Published online before print May 22, 2003, doi: 10.1161/01.RES.0000078491.79697.7F
© 2003 American Heart Association, Inc.
Molecular Medicine |
Functional Cooperation Between Smad Proteins and Activator Protein-1 Regulates Transforming Growth Factor-ß–Mediated Induction of Endothelin-1 Expression
From the 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), Madrid, Spain.
Correspondence to Dr Fernando Rodríguez-Pascual or Dr Santiago Lamas, Departamento de Estructura y Función de Proteínas, Centro de Investigaciones Biológicas, C.S.I.C., Velázquez 144, E-28006 Madrid, Spain. E-mail frodriguez{at}cib.csic.es or slamas@cib.csic.es
Endothelin-1 (ET-1) is a 21–amino-acid potent vasoconstrictor peptide that is mainly produced by vascular endothelial cells. Expression of the ET-1 gene is subject to complex regulation by numerous factors, among which transforming growth factor-ß (TGF-ß) is one of the most important. It has been widely documented that TGF-ß increases ET-1 mRNA and peptide levels. We have explored the mechanism by which TGF-ß upregulates ET-1 expression in endothelial cells. Transcriptional activation of the ET-1 promoter accounted for the TGF-ß–induced increase in ET-1 mRNA levels. We have identified within the ET-1 promoter two DNA elements indispensable for TGF-ß–mediated induction of ET-1: an activator protein-1 (AP-1) site at -108/-102, known to be important for constitutive and induced expression, and a novel regulatory sequence located at -193/-171, which constitutes a specific binding site for Smad transcription factors. Mutation of both elements abolished TGF-ß responsiveness. Binding of Smad3/Smad4 and c-Jun to their corresponding DNA elements was evidenced by electrophoretic mobility shift assays. Furthermore, the coactivator CREB-binding protein (CBP)/p300 was found to play an essential role in the induction of the gene. The simultaneous requirement for two distinct and independent DNA elements suggests that Smads and activator protein-1 functionally cooperate through CBP/p300 to mediate TGF-ß–induced transcriptional activation of the ET-1 gene.
Key Words: endothelin • Smad • activator protein-1 • CREB-binding protein/p300 • transcriptional regulation
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