The translation inhibitor anisomycin induces Elk-1-mediated transcriptional activation of egr-1 through multiple mitogen-activated protein kinase pathways

Shin, Soon Young; Lee, Woo Jung; Min, Byung Wook; Lee, Young Han

doi:10.1038/emm.2006.80

Cited by 21 publications

(10 citation statements)

References 42 publications

(53 reference statements)

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“…It is well known that ERK1/2, EGR1 and the zinc-finger transcription factor, Snail, play critical roles in tumor metastasis in several cancer types [24-27]. However, it is not clear whether these signaling pathways are involved in the CCA.…”

Section: Resultsmentioning

confidence: 99%

Suppression of thymosin β10 increases cell migration and metastasis of cholangiocarcinoma

et al. 2013

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BackgroundThymosin β10 (Tβ10) expression is associated with malignant phenotypes in many cancers. However, the role and mechanisms of Tβ10 in liver fluke-associated cholangiocarcinoma (CCA) are not fully understood. In this study, we investigated the expression of Tβ10 in CCA tumor tissues and cell lines as well as molecular mechanisms of Tβ10 in tumor metastasis of CCA cell lines.MethodsTβ10 expression was determined by real time RT-PCR or immunocytochemistry. Tβ10 silence or overexpression in CCA cells was achieved using gene delivery techniques. Cell migration was assessed using modified Boyden chamber and wound healing assay. The effect of silencing Tβ10 on CCA tumor metastasis was determined in nude mice. Phosphorylation of ERK1/2 and the expression of EGR1, Snail and matrix metalloproteinases (MMPs) were studied.ResultsTen pairs of CCA tissues (primary and metastatic tumors) and 5 CCA cell lines were studied. With real time RT-PCR and immunostaining analysis, Tβ10 was highly expressed in primary tumors of CCA; while it was relatively low in the metastatic tumors. Five CCA cell lines showed differential expression levels of Tβ10. Silence of Tβ10 significantly increased cell migration, invasion and wound healing of CCA cells in vitro; reversely, overexpression of Tβ10 reduced cell migration compared with control cells (P<0.05). In addition, silence of Tβ10 in CCA cells increased liver metastasis in a nude mouse model of CCA implantation into the spleen. Furthermore, silence of Tβ10 activated ERK1/2 and increased the expression of Snail and MMPs in CCA cell lines. Ras-GTPase inhibitor, FPT inhibitor III, effectively blocked Tβ10 silence-associated ERK1/2 activation, Snail expression and cell migration.ConclusionsLow expression of Tβ10 is associated with metastatic phenotype of CCA in vitro and in vivo, which may be mediated by the activation of Ras, ERK1/2 and upregulation of Snail and MMPs. This study suggests a new molecular pathway of CCA pathogenesis and a novel strategy to treat or prevent CCA metastasis.

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Section: Resultsmentioning

confidence: 99%

Suppression of thymosin β10 increases cell migration and metastasis of cholangiocarcinoma

et al. 2013

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“…Egr factors are well-known to be regulated by MAP kinase pathways, especially by ERK-1/-2 (Lo et al 2001; McCubrey et al 2000; Park and Koh 1999); but the p38 pathway has also been shown to regulate Egr factors as well (Kim et al 2007; Lim et al 1998; Shin et al 2006). To our knowledge, Ras activation in response to P2X7 receptor stimulation has only been demonstrated in RAW 264.7 macrophages (Aga et al 2004), so we assessed its activation in microglia following treatment with BzATP.…”

Section: Resultsmentioning

confidence: 99%

The P2X7‐Egr pathway regulates nucleotide‐dependent inflammatory gene expression in microglia

Friedle

Brautigam

Nikodémová

et al. 2010

Glia

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Microglial hyperactivity contributes to neuronal damage resulting from CNS injury and disease. Therefore, a better understanding of endogenous microglial receptor systems that can be exploited to modulate their inflammatory functions is important if better, neuroprotective therapeutics are to be designed. Previous studies from our lab and others have demonstrated that the P2X7 purinergic receptor agonist BzATP attenuates microglial inflammatory mediator production stimulated by lipopolysaccharide (LPS), suggesting that purinergic receptors may be one such receptor system that can be used for manipulating microglial activation. However, although P2X7 receptor activation is well recognized to regulate processing and release of cytokines, little is known concerning its role in regulating the transcription of inflammatory genes, nor the molecular mechanisms underlying these transcriptional effects. In the present studies, we identify that the transcription factors early growth response (Egr)-1, -2 and -3 are downstream signaling targets of P2X7 receptors in microglia, and that their activation is sensitive to MEK and p38 mitogen-activated protein kinase (MAPK) inhibitors. Moreover, using RNAi, we demonstrate that Egr factors and P2X7 receptors are necessary for BzATP-mediated attenuation of iNOS, and stimulation of TNF-α and IL-6 gene expression. BzATP also attenuates neuronal death induced by LPS conditioned medium, and P2X7 receptors are required for this effect. These studies are the first to identify Egr factors as regulators of inflammatory gene expression following P2X7 receptor activation, and suggest that P2X7 receptors may utilize the MAPK-Egr pathway to exert differential effects on microglial inflammatory activities which are beneficial to neuron survival.

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“…Given [46][47][48] that regulates the promoters of other immediate early genes such as c-fos and c-jun. 49,50 An in vivo analysis of the EGR1 promoter using chromatin immunoprecipitation assays was performed to identify functional Elk-1 binding.…”

Section: Analyses Of the Egr1 Promoter Identified Several Sre Bindingmentioning

confidence: 99%

Transcriptional Regulation of EGR1 by EGF and the ERK Signaling Pathway in Prostate Cancer Cells

Gregg

Fraizer

2011

Genes & Cancer

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The early growth response gene 1, EGR1, is an important transcriptional regulator and acts as the convergent point between a variety of extracellular stimuli and activation of target genes. Unlike other tumor types, prostate tumors express high levels of EGR1 relative to normal tissues. However, the mechanism of EGR1 regulation in prostate tumor cells is unknown. As EGR1 expression and epidermal growth factor (EGF) signaling are frequently upregulated in prostate tumors, we tested the hypothesis that EGF induces EGR1 expression in prostate cancer cells. Using RT-PCR to quantify EGR1 transcripts, we found that EGF induced EGR1 expression in a dose-and time-dependent manner and the ERK pathway inhibitor, PD98059, abrogated the EGF-mediated EGR1 response in LNCaP and PC3 cells. Analysis of the EGR1 promoter using deletion constructs identified an EGF-responsive region in the proximal promoter (-771 to -245 bp) containing 3 potential serum response element (SRE) sites. In vivo chromatin immunoprecipitation assays demonstrated that Elk-1 binding at the SRE sites of the EGR1 promoter was enhanced by EGF treatment in PC3 cells. Overexpression of Elk-1 was sufficient to activate the EGF-responsive region of EGR1 promoter in PC3 cells and, similarly, a dominant-negative Elk-1 suppressed EGR1 promoter activity. Taken together, these results demonstrate for the first time that EGR1 expression in PC3 cells is mediated through an EGF-ERK-Elk-1 signaling cascade.

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The translation inhibitor anisomycin induces Elk-1-mediated transcriptional activation of egr-1 through multiple mitogen-activated protein kinase pathways

Cited by 21 publications

References 42 publications

Suppression of thymosin β10 increases cell migration and metastasis of cholangiocarcinoma

Suppression of thymosin β10 increases cell migration and metastasis of cholangiocarcinoma

The P2X7‐Egr pathway regulates nucleotide‐dependent inflammatory gene expression in microglia

Transcriptional Regulation of EGR1 by EGF and the ERK Signaling Pathway in Prostate Cancer Cells

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