Ets transcription factor binding site is required for positive and TNFα-Hnduced negative promoter regulation

Abstract

Thrombomodulin (TM) is expressed on vascular endothelial cells and plays an important role in the anticoagulant pathway by maintaining the thrombo-resistance of the blood vessel wall. We show that in primary human endothelial cells TM gene expression is repressed at the transcriptional level by Tumour necrosis factor (TNF alpha) through a protein kinase C independent pathway. The TM promoter is highly active in endothelial cells and is inhibited by TNF alpha. The -76/-56 region mediates both specific high basal activity and TNF alpha-repression. It binds a nuclear factor specific to endothelial cells, that appears to belong to the Ets-family by various criteria. The -76/-56 region contains three direct repeats of the ets-core sequence GGAA that are important for specific high basal activity, TNF alpha repression and trans-activation by expression of Ets-1 and 2. Although human Ets-1 (h-Ets-1) and chicken c-Ets-1 and 2 stimulate the TM promoter through the -76/-56 element, their activity is not suppressed by TNF alpha. c-Ets-1 competes and overrides TNF alpha repression in a concentration dependent manner. We propose that either a different member of the Ets domain protein family, or an Ets-associated co-factor, is the target of the TNF alpha signalling cascade in endothelial cells.

The transcription factor ERG regulates a low shear stress-induced anti-thrombotic pathway in the microvasculature

“…These studies suggest a model of cooperation between ERG and KLF2 in the transcriptional control of endothelial homeostasis, where ERG, partly by promoting KLF2 binding to DNA, is essential to maintain a basal, healthy and anti-thrombotic endothelium in the microvasculature of multiple organs. This pathway appears dispensable in blood vessels exposed to high SS, where the role of KLF2 becomes dominant, and possibly other ETS factors (such as ETS1 50 ) or other epigenetic mechanisms may step in to provide cooperation. Future studies will investigate the TF networks involved in shear-dependent, cooperative transcriptional and epigenetic networks.…”

Identification and characterization of a novel porcine endothelial cell‐specific Tie1 promoter

“…The Ets‐binding site, also called EBS, is highly conserved in the core DNA‐binding sequence GGA(A/T). Nearly every endothelial‐restricted promoter or enhancer contains several Ets‐binding sites such as thrombomodulin , von Willebrand factor , Flt‐1 , vascular endothelial cadherin , and ICAM‐2 . Ets factors in mouse and human Tie1 promoters have been shown to bind with these motifs to activate transcription.…”