This Article Full Text Full Text (PDF) All Versions of this Article: 95/5/479    most recent 01.RES.0000141135.36279.67v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Santiago, F. S. Articles by Khachigian, L. M. Search for Related Content PubMed PubMed Citation Articles by Santiago, F. S. Articles by Khachigian, L. M. Related Collections Gene expression Gene regulation Growth factors/cytokines

Ets-1 Stimulates Platelet-Derived Growth Factor A-Chain Gene Transcription and Vascular Smooth Muscle Cell Growth via Cooperative Interactions With Sp1

From the Centre for Vascular Research, The University of New South Wales, and the Department of Haematology, The Prince of Wales Hospital, Sydney, Australia.

Correspondence to Levon M. Khachigian, PhD, Centre for Vascular Research, Department of Pathology, The University of New South Wales, Sydney NSW 2052, Australia. E-mail L.Khachigian{at}unsw.edu.au

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 ^–555TTCC^–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 -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.

Key Words: Ets-1 • smooth muscle cells • transcription • growth • Sp1 • autocrine

This article has been cited by other articles:

				D. D. Pearse, R.-X. Tian, J. Nigro, J. B. Iorgulescu, L. Puzis, and E. A. Jaimes Angiotensin II increases the expression of the transcription factor ETS-1 in mesangial cells Am J Physiol Renal Physiol, May 1, 2008; 294(5): F1094 - F1100. [Abstract] [Full Text] [PDF]

				L. Sun, M. E. Diamond, A. J. Ottaviano, M. J. Joseph, V. Ananthanarayan, and H. G. Munshi Transforming Growth Factor-{beta}1 Promotes Matrix Metalloproteinase-9-Mediated Oral Cancer Invasion through Snail Expression Mol. Cancer Res., January 1, 2008; 6(1): 10 - 20. [Abstract] [Full Text] [PDF]

				M. F. Crook, M. Olive, H.-H. Xue, T. H. Langenickel, M. Boehm, W. J. Leonard, and E. G. Nabel GA-binding protein regulates KIS gene expression, cell migration, and cell cycle progression FASEB J, January 1, 2008; 22(1): 225 - 235. [Abstract] [Full Text] [PDF]

				J. Jiang, Y. Wei, J. Shen, D. Liu, X. Chen, J. Zhou, H. Zong, X. Yun, X. Kong, S. Zhang, et al. Functional Interaction of E1AF and Sp1 in Glioma Invasion Mol. Cell. Biol., December 15, 2007; 27(24): 8770 - 8782. [Abstract] [Full Text] [PDF]

				T. Sato and K. Furukawa Sequential Action of Ets-1 and Sp1 in the Activation of the Human beta-1,4-Galactosyltransferase V Gene Involved in Abnormal Glycosylation Characteristic of Cancer Cells J. Biol. Chem., September 21, 2007; 282(38): 27702 - 27712. [Abstract] [Full Text] [PDF]

				P. Oettgen Regulation of Vascular Inflammation and Remodeling by ETS Factors Circ. Res., November 24, 2006; 99(11): 1159 - 1166. [Abstract] [Full Text] [PDF]

				H. Nakatsuka, T. Sokabe, K. Yamamoto, Y. Sato, K. Hatakeyama, A. Kamiya, and J. Ando Shear stress induces hepatocyte PAI-1 gene expression through cooperative Sp1/Ets-1 activation of transcription Am J Physiol Gastrointest Liver Physiol, July 1, 2006; 291(1): G26 - G34. [Abstract] [Full Text] [PDF]

				M. Y. Liu, M. Eyries, C. Zhang, F. S. Santiago, and L. M. Khachigian Inducible platelet-derived growth factor D-chain expression by angiotensin II and hydrogen peroxide involves transcriptional regulation by Ets-1 and Sp1 Blood, March 15, 2006; 107(6): 2322 - 2329. [Abstract] [Full Text] [PDF]

				M. R. Bonello, Y. V. Bobryshev, and L. M. Khachigian Peroxide-Inducible Ets-1 Mediates Platelet-Derived Growth Factor Receptor-{alpha} Gene Transcription in Vascular Smooth Muscle Cells Am. J. Pathol., October 1, 2005; 167(4): 1149 - 1159. [Abstract] [Full Text] [PDF]