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Transcriptional activation of endoglin and transforming growth factor-? signaling components by cooperative interaction between Sp1 and KLF6: their potential role in the response to vascular injury

By Luisa M. Botella, Tilman Sánchez-Elsner, Francisco Sanz-Rodriguez, Soichi Kojima, Jun Shimada, Mercedes Guerrero-Esteo, Michael P. Cooreman, Vlad Ratziu, Carmen Langa, Calvin P.H. Vary, Jose R. Ramírez, Scott Friedman and Carmelo Bernabéu

Abstract

Endoglin is an endothelial membrane glycoprotein involved in cardiovascular morphogenesis and vascular remodeling. It associates with transforming growth factor-? (TGF-?) signaling receptors to bind TGF-? family members, forming a functional receptor complex. Arterial injury leads to up-regulation of endoglin, but the underlying regulatory events are unknown. The transcription factor KLF6, an immediate-early response gene induced in endothelial cells during vascular injury, transactivates TGF-?, TGF-? signaling receptors, and TGF-?-stimulated genes. KLF6 and, subsequently, endoglin were colocalized to vascular endothelium (ie, expressed in the same cell type) following carotid balloon injury in rats. After endothelial denudation, KLF6 was induced and translocated to the nucleus; this was followed 6 hours later by increased endoglin expression. Transient overexpression of KLF6, but not Egr-1, stimulated endogenous endoglin mRNA and transactivated the endoglin promoter. This transactivation was dependent on a GC-rich tract required for basal activity of the endoglin promoter driven by the related GC box binding protein, Sp1. In cells lacking Sp1 and KLF6, transfected KLF6 and Sp1 cooperatively transactivated the endoglin promoter and those of collagen alpha1(I), urokinase-type plasminogen activator, TGF-?1, and TGF-? receptor type 1. Direct physical interaction between Sp1 and KLF6 was documented by coimmunoprecipitation, pull-down experiments, and the GAL4 one-hybrid system, mapping the KLF6 interaction to the C-terminal domain of Sp1. These data provide evidence that injury-induced KLF6 and preexisting Sp1 may cooperate in regulating the expression of endoglin and related members of the TGF-? signaling complex in vascular repair

Topics: QP
Year: 2002
OAI identifier: oai:eprints.soton.ac.uk:47979
Provided by: e-Prints Soton
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