Regulation of promoter activity of the APP gene by cytokines and growth factors: implications in Alzheimer's disease.
One of the major pathological hallmarks of Alzheimer's disease (AD) is the presence of brain depositions of senile plaques that are primarily composed of potentially toxic amyloid beta-peptide (Abeta), which is generated from a family of Abeta-containing precursor proteins (APP; 695-770 amino acids). The role of inflammatory cytokines and growth factors has been implicated in the pathogenesis of AD. Our goal is to study the effects of these factors on the regulation of APP gene expression. Here we compared APP promoter activity in the presence of different growth factors and cytokines such as brain-derived neurotrophic factor (BDNF), interleukin (IL-1), nerve growth factor (NGF), neurotrofin-3 (NT-3), transforming growth factor (TGF-beta1), and tumor necrosis factor (TNF-alpha1). PC12 neuronal cells, which were treated separately with these agents, were transfected with the construct containing either 190 bp APP proximal promoter region (-46 to 144 bp with respect to the transcription start site [+1]), 94 bp APP 5'-untranslated region (UTR, +50 to 144) or other 5'-UTR-deleted regions. Each construct was cloned upstream of a reporter chloramphenicol acetyl transferase gene (CAT). The treatment of PC12 cells with NGF stimulated reporter activity in all constructs tested. The treatment of cells with BDNF, NT3, TGF-beta1, or TNF-alpha stimulated reporter activity in a promoter/UTR-specific manner. Transfection with the complete -46 to 144 region retained the maximum stimulatory activity for any treatment tested in PC12 cells. These results suggest that the regulatory elements of the APP gene respond to the stimulation of different growth factors, cytokines, and interleukins. This is consistent with the effects of the different growth factors, cytokines, and interleukins on APP message and protein levels.
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Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
Lahiri
D K
DK
D020121:5' Untranslated Regions / Q000235:genetics; D000544:Alzheimer Disease / Q000235:genetics*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000818:Animals; D002467:Cell Nucleus / Q000502:physiology; D016207:Cytokines / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D017930:Genes, Reporter; D051100:Glial Cell Line-Derived Neurotrophic Factor; D006133:Growth Substances / Q000494:pharmacology*; D006801:Humans; D020932:Nerve Growth Factor / Q000494:pharmacology; D009414:Nerve Growth Factors / Q000494:pharmacology; D016716:PC12 Cells; D010673:Pheochromocytoma; D011401:Promoter Regions, Genetic / Q000187:drug effects; D051381:Rats; D014162:Transfection
D020121:5' Untranslated Regions; D016564:Amyloid beta-Protein Precursor; D016207:Cytokines; C495039:GDNF protein, human; C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D006133:Growth Substances; D009414:Nerve Growth Factors; D020932:Nerve Growth Factor