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Genomic organization and promoter cloning of the human X11α gene APBA1.
- Source :
-
DNA and cell biology [DNA Cell Biol] 2012 May; Vol. 31 (5), pp. 651-9. Date of Electronic Publication: 2011 Dec 02. - Publication Year :
- 2012
-
Abstract
- X11α is a brain specific multi-modular protein that interacts with the Alzheimer's disease amyloid precursor protein (APP). Aggregation of amyloid-β peptide (Aβ), an APP cleavage product, is believed to be central to the pathogenesis of Alzheimer's disease. Recently, overexpression of X11α has been shown to reduce Aβ generation and to ameliorate memory deficit in a transgenic mouse model of Alzheimer's disease. Therefore, manipulating the expression level of X11α may provide a novel route for the treatment of Alzheimer's disease. Human X11α is encoded by the gene APBA1. As evidence suggests that X11α expression can be regulated at transcription level, we have determined the gene structure and cloned the promoter of APBA1. APBA1 spans over 244 kb on chromosome 9 and is composed of 13 exons and has multiple transcription start sites. A putative APBA1 promoter has been identified upstream of exon 1 and functional analysis revealed that this is highly active in neurons. By deletion analysis, the minimal promoter was found to be located between -224 and +14, a GC-rich region that contains a functional Sp3 binding site. In neurons, overexpression of Sp3 stimulates the APBA1 promoter while an Sp3 inhibitor suppresses the promoter activity. Moreover, inhibition of Sp3 reduces endogenous X11α expression and promotes the generation of Aβ. Our findings reveal that Sp3 play an essential role in APBA1 transcription.
- Subjects :
- Animals
Base Sequence
Blotting, Western
Cells, Cultured
Cerebral Cortex cytology
Cloning, Molecular
Electrophoretic Mobility Shift Assay
Enzyme-Linked Immunosorbent Assay
Humans
Luciferases metabolism
Molecular Sequence Data
Neurons cytology
RNA, Messenger genetics
Rats
Rats, Sprague-Dawley
Real-Time Polymerase Chain Reaction
Reverse Transcriptase Polymerase Chain Reaction
Transcription Initiation Site
Adaptor Proteins, Signal Transducing genetics
Cerebral Cortex metabolism
Exons genetics
Genomics
Nerve Tissue Proteins genetics
Neurons metabolism
Promoter Regions, Genetic genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1557-7430
- Volume :
- 31
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- DNA and cell biology
- Publication Type :
- Academic Journal
- Accession number :
- 22136355
- Full Text :
- https://doi.org/10.1089/dna.2011.1447