Functional domains of the BACE1 and BACE2 promoters and mechanisms of transcriptional suppression of the BACE2 promoter in normal neuronal cells

Debomoy Lahiri, Bryan Maloney, Yuan Wen Ge

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

The β-amyloid (Aβ) protein present in the neuritic plaques of Alzheimer's disease is cleaved from Aβ precursor protein (APP) by β- and γ-secretases. Following identification of β-APP cleaving enzyme (BACE1) as the β-secretase, a homologous β-secretase 2 (BACE2) was described. Our goal is to characterize the regulatory region of the BACE genes. We compare functional domains within the BACE1 and BACE2 regulatory regions. Both BACE genes lack canonical TATAand CAAT boxes, but they contain distinguishing transcription start sites and transcription factor-binding sites. The BACE1 sequence contains more repetitive elements than does BACE2 (no elements). Regulatory domains do not overlap strongly between the two promoter regions. The BACE1upstream sequence contains both negative and positive domains, separated from the transcription seat by a long neutral domain. The corresponding BACE2sequence consists of a weakly positive domain directly upstream of a strongly positive domain, near a functionally active domain. DNA-protein interaction was corroborated by functional data. In primary rat cortical cultures, BACE1-driven reporter protein's expression was twice that of BACE2- driven reporter. The BACE2 gene promoter relatively reduced function in neuronal cells compared with BACE1. The BACE1 gene might operate through a single transcriptional control site. BACE2 operates through dual transcriptional control sites. Two (or more) regulatory pathways might control transcription in BACE2. Thus, BACE2 is partially suppressed in normal neuronal cells and likely to be a highly regulated gene expressed in a particularly tissue-specific fashion.

Original languageEnglish
Pages (from-to)65-80
Number of pages16
JournalJournal of Molecular Neuroscience
Volume29
Issue number1
DOIs
StatePublished - May 2006

Fingerprint

Genes
Amyloid Precursor Protein Secretases
Protein Precursors
Nucleic Acid Regulatory Sequences
Transcription
Serum Amyloid A Protein
Transcription Initiation Site
Amyloid Plaques
Seats
Genetic Promoter Regions
Rats
Alzheimer Disease
Proteins
Transcription Factors
Binding Sites
Tissue
DNA
Enzymes

Keywords

  • Aging
  • Amyloid
  • Dementia
  • Neurons
  • Promoter
  • Secretase
  • Transcription factors

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry
  • Genetics

Cite this

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abstract = "The β-amyloid (Aβ) protein present in the neuritic plaques of Alzheimer's disease is cleaved from Aβ precursor protein (APP) by β- and γ-secretases. Following identification of β-APP cleaving enzyme (BACE1) as the β-secretase, a homologous β-secretase 2 (BACE2) was described. Our goal is to characterize the regulatory region of the BACE genes. We compare functional domains within the BACE1 and BACE2 regulatory regions. Both BACE genes lack canonical TATAand CAAT boxes, but they contain distinguishing transcription start sites and transcription factor-binding sites. The BACE1 sequence contains more repetitive elements than does BACE2 (no elements). Regulatory domains do not overlap strongly between the two promoter regions. The BACE1upstream sequence contains both negative and positive domains, separated from the transcription seat by a long neutral domain. The corresponding BACE2sequence consists of a weakly positive domain directly upstream of a strongly positive domain, near a functionally active domain. DNA-protein interaction was corroborated by functional data. In primary rat cortical cultures, BACE1-driven reporter protein's expression was twice that of BACE2- driven reporter. The BACE2 gene promoter relatively reduced function in neuronal cells compared with BACE1. The BACE1 gene might operate through a single transcriptional control site. BACE2 operates through dual transcriptional control sites. Two (or more) regulatory pathways might control transcription in BACE2. Thus, BACE2 is partially suppressed in normal neuronal cells and likely to be a highly regulated gene expressed in a particularly tissue-specific fashion.",
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AU - Maloney, Bryan

AU - Ge, Yuan Wen

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N2 - The β-amyloid (Aβ) protein present in the neuritic plaques of Alzheimer's disease is cleaved from Aβ precursor protein (APP) by β- and γ-secretases. Following identification of β-APP cleaving enzyme (BACE1) as the β-secretase, a homologous β-secretase 2 (BACE2) was described. Our goal is to characterize the regulatory region of the BACE genes. We compare functional domains within the BACE1 and BACE2 regulatory regions. Both BACE genes lack canonical TATAand CAAT boxes, but they contain distinguishing transcription start sites and transcription factor-binding sites. The BACE1 sequence contains more repetitive elements than does BACE2 (no elements). Regulatory domains do not overlap strongly between the two promoter regions. The BACE1upstream sequence contains both negative and positive domains, separated from the transcription seat by a long neutral domain. The corresponding BACE2sequence consists of a weakly positive domain directly upstream of a strongly positive domain, near a functionally active domain. DNA-protein interaction was corroborated by functional data. In primary rat cortical cultures, BACE1-driven reporter protein's expression was twice that of BACE2- driven reporter. The BACE2 gene promoter relatively reduced function in neuronal cells compared with BACE1. The BACE1 gene might operate through a single transcriptional control site. BACE2 operates through dual transcriptional control sites. Two (or more) regulatory pathways might control transcription in BACE2. Thus, BACE2 is partially suppressed in normal neuronal cells and likely to be a highly regulated gene expressed in a particularly tissue-specific fashion.

AB - The β-amyloid (Aβ) protein present in the neuritic plaques of Alzheimer's disease is cleaved from Aβ precursor protein (APP) by β- and γ-secretases. Following identification of β-APP cleaving enzyme (BACE1) as the β-secretase, a homologous β-secretase 2 (BACE2) was described. Our goal is to characterize the regulatory region of the BACE genes. We compare functional domains within the BACE1 and BACE2 regulatory regions. Both BACE genes lack canonical TATAand CAAT boxes, but they contain distinguishing transcription start sites and transcription factor-binding sites. The BACE1 sequence contains more repetitive elements than does BACE2 (no elements). Regulatory domains do not overlap strongly between the two promoter regions. The BACE1upstream sequence contains both negative and positive domains, separated from the transcription seat by a long neutral domain. The corresponding BACE2sequence consists of a weakly positive domain directly upstream of a strongly positive domain, near a functionally active domain. DNA-protein interaction was corroborated by functional data. In primary rat cortical cultures, BACE1-driven reporter protein's expression was twice that of BACE2- driven reporter. The BACE2 gene promoter relatively reduced function in neuronal cells compared with BACE1. The BACE1 gene might operate through a single transcriptional control site. BACE2 operates through dual transcriptional control sites. Two (or more) regulatory pathways might control transcription in BACE2. Thus, BACE2 is partially suppressed in normal neuronal cells and likely to be a highly regulated gene expressed in a particularly tissue-specific fashion.

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