HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Castañares, C. Articles by Rodriguez-Pascual, F. Search for Related Content PubMed PubMed Citation Articles by Castañares, C. Articles by Rodriguez-Pascual, F.

---

BASIC BIOLOGY

Transforming Growth Factor-ß Receptor Requirements for the Induction of the Endothelin-1 Gene

Departamento de Estructura y Función de Proteínas, Centro de Investigaciones Biológicas, C.S.I.C., Instituto "Reina Sofía" de Investigaciones Nefrológicas and Centro Nacional de Investigaciones Cardiovasculares (CNIC), Ramiro de Maeztu 9, E-28040, Madrid, Spain

To whom requests for reprints should be addressed at ¹ Departamento de Estructura y Función de Proteínas, Centro de Investigaciones Biológicas, C.S.I.C., Ramiro de Maeztu 9, E-28040, Madrid, Spain. E-mail: frodriguez{at}cib.csic.es

Abstract

Expression of the endothelin (ET)-1 gene is subject to complex regulation by numerous factors, among which the cytokine transforming growth factor-ß (TGF-ß) is one of the most important. TGF-ß action is based on the activation of the Smad signaling pathway. Smad proteins activate transcription of the gene by cooperation with activator protein-1 (AP-1) at specific sites on the ET-1 promoter. Smad signaling pathway is initiated by binding of the cytokine to a heteromeric complex of type I and type II receptors. Signal is then propagated to the nucleus by specific members of the Smad family. Most cell types contain a type I receptor known as ALK5. However, endothelial cells are unique because they coexpress an additional type I receptor named ALK1. These forms do not constitute redundant receptors with the same function, but they actually activate different Smad-mediated expression programs that lead to specific endothelial phenotypes. TGF-ß/ALK5/Smad3 pathway is associated to a mature endothelium because it leads to inhibition of cell migration/proliferation. Conversely, TGF-ß/ALK1/Smad5 activates both processes and is more related to the angiogenic state. We have analyzed the TGF-ß receptor subtype requirements for the activation of the ET-1 gene. For that purpose, we have overexpressed type I receptor and Smad isoforms in endothelial cells and analyzed the effect on ET-1 expression. Our experiments indicate that TGF-ß induces ET-1 expression preferentially through the activation of the ALK5/Smad3 pathway and, therefore, the expression of the vaso-constrictor may be associated to a quiescent and mature endothelial phenotype.

Key Words: endothelin-1 • transforming growth factor-ß • • Smad signaling pathway • endothelial cells • ALK5 receptor