Antiinflammatory Effects of the ETS Factor ERG in Endothelial Cells Are Mediated Through Transcriptional Repression of the Interleukin-8 Gene

Yuan, Lei; Nikolova-Krstevski, Vesna; Zhan, Yumei; Kondo, Maiko; Bhasin, Manoj; Varghese, Laya; Yano, Kimihiko; Carman, Christopher V.; Aird, William C.; Oettgen, Peter

doi:10.1161/circresaha.108.190751

Cited by 80 publications

(130 citation statements)

References 46 publications

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“…We have previously tested 4 independent ERG siRNAs (1-4) to knock down ERG compared with control siRNA (CTR) in HUVECs using Western blot analysis. 20 Eighty to 90% reductions in ERG protein levels were observed with siRNA 2 and 4, respectively, whereas only ϳ a 60% reduction was observed with ERG siRNA 3 (data not shown). To ensure the specificity of the ERG siRNA, we previously examined the expression levels of a panel of other ETS factors, including Ets-1, Ets-2, Fli-1, Ese-1, ELF-1, and Nerf1, before and after ERG siRNA treatment.…”

Section: Erg Is Required For Ec Lumen and Tube Formation In 3d Collagmentioning

confidence: 89%

“…No change in the expression of any of the other ETS factors except ERG was observed after ERG siRNA treatment. 20 ERG siRNAs 2 and 4 significantly blunted EC lumen and tube formation compared with control siRNA ( Figure 1A). It has been shown previously that suppression of ERG leads to EC apoptosis.…”

Section: Erg Is Required For Ec Lumen and Tube Formation In 3d Collagmentioning

confidence: 95%

“…However, several recent studies-including those from our own laboratory-have shown that the ETS factor ERG exhibits an EC-restricted expression pattern. [17][18][19][20] Furthermore, it has also been shown that several ECrestricted genes, including VE-cadherin, endoglin, and VWF, are regulated by ERG. [21][22][23] In addition to its function as a regulator of EC-specific gene expression, ERG also plays a developmental role during the differentiation of embryonic stem cells into ECs.…”

Section: Introductionmentioning

confidence: 99%

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RhoJ is an endothelial cell-restricted Rho GTPase that mediates vascular morphogenesis and is regulated by the transcription factor ERG

Yuan

Sacharidou

Stratman

et al. 2011

Blood

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ERG is a member of the ETS transcription factor family that is highly enriched in endothelial cells (ECs). IntroductionBlood vessel lumenization is a critical step in the development of a functional vascular system during vascular morphogenesis. 1,2 Major mechanisms of lumen formation include cell wrapping, budding, cavitation, cord hollowing, and cell hollowing. 3 Recently, there have been significant advances in our understanding of how endothelial cells (ECs) make lumens and tubes in 3D extracellular matrices. 4,5 We have shown that this process is regulated by the formation of intracellular vacuoles within ECs that aggregate and coalesce. 6 EC lumen and tube expansion occurs through MT1-MMP (membrane type 1-matrix metalloprotease)-dependent proteolysis of 3D collagen matrices. One of the key regulators of lumen formation is the Rho GTPase Cdc42, which was first shown to control this process in ECs and later in epithelial cells. [6][7][8][9] During EC tube formation, Cdc42 activates a signaling cascade that includes PKC⑀, p21 protein-activated kinase Pak2, Pak4, Srcfamily kinases (SFKs) Src, Yes, B-Raf, C-Raf, and ERK1/2. 10 Other Rho GTPases that have recently been evaluated for their role in EC tube formation include RhoA and Rac1. 5 Whereas knockdown of Rac1 with siRNA markedly inhibits EC lumen formation, suppression of RhoA has no effect.The ETS factors are a family of approximately 30 transcription factors that share a highly conserved DNA-binding domain. 11 ETS factors were originally identified as playing a central role in regulating several B-and T-cell-specific genes involved in hematopoiesis. We and others have also demonstrated a critical role for selected ETS family members in the regulation of several vascular specific genes, including Tie1, Tie2, VWF, Robo4, and endothelial nitric oxide synthase. [12][13][14][15][16] Although many ETS factors participate in the regulation of EC-restricted genes, most do not exhibit a vascular-specific expression pattern. However, several recent studies-including those from our own laboratory-have shown that the ETS factor ERG exhibits an EC-restricted expression pattern. [17][18][19][20] Furthermore, it has also been shown that several ECrestricted genes, including VE-cadherin, endoglin, and VWF, are regulated by ERG. [21][22][23] In addition to its function as a regulator of EC-specific gene expression, ERG also plays a developmental role during the differentiation of embryonic stem cells into ECs. 24,25 More recently, ERG has been shown to play a role in endothelial tube formation and angiogenesis. 21 In particular, one of the main downstream targets of ERG identified as playing a role in this process was VE-cadherin. The purpose of this study was to further define the regulatory role of ERG during EC morphogenesis. We found a dramatic inhibitory effect on EC tube and lumen formation in 3D collagen gels as a result of siRNA suppression of ERG. Using quantitative PCR (QPCR) of potential candidate genes we were able to identify the Rho GTPase family member, Rho...

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Section: Erg Is Required For Ec Lumen and Tube Formation In 3d Collagmentioning

confidence: 89%

Section: Erg Is Required For Ec Lumen and Tube Formation In 3d Collagmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

RhoJ is an endothelial cell-restricted Rho GTPase that mediates vascular morphogenesis and is regulated by the transcription factor ERG

Yuan

Sacharidou

Stratman

et al. 2011

Blood

Self Cite

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“…9 Quantitative reverse transcriptase PCR Quantitative reverse transcriptase polymerase chain reaction (PCR) was carried out as previously described. 9,10 Generation and analysis of Hprt-targeted transgenic mice…”

Section: Transfection With Sirnamentioning

confidence: 99%

“…25 We recently demonstrated that TNF-␣ suppresses ERG expression in endothelial cells. 9 To confirm that TNF-␣ results in concomitant inhibition of ERG and VWF, HUVECs were treated with 20 ng/mL TNF-␣ for varying times and assayed for mRNA expression using quantitative real-time PCR. As shown in Figure 5B, TNF-␣ resulted in a time-dependent reduction in ERG and VWF mRNA (46% and 52% of control at 24 hours, respectively) but not CD31, ␤-actin, or the ETS transcription factor, friend leukemia virus integration (Fli)-1.…”

Section: Org Frommentioning

confidence: 99%

Vascular bed–specific regulation of the von Willebrand factor promoter in the heart and skeletal muscle

Liu

Yuan

Molema

et al. 2011

Blood

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A region of the human von Willebrand factor (VWF) gene between ؊2812 and the end of the first intron (termed vWF2) was previously shown to direct expression in the endothelium of capillaries and a subset of larger blood vessels in the heart and skeletal muscle. Here, our goal was to delineate the DNA sequences responsible for this effect. A series of constructs containing deletions or mutations of vWF2 coupled to LacZ were targeted to the Hprt locus of mice, and the resulting animals were analyzed for reporter gene expression. The findings demonstrate that DNA sequences between ؊843 and ؊620 are necessary for expression in capillary but not large vessel endothelium in heart and skeletal muscle. Further, expression of VWF in capillaries and larger vessels of both tissues required the presence of a native or heterologous intron. In vitro assays implicated a role for ERG-binding ETS motif at ؊56 in mediating basal expression of VWF. In Hprt-targeted mice, mutation of the ETS consensus motif resulted in loss of LacZ expression in the endothelium of the heart and skeletal muscle. Together, these data indicate that distinct DNA modules regulate vascular bed-specific expression of VWF. (Blood. 2011;117(1):342-351) IntroductionThe von Willebrand factor (VWF) is a high-molecular weight glycoprotein that mediates platelet-vessel wall interactions. VWF is expressed specifically in endothelial cells and megakaryocytes. Its expression in the intact endothelium varies both spatially and temporally. For example, in mice VWF mRNA levels are higher in the lung and heart compared with the liver and kidney, and within a given tissue, VWF expression is generally greater on the venous side of the circulation. 1 Expression of VWF may change in pathophysiological conditions. For example, in a mouse model of endotoxemia, VWF mRNA levels were down-regulated in aorta, brain, adipose tissue, testis, thymus, adrenal, skeletal muscle, gut, and liver but increased in the heart and kidney. 1 The elucidation of the mechanisms underlying VWF expression may provide important insights into the molecular basis of vascular diversity.The structural organization of the mouse, human, and bovine VWF promoter-proximal region is closely related. [2][3][4] The first exon (ϩ1 to ϩ246 in human VWF) encodes 5Ј untranslated sequence. The second exon contains the ATG translational start site. Exons 1 and 2 are separated by an intron (ϩ247 to ϩ1475 in human VWF). A previous in vitro analysis of the human gene demonstrated that a 734-bp region between Ϫ487 and ϩ246 contains information for lineage-specific expression in cultured endothelial cells. 5 In standard transgenic mice, this promoter fragment (which we have termed vWF1) retained endothelial cell specificity. However, expression was limited to blood vessels of the brain. 6 In contrast, standard transgenic mice carrying a larger region of the VWF gene (between Ϫ2182 and the end of the first intron; designated vWF2) directed expression not only in blood vessels of the brain but also in capillaries of the he...

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Erg mediates downregulation of claudin‐5 in the brain endothelium of a murine experimental model of cerebral malaria

Liu

Fang-shu

et al. 2019

FEBS Letters

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Cerebral malaria (CM) is a severe complication with brain vascular hyperpermeability. Claudin‐5 is the major component of tight junctions. To investigate the expression of claudin‐5 in CM, we established a murine experimental cerebral malaria (ECM) model and an in vitro model by treating murine brain endothelial cells (bEnd3) with plasma from ECM mice. Expression of claudin‐5 and the ETS transcription factor Erg was reduced in the brain endothelium of ECM mice. In bEnd3 cells exposed to ECM plasma, decreased expression of claudin‐5 and Erg, and increased permeability were observed. Silencing of Erg significantly reduced Cldn5 expression. ChIP assays indicated that Erg binds to the −813 ETS motif of the murine Cldn5 gene promoter, and the binding is decreased by treatment with ECM plasma.

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Antiinflammatory Effects of the ETS Factor ERG in Endothelial Cells Are Mediated Through Transcriptional Repression of the Interleukin-8 Gene

Cited by 80 publications

References 46 publications

RhoJ is an endothelial cell-restricted Rho GTPase that mediates vascular morphogenesis and is regulated by the transcription factor ERG

RhoJ is an endothelial cell-restricted Rho GTPase that mediates vascular morphogenesis and is regulated by the transcription factor ERG

Vascular bed–specific regulation of the von Willebrand factor promoter in the heart and skeletal muscle

Erg mediates downregulation of claudin‐5 in the brain endothelium of a murine experimental model of cerebral malaria

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