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PMID: 14701757 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Transcriptional regulation of BACE1, the beta-amyloid precursor protein beta-secretase, by Sp1.

Molecular and cellular biology ·Vol. 24 ·No. 2 ·2004-01-00 ·Pages 865-74

Christensen MA, Zhou W, Qing H, Lehman A, Philipsen S, Song W

Abstract

Proteolytic processing of the beta-amyloid precursor protein (APP) at the beta site is essential to generate Abeta. BACE1, the major beta-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 Abeta. 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 Abeta in Alzheimer's disease.

MeSH Terms
Alzheimer Disease/genetics,metabolism Amyloid Precursor Protein Secretases Amyloid beta-Protein Precursor/metabolism Animals Aspartic Acid Endopeptidases/genetics Base Sequence Cell Line Chromosome Mapping Cloning, Molecular DNA/genetics Endopeptidases Humans Mice Mice, Knockout Molecular Sequence Data Plicamycin/analogs & derivatives,pharmacology Promoter Regions, Genetic/drug effects Protein Processing, Post-Translational Rats Sequence Deletion Sp1 Transcription Factor/deficiency,genetics,metabolism Transcription, Genetic Up-Regulation
Chemicals
Amyloid beta-Protein Precursor Sp1 Transcription Factor DNA mithramycin A Amyloid Precursor Protein Secretases Endopeptidases Aspartic Acid Endopeptidases BACE1 protein, human Bace1 protein, mouse Bace1 protein, rat Plicamycin
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Christensen Michelle A
Department of Psychiatry, Brain Research Center, The University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
Zhou Weihui
Qing Hong
Lehman Anna
Philipsen Sjaak
Song Weihong
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.24.2.865-874.2004
Published
2004-01-00
Pages
865-74
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC343820
Subset
IM
Databases
GENBANK
AY162468
External Links
PubMed source DOI: 10.1128/MCB.24.2.865-874.2004 PMC Full Text View journal details
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