Transcriptional Regulation of BACE1, the β-Amyloid Precursor Protein β-Secretase, by Sp1
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Published:2004-01-15
Issue:2
Volume:24
Page:865-874
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ISSN:0270-7306
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Container-title:Molecular and Cellular Biology
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language:en
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Short-container-title:Mol Cell Biol
Author:
Christensen Michelle A.1, Zhou Weihui1, Qing Hong1, Lehman Anna1, Philipsen Sjaak2, Song Weihong1
Affiliation:
1. Department of Psychiatry, Brain Research Center, The University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada 2. Department of Cell Biology, Erasmus University Rotterdam, 3000 DR Rotterdam, The Netherlands
Abstract
ABSTRACT
Proteolytic processing of the β-amyloid precursor protein (APP) at the β site is essential to generate Aβ. BACE1, the major β-secretase involved in cleaving APP, has been identified as a type 1 membrane-associated aspartyl protease. We have cloned a 2.1-kb fragment upstream of the human
BACE1
gene and identified key regions necessary for promoter activity.
BACE1
gene expression is controlled by a TATA-less promoter. The region of bp −619 to +46 is the minimal promoter to control the transcription of the
BACE1
gene. Several putative
cis
-acting elements, such as a GC box, HSF-1, a PU box, AP1, AP2, and lymphokine response element, are found in the 5′ flanking region of the
BACE1
gene. Transcriptional activation and gel shift assays demonstrated that the BACE1 promoter contains a functional Sp1 response element, and overexpression of the transcription factor Sp1 potentiates BACE gene expression and APP processing to generate Aβ. Furthermore, Sp1 knockout reduced BACE1 expression. These results suggest that
BACE1
gene expression is tightly regulated at the transcriptional level and that the transcription factor Sp1 plays an important role in regulation of BACE1 to process APP generating Aβ in Alzheimer's disease.
Publisher
American Society for Microbiology
Subject
Cell Biology,Molecular Biology
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