title: A proximal gene promoter region for the beta-amyloid precursor protein provides a link between development, apoptosis, and Alzheimer's disease.
abstract: Abnormalities in regulation of the beta-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.
authors.affiliation: Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA. dlahiri@iupui.edu
authors.forename: D K
authors.initials: DK
authors.lastname: Lahiri
authors.forename: C
authors.initials: C
authors.lastname: Ghosh
authors.forename: Y-W
authors.initials: YW
authors.lastname: Ge
mesh_terms: D016475:3T3 Cells; D000375:Aging / Q000235:genetics*; D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D016923:Cell Death; D045744:Cell Line, Tumor; D017930:Genes, Reporter; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D009447:Neuroblastoma; D009474:Neurons / Q000473:pathology; D016716:PC12 Cells; D011401:Promoter Regions, Genetic; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D014162:Transfection
chemical_list: D016564:Amyloid beta-Protein Precursor; D011994:Recombinant Proteins