Egr-1 upregulates the Alzheimer's disease presenilin-2 gene in neuronal cells

Renbaum, Paul; Beeri, Rachel; Gabai, E; Amiel, Merav; Gal, Moran; Ehrengruber, Markus U.; Levy-Lahad, Ephrat

doi:10.1016/s0378-1119(03)00766-2

Cited by 42 publications

(44 citation statements)

References 30 publications

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“…Consistent with our data, a previous study showed that Egr-1 does not bind to the murine PS2 promoter and does not regulate PS2 gene expression (48). However, another study reported that Egr-1 is a transcriptional activator of human PS2 genes in neural cells (49). It appears that the PS2 gene expression is regulated by different mechanisms in mice and humans.…”

Section: Discussionsupporting

confidence: 91%

Early Growth Response 1 (Egr-1) Is a Transcriptional Activator of β-Secretase 1 (BACE-1) in the Brain

Qin

Wang

Paudel

2016

Journal of Biological Chemistry

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Accumulation of amyloid-␤ peptide (A␤) in the brain is regarded as central to Alzheimer's disease (AD) pathogenesis. A␤ is generated by a sequential cleavage of amyloid precursor protein (APP) by ␤-secretase 1 (BACE-1) followed by ␥-secretase. BACE-1 cleavage of APP is the committed step in A␤ synthesis. Understanding the mechanism by which BACE-1 is activated leading to A␤ synthesis in the brain can provide better understanding of AD pathology and help to develop novel therapies. In this study, we found that the levels of A␤ and BACE-1 are significantly reduced in the brains of mice lacking transcription factor early growth response 1 (Egr-1) when compared with the WT. We demonstrate that in COS-7 cells, Egr-1 binds to the BACE-1 promoter and activates BACE-1 transcription. In rat hippocampal primary neurons, overexpression of Egr-1 induces BACE-1 expression, activates BACE-1, promotes amyloidogenic APP processing, and enhances A␤ synthesis. In mouse hippocampal primary neurons, knockdown of BACE-1 almost completely blocks Egr-1-induced amyloidogenic APP processing and A␤ synthesis. Our data indicate that Egr-1 promotes A␤ synthesis via transcriptional activation of BACE-1 and suggest that Egr-1 plays role in activation of BACE-1 and acceleration of A␤ synthesis in AD brain. Egr-1 is a potential therapeutic target for AD.Progressive accumulation of A␤ 2 in the brain is strongly implicated in the pathogenesis of Alzheimer's disease (AD). A␤ is derived from amyloid precursor protein (APP) (1). In the amyloidogenic pathway, APP is cleaved by ␤-secretase (BACE-1) to generate a 99-amino acid membrane-bound protein C99 and soluble APP␤. C99 is further cleaved by ␥-secretase to produce the A␤ peptide. APP is also cleaved by ␣-secretase within the A␤ domain generating an 83-kDa protein C83. Subsequent cleavage of C83 by ␥-secretase generates a nontoxic short peptide P3 containing the C-terminal region of A␤.BACE-1 cleavage of APP is the rate-limiting step in A␤ production. BACE-1 is regarded as the essential enzyme in the A␤ synthesis in the brain (1).A number of studies have shown that the level of BACE-1 protein is significantly up-regulated in AD brain (2-6). It has been suggested that the up-regulation of BACE-1 initiates and/or accelerates A␤ synthesis and promotes AD pathogenesis (1). Determining the mechanism by which BACE-1 is activated in AD brain can provide better understanding of AD pathology and help develop therapies against AD. However, what activates BACE-1 in AD brain is not known. Interestingly, in rat brain, BACE-1 level is elevated following experimental traumatic brain injury (7), transient cerebral ischemia (8), and following occlusion of the middle cerebral artery (9). Oxidative stress induces BACE-1 expression in mouse brains (10) and vascular smooth and HEK-293 cells (11,12). Thus, several cellular events triggered by vascular insults elevate BACE-1 levels in the brain. It has been suggested that the biochemical pathway that is activated by vascular injuries may be involved in up-regulating BAC...

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Section: Discussionsupporting

confidence: 91%

Early Growth Response 1 (Egr-1) Is a Transcriptional Activator of β-Secretase 1 (BACE-1) in the Brain

Qin

Wang

Paudel

2016

Journal of Biological Chemistry

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“…Among the four ␥-secretase components, however, only the promoter of PS and its transcriptional regulation have been studied so far (1,30,33,34,35). Pastorcic and Das (33) showed that Ets factors were involved in regulation of PS1 and that Ets factors were differentially utilized in human neuroblastoma SH-SY5Y and SK-N-SH cells.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional Regulation of PEN-2, a Key Component of the γ-Secretase Complex, by CREB

Wang

Zhang

Sun

et al. 2006

Molecular and Cellular Biology

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Gamma-secretase, which is responsible for the intramembranous cleavage of Alzheimer's ␤-amyloid precursor protein (APP), the signaling receptor Notch, and many other substrates, is a multiprotein complex consisting of at least four components: presenilin (PS), nicastrin, APH-1, and PEN-2. Despite the fact that PEN-2 is known to mediate endoproteolytic cleavage of full-length PS and APH-1 and nicastrin are required for maintaining the stability of the complex, the detailed physiological function of each component remain elusive. Unlike that of PS, the transcriptional regulation of PEN-2, APH-1, and nicastrin has not been investigated. Here, we characterized the upstream regions of the human PEN-2 gene and identified a 238-bp fragment located 353 bp upstream of the translational start codon as the key region necessary for the promoter activity. Further analysis revealed a CREB binding site located in the 238-bp region that is essential for the transcriptional activity of the PEN-2 promoter. Mutation of the CREB site abolished the transcriptional activity of the PEN-2 promoter. Electrophoretic mobility shift assays and chromatin immunoprecipitation analysis showed the binding of CREB to the PEN-2 promoter region both in vitro and in vivo. Activation of the CREB transcriptional factor by forskolin dramatically promoted the expression of PEN-2 mRNA and protein, whereas the other components of the ␥-secretase complex remained unaffected. Forskolin treatment slightly increases the secretion of soluble APP␣ and A␤ without affecting Notch cleavage. These results demonstrate that expression of PEN-2 is regulated by CREB and suggest that the specific control of PEN-2 expression may imply additional physiological functions uniquely assigned to PEN-2.

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“…Previous studies have demonstrated the regulation of PSEN1 promoter transcription by ETS proteins, particularly Elk-1 and ER81 (Pastorcic and Das, 2000;Pastorcic and Das, 2003), cAMP-response element-binding protein (CREB) (Mitsuda et al, 2001) or p53 (Pastorcic andDas, 2000;Roperch et al, 1998). The transcription of PSEN2 involves Sp1 and Egr-1 (Renbaum et al, 2003). Recently, APH1A and Pen2 promoter sequences have been described (Wang et al, 2006b).…”

Section: Journal Of Cell Sciencementioning

confidence: 99%

“…The human Pen2 promoter (hpPen-2) in frame with luciferase reporter gene has been previously described (Mitsuda et al, 1997;Renbaum et al, 2003;Wang et al, 2006a). Cells were grown in 12-well plates until they reach 60-70% confluency and were then cotransfected with 1 g Pen2-luciferase cDNA and 0.5 g of a -galactosidase transfection vector (to normalize transfection efficiency) with or without 1 g of either pcDNA3, AICD59, AICD50 or p53 cDNA by means of the Lipofectamine 2000 reagent (Invitrogen) or the Amaxa Transfection System (Amaxa Biosystems) according to the manufacturer's protocol.…”

Section: Promoter Activity Measurementsmentioning

confidence: 99%

p53-dependent control of transactivation of the Pen2 promoter by presenilins

Dunys

Sévalle

Giaime

et al. 2009

Journal of Cell Science

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ResultsPresenilins regulate the transactivation of the Pen2 promoter As was consistently reported in previous studies (Bergman et al., 2004; Crystal et al., 2004; Dunys et al., 2006), PEN-2 expressionThe senile plaques found in the brains of patients with Alzheimer's disease are mainly due to the accumulation of amyloid -peptides (A) that are liberated by -secretase, a high molecular weight complex including presenilins, PEN-2, APH-1 and nicastrin. The depletion of each of these proteins disrupts the complex assembly into a functional protease. Here, we describe another level of regulation of this multimeric protease. The depletion of both presenilins drastically reduces Pen2 mRNA levels and its promoter transactivation. Furthermore, overexpression of presenilin-1 lowers Pen2 promoter transactivation, a phenotype abolished by a double mutation known to prevent presenilin-dependent -secretase activity. PEN-2 expression is decreased by depletion of -amyloid precursor protein (APP) and increased by the APP intracellular domain (AICD). We show that AICD and APP complement for Pen2 mRNA levels in APP/APLP1-2 knockout fibroblasts. Interestingly, overexpression of presenilin-2 greatly increasesPen2 promoter transactivation. The opposite effect triggered by both presenilins was reminiscent of our previous study, which showed that these two proteins elicit antagonistic effects on p53. Therefore, we examined the contribution of p53 on Pen2 transcription. Pen2 promoter transactivation, and Pen2 mRNA and protein levels were drastically reduced in p53 -/-fibroblasts. Furthermore, PEN-2 expression could be rescued by p53 complementation in p53-and APP-deficient cells. Interestingly, PEN-2 expression was also reduced in p53-deficient mouse brain. Overall, our study describes a p53-dependent regulation of PEN-2 expression by other members of the -secretase complex, namely presenilins. is drastically reduced by the depletion of both PS1 and PS2 in fibroblasts (Fig. 1A). We examined whether part of this phenotype could be accounted for by reduced Pen2 gene transcription. Indeed, we established that presenilin-depleted fibroblasts displayed a significant reduction of Pen2 promoter transactivation (Fig. 1B) and mRNA levels (Fig. 1C), indicating that reduced transcription of the Pen2 promoter could also potentially contribute to the lowered levels of PEN-2 in these cells. Interestingly, PEN-2 protein levels in presenilin -/-fibroblasts could be enhanced by complementation with both PS1 and PS2 (Fig. 1D).We examined whether PS1 and PS2 similarly influenced Pen2 promoter transactivation. Interestingly, PS1 and PS2 elicited opposing effects. Thus, as was previously described (Alves da Costa et al., 2002;Alves da Costa et al., 2006; Kang et al., 2005), PS1 overexpression reduced PS2 expression ( Fig. 2A), which was accompanied by a reduction of Pen2 promoter transactivation (Fig. 2B). Conversely, PS2 overexpression reduced PS1 levels ( Fig. 2A) and drastically enhanced Pen2 promoter transactivation (Fig. 2B). Conversely, PS2 d...

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Egr-1 upregulates the Alzheimer's disease presenilin-2 gene in neuronal cells

Cited by 42 publications

References 30 publications

Early Growth Response 1 (Egr-1) Is a Transcriptional Activator of β-Secretase 1 (BACE-1) in the Brain

Early Growth Response 1 (Egr-1) Is a Transcriptional Activator of β-Secretase 1 (BACE-1) in the Brain

Transcriptional Regulation of PEN-2, a Key Component of the γ-Secretase Complex, by CREB

p53-dependent control of transactivation of the Pen2 promoter by presenilins

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