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Regulation of human BACE1 gene expression by NF-kappa B signaling Chen, Chia-Hsiung Alan
Abstract
Nuclear Factor-Kappa B (NF-κB) signaling plays an important role in gene regulation and is implicated in cell apoptosis, inflammation and oxidative stress. Binding of Inhibitor of Kappa B (IκB) to NF-κB dimers, mostly RelA (p65)/p50, causes the dimers to be sequestered in cytoplasm and remain inactive. When NF-κB-activating stimuli activate the Inhibitor of Kappa B Kinase (IKK) complex, IKK phosphorylates IκB , and NF-κB is released and translocates to the nucleus, where it interacts with NF-κB binding elements in the promoter of NF-κB target genes to modulate gene expression. One of the hallmark neuropathological features of Alzheimer's disease (AD) is the senile plaques formed by the deposition of amyloid-β peptide (Aβ) in the brain. Aβgeneration is achieved by sequential proteolytic cleavage of β-amyloid precursor protein (APP) by β-site APP cleaving enzyme (BACE1) and y-secretase. Regulation of BACE1 activity is efficient to modify Aβ production and BACE1 inhibition has become a potential target in AD treatment. BACE1 is reported to be tightly regulated at both the transcriptional and translational level. Several putative NF-κB binding elements in the human BACE1 promoter region have been identified, but the precise role of NF-κB in BACE1 gene expression remains to be defined. To investigate whether NF-KB modulates BACE1 gene expression, we first identified functional NF-κB binding elements in the BACE1 promoter region. Co-expression of NF-κB p65 and BACE1 reporter plasmid in HEK293 cells resulted in increased BACE1 promoter activity and dual-luciferase reporter assays and RT-PCR analysis revealed that N F-κB p65 regulates BACE1 gene at the transcriptional level. Neurons are speculated to be the major source of AP generation, contributing to the elevated Ap burden in AD pathogenesis, and NF- KB p65 was also demonstrated to elevate BACE1 promoter activity in neuronal-like cells. In addition, NF-κB p65 overexpression leads to elevation of C99 protein levels and increased production of Aβ40. Therefore, our results show that by modulating NF-κB signalling, BACE1 gene transcription is regulated and amyloidogenic APP processing is altered
Item Metadata
Title |
Regulation of human BACE1 gene expression by NF-kappa B signaling
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Creator | |
Publisher |
University of British Columbia
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Date Issued |
2007
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Description |
Nuclear Factor-Kappa B (NF-κB) signaling plays an important role in gene regulation
and is implicated in cell apoptosis, inflammation and oxidative stress. Binding of Inhibitor of
Kappa B (IκB) to NF-κB dimers, mostly RelA (p65)/p50, causes the dimers to be sequestered
in cytoplasm and remain inactive. When NF-κB-activating stimuli activate the Inhibitor of
Kappa B Kinase (IKK) complex, IKK phosphorylates IκB , and NF-κB is released and
translocates to the nucleus, where it interacts with NF-κB binding elements in the promoter of
NF-κB target genes to modulate gene expression.
One of the hallmark neuropathological features of Alzheimer's disease (AD) is the
senile plaques formed by the deposition of amyloid-β peptide (Aβ) in the brain. Aβgeneration
is achieved by sequential proteolytic cleavage of β-amyloid precursor protein (APP) by β-site
APP cleaving enzyme (BACE1) and y-secretase. Regulation of BACE1 activity is efficient to
modify Aβ production and BACE1 inhibition has become a potential target in AD treatment.
BACE1 is reported to be tightly regulated at both the transcriptional and translational level.
Several putative NF-κB binding elements in the human BACE1 promoter region have been
identified, but the precise role of NF-κB in BACE1 gene expression remains to be defined.
To investigate whether NF-KB modulates BACE1 gene expression, we first identified
functional NF-κB binding elements in the BACE1 promoter region. Co-expression of NF-κB
p65 and BACE1 reporter plasmid in HEK293 cells resulted in increased BACE1 promoter
activity and dual-luciferase reporter assays and RT-PCR analysis revealed that N F-κB p65
regulates BACE1 gene at the transcriptional level. Neurons are speculated to be the major
source of AP generation, contributing to the elevated Ap burden in AD pathogenesis, and NF- KB p65 was also demonstrated to elevate BACE1 promoter activity in neuronal-like cells. In
addition, NF-κB p65 overexpression leads to elevation of C99 protein levels and increased
production of Aβ40. Therefore, our results show that by modulating NF-κB signalling, BACE1
gene transcription is regulated and amyloidogenic APP processing is altered
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Genre | |
Type | |
Language |
eng
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Date Available |
2011-03-04
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Provider |
Vancouver : University of British Columbia Library
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Rights |
For non-commercial purposes only, such as research, private study and education. Additional conditions apply, see Terms of Use https://open.library.ubc.ca/terms_of_use.
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DOI |
10.14288/1.0100990
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URI | |
Degree | |
Program | |
Affiliation | |
Degree Grantor |
University of British Columbia
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Campus | |
Scholarly Level |
Graduate
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Aggregated Source Repository |
DSpace
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Rights
For non-commercial purposes only, such as research, private study and education. Additional conditions apply, see Terms of Use https://open.library.ubc.ca/terms_of_use.