In:
Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 92, No. 12 ( 2003-06-27), p. 1288-1295
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-β (TGF-β) is one of the most important. It has been widely documented that TGF-β increases ET-1 mRNA and peptide levels. We have explored the mechanism by which TGF-β upregulates ET-1 expression in endothelial cells. Transcriptional activation of the ET-1 promoter accounted for the TGF-β–induced increase in ET-1 mRNA levels. We have identified within the ET-1 promoter two DNA elements indispensable for TGF-β–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-β 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-β–induced transcriptional activation of the ET-1 gene.
Type of Medium:
Online Resource
ISSN:
0009-7330
,
1524-4571
DOI:
10.1161/01.RES.0000078491.79697.7F
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2003
detail.hit.zdb_id:
1467838-X
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