The Transcription Factor Erg Inhibits Vascular Inflammation by Repressing NF-κB Activation and Proinflammatory Gene Expression in Endothelial Cells

Sperone, Andrea; Dryden, Nicola H.; Birdsey, Graeme M.; Madden, Leigh A.; Johns, Mike; Evans, Paul C.; Mason, Justin C.; Haskard, Dorian O.; Boyle, Joseph J.; Paleolog, Ewa; Randi, Anna M.

doi:10.1161/atvbaha.110.216473

Cited by 74 publications

(117 citation statements)

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“…Erg is a member of the ETS family of transcription factors, which is mainly expressed by endothelial cells (34,35). Erg maintains endothelial cells in a non-activated state by constitutively repressing NF-B activity and ICAM-1 expression after TNF␣ stimulation (36,37). Erg also reduces the expression of inflammatory cytokines such as interleukin-8 (38), and its down-regulation leads to spontaneous neutrophil attachment to nonstimulated endothelial cells.…”

Section: Discussionmentioning

confidence: 99%

Endothelial Cell Activation Is Regulated by Epidermal Growth Factor-like Domain 7 (Egfl7) during Inflammation

Pinte

Caetano

Bras

et al. 2016

Journal of Biological Chemistry

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Edited by Dennis VoelkerActivation of the blood vessel endothelium is a critical step during inflammation. Endothelial cells stimulated by pro-inflammatory cytokines play an essential part in the adhesion and extravasation of circulating leukocytes into inflamed tissues. The endothelial egfl7 gene (VE-statin) represses endothelial cell activation in tumors, and prior observations suggested that it could also participate in the regulation of endothelial cell activation during inflammation. We show here that Egfl7 expression is strongly repressed in mouse lung endothelial cells during LPS-and TNF␣-induced inflammation in vivo. LPS have a limited effect on Egfl7 expression by endothelial cells in vitro, whereas the pro-inflammatory cytokine TNF␣ strongly represses Egfl7 expression in endothelial cells. TNF␣ regulates the egfl7 gene promoter through regions located between ؊7585 and ؊5550 bp ahead of the main transcription start site and via an NF-B-dependent mechanism. Conversely, Egfl7 regulates the response of endothelial cells to TNF␣ by restraining the induced expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin, resulting in a decreased adhesion of leukocytes onto endothelial cells stimulated by TNF␣. Egfl7 regulates the expression of these adhesion molecules through the NF-B and MEK/Erk pathways, in particular by preventing the proteasomemediated degradation of IkB␣ both in non-activated endothelial cells and during activation. Egfl7 is thus an endogenous and constitutive repressor of blood vessel endothelial cell activation in normal and inflammatory conditions and participates in a loop of regulation of activation of these cells by pro-inflammatory cytokines.Endothelial cells line the luminal side of blood vessels in direct contact with the circulation. Under normal conditions, the endothelium forms a non-adhesive and non-thrombogenic surface on which blood cells slide with minimal interactions with the vascular wall. During inflammation, endothelial cells become activated in response to pro-inflammatory cytokines, which promote a strong increase in the expression levels of leukocyte adhesion molecules such as E-selectin, intercellular adhesion molecule-1 (ICAM-1), 4 and vascular cell adhesion molecule-1 (VCAM-1). These adhesion molecules are expressed at the endothelial cell surface and participate in the rolling, arrest, firm adhesion, and extravasation of immune cells from the circulation through the endothelium and toward the tissues (1). Endothelial cell activation in response to inflammation and its subsequent capture of leukocytes is thus a vital response, and its regulation is critical. Excessive or aberrant local activation of endothelial cells leads to inflammatory disorders such as atherosclerosis, chronic inflammation, multiple sclerosis, and rheumatoid arthritis. Activation of the endothelium is transitory, and endothelial cells resume a basal, nonactivated condition when pro-inflammatory cytokines levels recess. Thus, most of the ...

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Section: Discussionmentioning

confidence: 99%

Endothelial Cell Activation Is Regulated by Epidermal Growth Factor-like Domain 7 (Egfl7) during Inflammation

Pinte

Caetano

Bras

et al. 2016

Journal of Biological Chemistry

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“…ERG is a key regulator of cell proliferation and differentiation, and angiogenesis. 39 Regarding the top 10 overexpressed genes, RPL7A is a ribosomal protein and an altered pattern of RPL7 expression has been described in colorectal carcinoma. 40 …”

Section: Genes Differentially Expressed Between Mgus and Smmmentioning

confidence: 99%

Transcriptome analysis reveals molecular profiles associated with evolving steps of monoclonal gammopathies

et al. 2014

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“…16,17 It is also constitutively expressed in normal endothelial cells and regulates angiogenesis and endothelial apoptosis. [18][19][20] Several studies have shown anti-ERG antibody useful for prostate carcinoma, metastatic and primary, and prostatic intraepithelial neoplasias. [10][11][12]21,22 The detection of ERG is highly correlated with both ERG rearrangement by fluorescence in-situ hybridization and with ERG mRNA overexpression.…”

mentioning

confidence: 99%

Expression of ERG, an Ets family transcription factor, identifies ERG-rearranged Ewing sarcoma

et al. 2012

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ERG gene encodes for an Ets family regulatory transcription factor and is involved in recurrent chromosomal translocations found in a subset of acute myeloid leukemias, prostate carcinomas and Ewing sarcomas. The purpose of this study was to examine the utility of an ERG antibody to detect EWSR1-ERG rearranged Ewing sarcomas. A formalin-fixed paraffin-embedded tissue microarray and whole-tissue sections from 32 genetically characterized Ewing sarcomas were examined: 22 with EWSR1-FLI1, 8 with EWSR1-ERG and 2 with EWSR1-NFATC2. Immunohistochemistry was performed using a rabbit anti-ERG monoclonal antibody directed against the C-terminus of the protein and a mouse anti-FLI1 monoclonal antibody against a FLI1 Ets domain (C-terminus) fusion protein. Immunoreactivity was graded for extent and intensity of positive tumor cell nuclei. ERG labeling was seen in 7/8 EWSR1-ERG cases (predominantly diffuse (5 þ ), moderate to strong), while only 3/24 non-EWR1-ERG cases showed labeling (very weak). FLI1 labeling was observed in 29/31 cases regardless of fusion variant; 23 displayed diffuse (5 þ ) strong/moderate labeling (5/7 EWSR1-ERG, 18/22 EWSR1-FLI1). Both EWSR1-NFATC2 cases had weak reactivity with FLI1 and weak or no reactivity for ERG. In conclusion, strong nuclear ERG immunoreactivity is specific for Ewing sarcomas with EWSR1-ERG rearrangement. In contrast, FLI1 was not specific to rearrangement type, likely because of cross reactivity with the highly homologous Ets DNA-binding domain present in the C-terminus of both ERG and FLI1. Modern Pathology (2012) 25, 1378-1383; doi:10.1038/modpathol.2012.97; published online 6 July 2012Keywords: Ewing sarcoma; EWSR1; ERG; FLI1; immunohistochemistry Ewing sarcoma is characterized by a recurrent translocation involving EWSR1 on 22q12. The most frequent partner is FLI1 located on 11q22, occurring in B85% of cases. 1-3 However, a minority of tumors will harbor a translocation involving EWSR1 and an alternative partner, the most common of which is ERG located on 21q12. 2-4 These characteristic translocations result in the constitutive expression of an abnormal transcription factor that is critical for Ewing sarcoma tumorigenesis, and is composed of the amino end of EWSR1, a potent transcriptional activator, and the C-terminus of FLI1/ERG that contains the Ets DNA-binding domain. Both FLI1 and ERG belong to the Ets family of transcription factors, which regulate several genes involved in cellular differentiation and growth. 2,5 Chimeric variants of EWSR1 with other Ets genes, including ETV4 and FEV, have been described but are very rare. 6 Rearrangements of EWSR1 with non-Ets family genes, including NFATc2, POU5F1, SMARCA5, ZSG and SP3, are also rare. 2,6-8

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The Transcription Factor Erg Inhibits Vascular Inflammation by Repressing NF-κB Activation and Proinflammatory Gene Expression in Endothelial Cells

Abstract: We have identified a novel physiological anti-inflammatory pathway under the control of the transcription factor Erg; this pathway inhibits NF-κB-dependent transcription and TNF-α-induced inflammation in vivo. These results suggest a novel approach to anti-inflammatory therapies.

Cited by 74 publications

References 40 publications

Endothelial Cell Activation Is Regulated by Epidermal Growth Factor-like Domain 7 (Egfl7) during Inflammation

Endothelial Cell Activation Is Regulated by Epidermal Growth Factor-like Domain 7 (Egfl7) during Inflammation

Transcriptome analysis reveals molecular profiles associated with evolving steps of monoclonal gammopathies

Expression of ERG, an Ets family transcription factor, identifies ERG-rearranged Ewing sarcoma

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