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Transcriptional Regulation of BACE1, the ß-Amyloid Precursor Protein ß-Secretase, by Sp1

Michelle A. Christensen,^1, Weihui Zhou,^1, Hong Qing,^1, Anna Lehman,¹ Sjaak Philipsen,² and Weihong Song^1*

Department of Psychiatry, Brain Research Center, The University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada,¹ Department of Cell Biology, Erasmus University Rotterdam, 3000 DR Rotterdam, The Netherlands²

Received 13 December 2002/ Returned for modification 28 May 2003/ Accepted 22 October 2003

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

M.A.C., W.Z., and H.Q. contributed equally to this work.

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