Nucleic Acids Research, 1993, Vol. 21, No. 24 5636-5643
© 1993
MOLECULAR BIOLOGY |
Ets transcription factor binding site is required for positive and TNF
-Hnduced negative promoter regulation
Haemostasis Research Unit, Kerckhoff-Klinik, Max-Planck-lnstitut Sprudelhof 11, D-61231 Bad Nauheim, Germany 1Laboratoire de Genetique Moleculaire des Eucaryotes du CNRS, Unite 184 de Biologie Moleculaire et du Genie Genetique de I'lNSERM, Institut de Chimie Biologique, Faculte de Medecine 11 rue Humann, 67085 Strasbourg Cedex, France
*To whom correspondence should be addressed
Received September 7, 1993. Revised October 27, 1993. Accepted October 27, 1993.
Thrombomodulin (TM) is expressed on vascular endothelial cells and plays an important role in the anticoagulant pathway by maintaining the thromboresistance 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
) through a protein kinase C independent pathway. The TM promoter is highly active in endothelial cells and is inhibited by TNF. The - 7 6 / - 5 6 region mediates both specific high basal activity and TNF-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 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 - 7 6 / - 5 6 element, their activity is not suppressed by TNF. c-Ets-1 competes and overrides TNF 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 signalling cascade in endothelial cells.
+Present address: Friedrich Miescher-Institut, PO Box 2543, CH-4002 Basel, Switzerlandy
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