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The transcription factor Erg controls endothelial cell quiescence by repressing activity of nuclear factor (NF)-κB p65.

Dryden, NH; Sperone, A; Martin-Almedina, S; Hannah, RL; Birdsey, GM; Khan, ST; Layhadi, JA; Mason, JC; Haskard, DO; Göttgens, B; et al. Dryden, NH; Sperone, A; Martin-Almedina, S; Hannah, RL; Birdsey, GM; Khan, ST; Layhadi, JA; Mason, JC; Haskard, DO; Göttgens, B; Randi, AM (2012) The transcription factor Erg controls endothelial cell quiescence by repressing activity of nuclear factor (NF)-κB p65. J Biol Chem, 287 (15). 12331 - 12342. https://doi.org/10.1074/jbc.M112.346791
SGUL Authors: Martin Almedina, Silvia

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Abstract

The interaction of transcription factors with specific DNA sequences is critical for activation of gene expression programs. In endothelial cells (EC), the transcription factor NF-κB is important in the switch from quiescence to activation, and is tightly controlled to avoid excessive inflammation and organ damage. Here we describe a novel mechanism that controls the activation of NF-κB in EC. The transcription factor Erg, the most highly expressed ETS member in resting EC, controls quiescence by repressing proinflammatory gene expression. Focusing on intercellular adhesion molecule 1(ICAM)-1 as a model, we identify two ETS binding sites (EBS -118 and -181) within the ICAM-1 promoter required for Erg-mediated repression. We show that Erg binds to both EBS -118 and EBS -181, the latter located within the NF-κB binding site. Interestingly, inhibition of Erg expression in quiescent EC results in increased NF-κB-dependent ICAM-1 expression, indicating that Erg represses basal NF-κB activity. Erg prevents NF-κB p65 from binding to the ICAM-1 promoter, suggesting a direct mechanism of interference. Gene set enrichment analysis of transcriptome profiles of Erg and NF-κB-dependent genes, together with chromatin immunoprecipitation (ChIP) studies, reveals that this mechanism is common to other proinflammatory genes, including cIAP-2 and IL-8. These results identify a role for Erg as a gatekeeper controlling vascular inflammation, thus providing an important barrier to protect against inappropriate endothelial activation.

Item Type: Article
Additional Information: PMCID: PMC3320982
Keywords: Binding Sites, Binding, Competitive, Cells, Cultured, DNA, Electrophoretic Mobility Shift Assay, G0 Phase, Gene Expression Profiling, Gene Expression Regulation, Genes, Reporter, Human Umbilical Vein Endothelial Cells, Humans, Intercellular Adhesion Molecule-1, Luciferases, Renilla, Promoter Regions, Genetic, Protein Binding, Trans-Activators, Transcription Factor RelA, Transcription Initiation Site, Transcription, Genetic
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Academic Structure > Molecular and Clinical Sciences Research Institute (MCS) > Cell Sciences (INCCCS)
Journal or Publication Title: J Biol Chem
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Dates:
DateEvent
6 April 2012Published
PubMed ID: 22337883
Web of Science ID: 22337883
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URI: https://openaccess.sgul.ac.uk/id/eprint/104663
Publisher's version: https://doi.org/10.1074/jbc.M112.346791

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