Bace1 promoter sequences

C - Chemistry – Metallurgy – 12 – N

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C12N 15/85 (2006.01) A61P 25/28 (2006.01) C12Q 1/02 (2006.01) C12Q 1/68 (2006.01)

Patent

CA 2426781

Proteolytic processing of the .beta.-amyloid precursor protein (APP) at the .beta. site is essential to generate .alpha..beta. BACE (or 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 BACE gene and identified key regions necessary for promoter activity. BACE gene expression is controlled by a TATA-less promoter. The region of -619 bp to +46 bp is the minimal promoter to control the transcription of the BACE gene. Several putative cis-acting elements such as a GC box, HSF-1, PU-box, AP1, AP2, and lymphokine response element are found in the 5' flanking region of the BACE gene. Transcriptional activation and Gel Shift assays demonstrated that the BACE promoter contains a functional Sp1 response element and overexpression of the transcription factor Sp1 potentiates the BACE gene expression and APP processing to generate A.beta.. These results suggest that the BALE gene expression is tightly regulated at the transcriptional level and the transcription factor Sp1 plays a central role in regulation of BACE to process APP generating .ALPHA..beta. in Alzheimer's Disease (AD).

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