The <scp>GATA</scp> transcription factor/<scp>MTA</scp>‐1 homolog <i>egr‐1</i> promotes longevity and stress resistance in <i><scp>C</scp>aenorhabditis elegans</i>

Zimmerman, Stephanie M.; Kim, Stuart K.

doi:10.1111/acel.12179

Cited by 11 publications

(11 citation statements)

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“…Previous studies have shown that the Egr-1 level is up-regulated in AD brains (18 -21, 37). Furthermore, levels of both BACE-1 and Egr-1 are elevated in the brain during aging (22,38,39), hypoxia, brain injury, ischemia, and inflammation (13,14) and in AD mouse models (13,21,23). These observations together indicate that Egr-1 is an activator of BACE-1 in the CNS and suggest that Egr-1 plays role in the up-regulation of levels of BACE-1 and A␤ in AD brain.…”

Section: Discussionmentioning

confidence: 82%

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: Discussionmentioning

confidence: 82%

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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“…SOD-3 is expressed in the pharynx in the head, intestine, muscle, vulva, and tail34. In general, weak expression of SOD-3 is expected in the intestine34.…”

Section: Resultsmentioning

confidence: 98%

Intestinal Insulin Signaling Encodes Two Different Molecular Mechanisms for the Shortened Longevity Induced by Graphene Oxide in Caenorhabditis elegans

Zhao

Yang

Rui

et al. 2016

Sci Rep

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Graphene oxide (GO) has been shown to cause multiple toxicities in various organisms. However, the underlying molecular mechanisms for GO-induced shortened longevity are still unclear. We employed Caenorhabditis elegans to investigate the possible involvement of insulin signaling pathway in the control of GO toxicity and its underlying molecular mechanisms. Mutation of daf-2, age-1, akt-1, or akt-2 gene induced a resistant property of nematodes to GO toxicity, while mutation of daf-16 gene led to a susceptible property of nematodes to GO toxicity, suggesting that GO may dysregulate the functions of DAF-2/IGF-1 receptor, AGE-1, AKT-1 and AKT-2-mediated kinase cascade, and DAF-16/FOXO transcription factor. Genetic interaction analysis suggested the involvement of signaling cascade of DAF-2-AGE-1-AKT-1/2-DAF-16 in the control of GO toxicity on longevity. Moreover, intestinal RNA interference (RNAi) analysis demonstrated that GO reduced longevity by affecting the functions of signaling cascade of DAF-2-AGE-1-AKT-1/2-DAF-16 in the intestine. DAF-16 could also regulate GO toxicity on longevity by functioning upstream of SOD-3, which encodes an antioxidation system that prevents the accumulation of oxidative stress. Therefore, intestinal insulin signaling may encode two different molecular mechanisms responsible for the GO toxicity in inducing the shortened longevity. Our results highlight the key role of insulin signaling pathway in the control of GO toxicity in organisms.

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“…LIN-40 is an essential component of the nucleosome remodeling deacetylase (NuRD) complex (Johnsen and Baillie 1991;Solari et al 1999) that was recently shown to promote stress resistance and longevity in a circuit that involves the germline and the insulin pathway (Zimmerman and Kim 2014). The integration of BLMP-1-mediated action into this stress response is feasible, given that BLMP-1 is already known to direct migration of gonadal precursor cells (Huang et al 2014b) and our findings that show starvation is equally as effective as hypoxia for induction of the blmp-1-dependent 3kb-F45D3.4::GFP reporter.…”

Section: Discussionmentioning

confidence: 99%

A HIF-Independent Mediator of Transcriptional Responses to Oxygen Deprivation in Caenorhabditis elegans

et al. 2014

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The adaptive response to hypoxia is accompanied by widespread transcriptional changes that allow for prolonged survival in low oxygen. Many of these changes are directly regulated by the conserved hypoxia-inducible factor-1 (HIF-1) complex; however, even in its absence, many oxygen-sensitive transcripts in Caenorhabditis elegans are appropriately regulated in hypoxia. To identify mediators of these non-HIF-dependent responses, we established a hif-1 mutant reporter line that expresses GFP in hypoxia or when worms are treated with the hypoxia mimetic cobalt chloride (CoCl 2 ). The reporter is selective and HIF independent, in that it remains insensitive to a number of cellular stresses, but is unaffected by mutation of the prolyl hydroxylase egl-9, suggesting that the regulators of this response pathway are different from those controlling the HIF pathway. We used the HIF-independent reporter to screen a transcription factor RNA interference (RNAi) library and identified genes that are required for hypoxia-sensitive and CoCl 2 -induced GFP expression. We identified the zinc finger protein BLMP-1 as a mediator of the HIF-independent response. We show that mutation of blmp-1 renders animals sensitive to hypoxic exposure and that blmp-1 is required for appropriate hypoxic-induced expression of HIF-independent transcripts. Further, we demonstrate that BLMP-1 is necessary for an increase of hypoxia-dependent histone acetylation within the promoter of a non-HIF-dependent hypoxia response gene.KEYWORDS hypoxia; HIF independent; BLMP-1; C. elegans C ELLS are routinely challenged with low-oxygen conditions that drive compensatory responses. For instance, in development, low-oxygen conditions induce differentiation of placental cells (Dunwoodie 2009), and in diseased states, hypoxia is often a major contributing factor in cardiovascular disease and in the progression of solid tumor growth (Denko 2008;Semenza 2014). These low-oxygen challenges, whether scripted as in development or as consequences of physiologic dysfunction, are confronted by rapid cellular changes and by slower responses such as those mediated by the hypoxiainducible factor-1 (HIF-1) transcription pathway.The conserved HIF-1 complex regulates the expression of a broad set of genes that affect various aspects of metabolism, vascularization, and cell survival across species (Semenza 2011). In normoxia, the HIF-1 pathway is rendered inactive by prolyl hydroxylases (PHDs) that use molecular oxygen to modify conserved proline residues on the HIF-1a subunit of the transcription factor. The proline-hydroxylated HIF-1a is recognized by the von Hippel-Lindau (VHL) tumor suppressor protein, which targets HIF-1a for degradation (Bruick and McKnight 2001;Epstein et al. 2001). In hypoxia, owing to the reduced activity of PHD, unmodified HIF-1a pairs with the oxygen insensitive HIF-1b and the complex is transcriptionally active (Berra et al. 2006).The nematode Caenorhabditis elegans is adept at enduring periods of low oxygen (Powell-Coffman 2010). Not surprisin...

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The GATA transcription factor/MTA‐1 homolog egr‐1 promotes longevity and stress resistance in Caenorhabditis elegans

Cited by 11 publications

References 52 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

Intestinal Insulin Signaling Encodes Two Different Molecular Mechanisms for the Shortened Longevity Induced by Graphene Oxide in Caenorhabditis elegans

A HIF-Independent Mediator of Transcriptional Responses to Oxygen Deprivation in Caenorhabditis elegans

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