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A Proximal Gene Promoter Region for the β‐Amyloid Precursor Protein Provides a Link between Development, Apoptosis, and Alzheimer's Disease
Author(s) -
LAHIRI D K.,
GHOSH C,
GE YW
Publication year - 2003
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1196/annals.1299.118
Subject(s) - electrophoretic mobility shift assay , microbiology and biotechnology , apoptosis , transfection , negative regulatory element , biology , promoter , amyloid precursor protein , gene , chemistry , transcription factor , gene expression , alzheimer's disease , medicine , biochemistry , disease
A bstract : Abnormalities in regulation of the β‐amyloid precursor protein (APP) gene might be a crucial factor in Alzheimer's disease (AD). Our aim is to study the role of a specific proximal APP promoter element under the apoptotic condition. Our transfection studies with APP promoter deletion constructs indicate that each cell type differently regulates promoter activity. The minimum region that was sufficient to drive basal promoter activity in neuronal PC12 and neuroblastoma SK‐N‐SH cells was −75/+104 and −47/+104 bp, respectively. In SK‐N‐SH cells, the −47/+104 construct displayed the highest promoter activity, and the −75/−46 region acted as a negative regulatory element. Results from the gel electrophoretic mobility shift assay (EMSA) indicate that the −75/−46 region binds to a distinct DNA‐protein complex with nuclear protein(s) from HeLa, PC12, NIH‐3T3, and neuroblastoma cells. EMSA results from HeLa cells, which were stimulated by serum starvation (SR), indicate a significant induction in the signal of the DNA‐protein complex from controls. EMSA results from PC12 cells, which were subjected to hypoxia, indicate a significant reduction in the signal. Our results suggest that the −75/−46 region binds to a protein that is upregulated in serum starvation, and downregulated in hypoxia. Because serum starvation contributes to the induction of apoptosis, these results suggest a role of the 30‐bp proximal APP promoter element in enhanced apoptotic neuronal cell death.