Transcriptional regulation of BACE1, the β-amyloid precursor protein β-secretase, by Sp1
Transcriptional regulation of BACE1, the β-amyloid precursor protein β-secretase, by Sp1
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DOI：
10.1128/mcb.24.2.865-874.2004
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发表时间：
2004-01-01
影响因子：
5.3
通讯作者：
Song, WH
中科院分区：
文献类型：
--
作者：
Christensen, MA;Zhou, WH;Song, WH
β-淀粉样前体蛋白 (APP) 在 β 位点的蛋白水解加工对于生成 Abeta 至关重要。 BACE1 是参与裂解 APP 的主要 β 分泌酶，已被鉴定为 I 型膜相关天冬氨酰蛋白酶。我们克隆了人类 BACE1 基因上游的 2.1 kb 片段，并鉴定了启动子活性所需的关键区域。 BACE1 基因表达由无 TATA 的启动子控制。 bp -619 至 +46 区域是控制 BACE1 基因转录的最小启动子。在 BACE1 基因的 5' 侧翼区域中发现了几种推定的顺式作用元件，例如 GC 盒、HSF-1、PU 盒、AP1、AP2 和淋巴因子反应元件。转录激活和凝胶位移测定表明，BACE1 启动子含有功能性 Sp1 反应元件，转录因子 Sp1 的过度表达会增强 BACE 基因表达和 APP 加工，从而产生 AD。此外，Sp1 敲除降低了 BACE1 表达。这些结果表明，BACE1 基因表达在转录水平上受到严格调控，并且转录因子 Sp1 在调节 BACE1 处理阿尔茨海默病中 APP 生成 AD 方面发挥着重要作用。
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 I 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 AD. 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 AD in Alzheimer's disease.