RGD Reference Report - Ets-1 stimulates platelet-derived growth factor A-chain gene transcription and vascular smooth muscle cell growth via cooperative interactions with Sp1. - Rat Genome Database

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Ets-1 stimulates platelet-derived growth factor A-chain gene transcription and vascular smooth muscle cell growth via cooperative interactions with Sp1.

Authors: Santiago, FS  Khachigian, LM 
Citation: Santiago FS and Khachigian LM, Circ Res. 2004 Sep 3;95(5):479-87. Epub 2004 Aug 5.
RGD ID: 2313716
Pubmed: PMID:15297375   (View Abstract at PubMed)
DOI: DOI:10.1161/01.RES.0000141135.36279.67   (Journal Full-text)

The platelet-derived growth factor (PDGF) family of ligands (composed of A-, B-, C-, and D-chains), potent mitogens, and chemoattractants for cells of mesenchymal origin has been implicated in numerous vascular pathologies involving smooth muscle cell (SMC) hyperplasia. Understanding the molecular mechanisms mediating PDGF transcription would provide new insights into strategies to control PDGF-dependent pathophysiologic processes. We demonstrated previously that PDGF-A expression is under the positive regulatory influence of Sp1, Sp3, and Egr-1 and is negatively controlled by GCF2, NF-1(X), and WT-1. In this article, we demonstrate that Ets-1 induces PDGF-A expression in primary rat aortic SMCs at the level of transcription and mRNA expression. Electrophoretic mobility shift, supershift, and mutational analyses revealed a functional role for the (-555)TTCC(-552) motif in the PDGF-A promoter that binds endogenous Ets-1. Chromatin immunoprecipitation analysis showed the interaction of endogenous and exogenous Ets-1 or glutathione S-transferase-tagged Ets-1, bearing only the DNA-binding domain with the authentic PDGF-A promoter. Conversely, dominant-negative mutant of Ets-1 blocked the promoter interaction of endogenous Ets-1. Overexpression of Ets-1 but not the mutant form of Ets-1 activates the PDGF-A promoter cooperatively with Sp1. Sp1, which interacts with Ets-1, failed to induce PDGF-A promoter-dependent expression if the promoter contained a site-specific mutation in this novel Ets-binding site. Small interfering RNA to Ets-1 and Sp1 blocked PDGF-BB- and serum-inducible PDGF-A expression. SMC growth was stimulated by Ets-1 and Sp1 separately and further increased by both factors together. Ets-1-inducible mitogenesis is blocked by antibodies neutralizing PDGF-A and involves activation of the PDGF alpha-receptor, which binds PDGF-A. These findings identify a functional cis-acting element for Ets-1 in the PDGF-A promoter and demonstrate that Sp1 and Ets-1 cooperatively activate PDGF-A transcription in vascular SMCs.




Molecular Function

  
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Original Reference(s)
Ets1Ratprotein binding  IPISp1 (Rattus norvegicus) RGD 


Genes (Rattus norvegicus)
Ets1  (ETS proto-oncogene 1, transcription factor)