Gene structure and organization of the human β‐secretase ( BACE ) promoter

Abstract

The first step in the generation of the amyloid-beta peptide (Abeta) deposited in the brains of patients with Alzheimer's disease (AD) is the processing of the larger Abeta precursor protein (APP) by an integral membrane aspartyl protease named the beta-site APP-cleaving enzyme (BACE). We present the genomic organization of the BACE gene. BACE mRNAs are synthesized as nine exons and eight introns from a 30.6 kb region of chromosome 11q23.2-11q23.3. Regulation of BACE may play an important role in regulating the levels of Abeta produced and is therefore likely to play an important role in AD. Herein, we report the cloning and detailed analysis of 3765 nucleotides of the promoter region of BACE and 364 nucleotides of the 5' untranslated region of the BACE mRNA (5' UTR). Characteristic "CAAT" and "TATA" boxes are absent within 1.5 kb of the transcription start site (TSS). The promoter region and 5' UTR contain multiple transcription factor binding sites, such as activator protein (AP)1, AP2, cAMP response element binding protein (CREB), estrogen responsive element (ERE), glucocorticoid responsive element (GRE), "GC" box, nuclear factor (NF)-kappaB, signal transducer and activator of transcription (STAT)1, stimulating protein (SP)1, metal-regulatory elements, and possible Zeste binding sites. Limited interspecies similarity was observed between the human sequence and corresponding genomic DNA from the rat and mouse sequences, but several transcription factor-binding sites are conserved. Thus, the BACE gene contains basal regulatory elements, inducible features and sites for regulated activity by various transcription factors. These results identify the important regions for functional analysis of the binding domains and neuron-specific expression (1). Such a study will allow us to further examine the possible role of changes in the promoter of BACE in AD pathogenesis.

IFN‐γ‐induced BACE1 expression is mediated by activation of JAK2 and ERK1/2 signaling pathways and direct binding of STAT1 to BACE1 promoter in astrocytes

“…Other studies regarding BACE1 gene promoter reported that a 4.1 kb region contained BACE1 promoter. A 2.4 kb fragment of the human BACE 5 0 -flanking region, which was similar to our uBACE-2K, was found to bind to Sp1 and AP2 transcription factors Sambamurti et al, 2004). However, those studies did not examine the mechanism underlying the activation of BACE1 promoter.…”

Alzheimer's Disease (AD)-Like Pathology in Aged Monkeys after Infantile Exposure to Environmental Metal Lead (Pb): Evidence for a Developmental Origin and Environmental Link for AD

“…This does not exclude SP1 from an active role in latent Pbinduced pathogenesis. Although the APP and BACE1 promoters from humans and primates contain sites for SP1 binding (Song and Lahiri, 1998;Sambamurti et al, 2004), the specific position of these sites differ with regard to their respective transcription start sites. For example, active SP1 sites in the APP gene appear in its 5Ј-untranslated region (UTR) (Villa et al, 2004), whereas the active SP1 site in the BACE1 promoter is ϳ1 kb upstream of the transcription start (Christensen et al, 2004).…”

Nonsteroidal anti-inflammatory drugs repress β-secretase gene promoter activity by the activation of PPARγ

“…The upstream sequences of the BACE1 gene promoter are highly conserved among rat, mouse, and human, indicating that this region contains regulatory elements that modulate BACE1 gene transcription (11)(12)(13). We identified a putative PPAR␥ consensus sequence in the region located between nucleotides Ϫ1356 and Ϫ1338.…”

“…The untranslated 5Ј-BACE1 transcript leader contains upstream ORFs that can reduce the translation of the main ORF (10). The BACE1 gene promoter region was recently cloned, and several putative transcription factor-binding sites were identified (11)(12)(13).…”