Transforming growth factor-beta induces endothelin-1 expression through activation of the Smad signaling pathway.
Expression of the endothelin-1 gene is subject to complex regulation by different factors, among which transforming growth factor-beta is one of the most important. We have analyzed the mechanism by which transforming growth factor-beta increases endothelin-1 expression in vascular endothelial cells. Transcriptional activation of the endothelin-1 promoter accounted for the transforming growth factor-beta-induced increase in endothelin-1 mRNA levels. Two DNA elements within the promoter are responsible for this effect: a Smad binding element and a proximal activator protein-1 site. Mutation of both elements abolished transforming growth factor-beta responsiveness. Overexpression of the Smad3 isoform strongly potentiates transforming growth factor-beta- induced endothelin-1 promoter activity in a phosphorylation-dependent manner. These results demonstrate that transforming growth factor-beta induces endothelin-1 expression by a functional cooperation between Smads and activator protein-1 through activation of the Smad signaling pathway.
Rodríguez-Pascual
Fernando
F
Departamento de Estructura y Función de Proteínas, Centro de Investigaciones Biológicas, C.S.I.C., Instituto Reina Sofía de Investigaciones Nefrológicas, Madrid, Spain. frodriguez@cib.csic.es
Reimunde
Francisco Manuel
FM
Redondo-Horcajo
Mariano
M
Lamas
Santiago
S
D000818:Animals; D002417:Cattle; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism*; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009154:Mutation; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000378:metabolism; D015533:Transcriptional Activation; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D015854:Up-Regulation
D019332:Endothelin-1; D011994:Recombinant Proteins; D051900:Smad3 Protein; D018808:Transcription Factor AP-1; D053773:Transforming Growth Factor beta1