Document Detail

TGF-beta(1), regulation of alzheimer amyloid precursor protein mRNA expression in a normal human astrocyte cell line: mRNA stabilization.
MedLine Citation:
PMID:  10407185     Owner:  NLM     Status:  MEDLINE    
The transforming growth factor, TGF-beta(1), has been found to be increased in the central nervous system of Alzheimer's disease (AD) patients, elevates amyloid precursor protein (APP) mRNA levels in rat primary astrocytes, and may initiate or promote the deposition of amyloid-beta (Abeta) peptide in AD. Excess APP production in AD, which potentially leads to amyloidogenesis, is in part due to over expression of APP mRNA. The production of APP in a normal human cell line in contrast to transformed or animal cells provides a meaningful model to study the regulation of APP gene expression by cytokines that promotes amyloidogenesis. Here, we report that TGF-beta(1) treatment of human astrocytes markedly elevated APP mRNA levels, and also increased the half-life of APP message by at least five-fold. Under this condition, as detected by mobility shift and UV cross-linking analysis, a novel 68 kDa RNA-protein complex was formed, involving an 81 nucleotide (nt) fragment within the 3'-untranslated region (UTR), but not the 5'-UTR and coding region of APP mRNA. Insertion of the 3'-UTR onto the chloramphenicol acetyl transferase (CAT) mRNA conferred TGF-beta(1) mediated mRNA stability in transfected human astrocytes. On the other hand, the same insert carrying a deletion of the APP mRNA cis-element fragment had no effect on CAT mRNA stability. A model of APP mRNA regulation is presented in which TGF-beta(1) induced stabilization of APP message involves the binding activity of a 68 kDa RNA-protein complex within the 3'-UTR, which is likely linked to a reduction in the rate of APP mRNA decay.
F M Amara; A Junaid; R R Clough; B Liang
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Brain research. Molecular brain research     Volume:  71     ISSN:  0169-328X     ISO Abbreviation:  Brain Res. Mol. Brain Res.     Publication Date:  1999 Jul 
Date Detail:
Created Date:  1999-12-22     Completed Date:  1999-12-22     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  8908640     Medline TA:  Brain Res Mol Brain Res     Country:  NETHERLANDS    
Other Details:
Languages:  eng     Pagination:  42-9     Citation Subset:  IM    
Copyright Information:
Copyright 1999 Elsevier Science B.V.
Center for Health Research on Aging, Division of Alzheimer's Disease, St. Boniface General Hospital Research Center, 351 Taché Avenue, Winnipeg, MB, Canada.
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MeSH Terms
3' Untranslated Regions / genetics
Amyloid beta-Protein Precursor / genetics*
Astrocytes / drug effects,  metabolism*
Brain / metabolism*
Cell Line
Chloramphenicol O-Acetyltransferase / genetics
Gene Expression Regulation / drug effects*
RNA, Messenger / genetics,  metabolism*
Recombinant Fusion Proteins / biosynthesis
Templates, Genetic
Transcription, Genetic / drug effects*
Transforming Growth Factor beta / pharmacology*
Reg. No./Substance:
0/3' Untranslated Regions; 0/Amyloid beta-Protein Precursor; 0/RNA, Messenger; 0/Recombinant Fusion Proteins; 0/Transforming Growth Factor beta; EC O-Acetyltransferase

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