-meshheading:12032152-Histone Acetyltransferases, pubmed-meshheading:12032152-Humans, pubmed-meshheading:12032152-Immunohistochemistry, pubmed-meshheading:12032152-In Situ Nick-End Labeling, pubmed-meshheading:12032152-L-Lactate Dehydrogenase, pubmed-meshheading:12032152-Protein Binding, pubmed-meshheading:12032152-Protein Structure, Tertiary, pubmed-meshheading:12032152-Rabbits, pubmed-meshheading:12032152-Spectrometry, Fluorescence, pubmed-meshheading:12032152-Time Factors, pubmed-meshheading:12032152-Transfection, pubmed-meshheading:12032152-Tumor Cells, Cultured
pubmed:year
2002
pubmed:articleTitle
The gamma secretase-generated carboxyl-terminal domain of the amyloid precursor protein induces apoptosis via Tip60 in H4 cells.
pubmed:affiliation
Alzheimer's Disease Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S.