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Functional cooperation between Smad proteins and activator protein-1 regulates transforming growth factor-beta-mediated induction of endothelin-1 expression.
Circ Res. 2003 Jun 27; 92(12):1288-95.CircR

Abstract

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-beta (TGF-beta) is one of the most important. It has been widely documented that TGF-beta increases ET-1 mRNA and peptide levels. We have explored the mechanism by which TGF-beta upregulates ET-1 expression in endothelial cells. Transcriptional activation of the ET-1 promoter accounted for the TGF-beta-induced increase in ET-1 mRNA levels. We have identified within the ET-1 promoter two DNA elements indispensable for TGF-beta-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-beta 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-beta-induced transcriptional activation of the ET-1 gene.

Authors+Show Affiliations

Departamento de Estructura y Función de Proteínas, Centro de Investigaciones Biológicas, C.S.I.C., Instituto Reina Sofía de Investigaciones Nefrológicas, Velázquez 144, E-28006 Madrid, Spain. frodriguez@cib.csic.esNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

12764024

Citation

Rodríguez-Pascual, Fernando, et al. "Functional Cooperation Between Smad Proteins and Activator Protein-1 Regulates Transforming Growth Factor-beta-mediated Induction of Endothelin-1 Expression." Circulation Research, vol. 92, no. 12, 2003, pp. 1288-95.
Rodríguez-Pascual F, Redondo-Horcajo M, Lamas S. Functional cooperation between Smad proteins and activator protein-1 regulates transforming growth factor-beta-mediated induction of endothelin-1 expression. Circ Res. 2003;92(12):1288-95.
Rodríguez-Pascual, F., Redondo-Horcajo, M., & Lamas, S. (2003). Functional cooperation between Smad proteins and activator protein-1 regulates transforming growth factor-beta-mediated induction of endothelin-1 expression. Circulation Research, 92(12), 1288-95.
Rodríguez-Pascual F, Redondo-Horcajo M, Lamas S. Functional Cooperation Between Smad Proteins and Activator Protein-1 Regulates Transforming Growth Factor-beta-mediated Induction of Endothelin-1 Expression. Circ Res. 2003 Jun 27;92(12):1288-95. PubMed PMID: 12764024.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Functional cooperation between Smad proteins and activator protein-1 regulates transforming growth factor-beta-mediated induction of endothelin-1 expression. AU - Rodríguez-Pascual,Fernando, AU - Redondo-Horcajo,Mariano, AU - Lamas,Santiago, Y1 - 2003/05/22/ PY - 2003/5/24/pubmed PY - 2003/9/25/medline PY - 2003/5/24/entrez SP - 1288 EP - 95 JF - Circulation research JO - Circ Res VL - 92 IS - 12 N2 - 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-beta (TGF-beta) is one of the most important. It has been widely documented that TGF-beta increases ET-1 mRNA and peptide levels. We have explored the mechanism by which TGF-beta upregulates ET-1 expression in endothelial cells. Transcriptional activation of the ET-1 promoter accounted for the TGF-beta-induced increase in ET-1 mRNA levels. We have identified within the ET-1 promoter two DNA elements indispensable for TGF-beta-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-beta 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-beta-induced transcriptional activation of the ET-1 gene. SN - 1524-4571 UR - https://www.unboundmedicine.com/medline/citation/12764024/Functional_cooperation_between_Smad_proteins_and_activator_protein_1_regulates_transforming_growth_factor_beta_mediated_induction_of_endothelin_1_expression_ L2 - https://www.ahajournals.org/doi/10.1161/01.RES.0000078491.79697.7F?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -