Christensen Michelle A, Zhou Weihui, Qing Hong, Lehman Anna, Philipsen Sjaak, Song Weihong
Department of Psychiatry, Brain Research Center, The University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
Mol Cell Biol. 2004 Jan;24(2):865-74. doi: 10.1128/MCB.24.2.865-874.2004.
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.
β淀粉样前体蛋白（APP）在β位点的蛋白水解加工对于生成Aβ至关重要。BACE1是参与切割APP的主要β分泌酶，已被鉴定为一种1型膜相关天冬氨酸蛋白酶。我们克隆了人BACE1基因上游的一个2.1 kb片段，并确定了启动子活性所需的关键区域。BACE1基因表达受一个无TATA框的启动子控制。-619至+46 bp的区域是控制BACE1基因转录的最小启动子。在BACE1基因的5'侧翼区域发现了几个推定的顺式作用元件，如GC框、HSF-1、PU框、AP1、AP2和淋巴因子反应元件。转录激活和凝胶迁移分析表明，BACE1启动子含有一个功能性的Sp1反应元件，转录因子Sp1的过表达增强了BACE基因表达和APP加工以生成Aβ。此外，Sp1基因敲除降低了BACE1表达。这些结果表明，BACE1基因表达在转录水平受到严格调控，转录因子Sp1在阿尔茨海默病中对BACE1加工APP生成Aβ的调控中起重要作用。
