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dc.contributor.authorChai, Ka-Ho
dc.contributor.authorMcLoughlin, Declan M
dc.contributor.authorChan, Ting Fung
dc.contributor.authorChan, Ho Yin Edwin
dc.contributor.authorLau, Kwok-Fai
dc.date.accessioned2012-09-17T09:00:56Z
dc.date.available2012-09-17T09:00:56Z
dc.date.issued2012-05
dc.identifier.citationGenomic organization and promoter cloning of the human X11α gene APBA1. 2012, 31 (5):651-9 DNA Cell Biol.en_GB
dc.identifier.issn1557-7430
dc.identifier.pmid22136355
dc.identifier.doi10.1089/dna.2011.1447
dc.identifier.urihttp://hdl.handle.net/10147/244221
dc.description.abstractX11α 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.
dc.language.isoenen
dc.rightsArchived with thanks to DNA and cell biologyen_GB
dc.subject.meshAdaptor Proteins, Signal Transducing
dc.subject.meshAnimals
dc.subject.meshBase Sequence
dc.subject.meshBlotting, Western
dc.subject.meshCells, Cultured
dc.subject.meshCerebral Cortex
dc.subject.meshCloning, Molecular
dc.subject.meshElectrophoretic Mobility Shift Assay
dc.subject.meshEnzyme-Linked Immunosorbent Assay
dc.subject.meshExons
dc.subject.meshGenomics
dc.subject.meshHumans
dc.subject.meshLuciferases
dc.subject.meshMolecular Sequence Data
dc.subject.meshNerve Tissue Proteins
dc.subject.meshNeurons
dc.subject.meshPromoter Regions, Genetic
dc.subject.meshRNA, Messenger
dc.subject.meshRats
dc.subject.meshRats, Sprague-Dawley
dc.subject.meshReal-Time Polymerase Chain Reaction
dc.subject.meshReverse Transcriptase Polymerase Chain Reaction
dc.subject.meshTranscription Initiation Site
dc.titleGenomic organization and promoter cloning of the human X11α gene APBA1.en_GB
dc.typeArticleen
dc.contributor.departmentBiochemistry Program, School Life Sciences, The Chinese University of Hong Kong , Shatin, New Territories, Hong Kong SAR.en_GB
dc.identifier.journalDNA and cell biologyen_GB
dc.description.provinceLeinsteren
html.description.abstractX11α 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.


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