This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart 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 Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Higgins, K. J. Articles by Safe, S. Search for Related Content PubMed PubMed Citation Articles by Higgins, K. J. Articles by Safe, S.

Vascular Endothelial Growth Factor Receptor-2 Expression Is Induced by 17ß-Estradiol in ZR-75 Breast Cancer Cells by Estrogen Receptor /Sp Proteins

Departments of Biochemistry and Biophysics (K.J.H., S.S.), Veterinary Physiology and Pharmacology (K.V., S.S.), and Veterinary Integrated Biosciences (W.P., R.P.M.), Texas A&M University, College Station, Texas 77843; and Institute of Biosciences and Technology (S.L., M.A., K.Y., S.S.), Texas A&M Health Science Center, Houston, Texas 77030

Address all correspondence and requests for reprints to: Stephen Safe, Department of Veterinary Physiology and Pharmacology, Texas A&M University, 4466 Texas A&M University, College Station, Texas 77843-4466. E-mail: ssafe{at}cvm.tamu.edu.

Vascular endothelial growth factor receptor-2 kinase insert domain receptor (VEGFR2/KDR) is critical for angiogenesis, and VEGFR2 mRNA and protein are expressed in ZR-75 breast cancer cells and induced by 17ß-estradiol (E2). Deletion analysis of the VEGFR2 promoter indicates that the proximal GC-rich region is required for both basal and hormone-induced transactivation, and mutation of one or both of the GC-rich motifs at –58 and –44 results in loss of transactivation. Electrophoretic mobility shift and chromatin immunoprecipitation assays show that Sp1, Sp3, and Sp4 proteins bind the GC-rich region of the VEGFR2 promoter. Results of the chromatin immunoprecipitation assay also demonstrate that ER is constitutively bound to the VEGFR2 promoter and that these interactions are not enhanced after treatment with E2, whereas ER binding to the region of the pS2 promoter containing an estrogen-responsive element is enhanced by E2. RNA interference studies show that hormone-induced activation of the VEGFR2 promoter constructs requires Sp3 and Sp4 but not Sp1, demonstrating that hormonal activation of VEGFR2 involves a nonclassical mechanism in which ER/Sp3 and ER/Sp4 complexes activate GC-rich sites where Sp proteins but not ER bind DNA. These results show for the first time that Sp3 and Sp4 cooperatively interact with ER to activate VEGFR2 and are in contrast to previous results showing that several hormone-responsive genes are activated by ER/Sp1 in breast cancer cell lines.

This article has been cited by other articles:

				F. Wu, I. Ivanov, R. Xu, and S. Safe Role of SP transcription factors in hormone-dependent modulation of genes in MCF-7 breast cancer cells: microarray and RNA interference studies J. Mol. Endocrinol., January 1, 2009; 42(1): 19 - 33. [Abstract] [Full Text] [PDF]

				F. Wu, R. Xu, K. Kim, J. Martin, and S. Safe In Vivo Profiling of Estrogen Receptor/Specificity Protein-Dependent Transactivation Endocrinology, November 1, 2008; 149(11): 5696 - 5705. [Abstract] [Full Text] [PDF]

				N. Kimura, N. Takamatsu, Y. Yaoita, R Y. Osamura, and N. Kimura Identification of transcriptional regulatory elements in the human somatostatin receptor sst2 promoter and regions including estrogen response element half-site for estrogen activation J. Mol. Endocrinol., February 1, 2008; 40(2): 75 - 91. [Abstract] [Full Text] [PDF]

				K. J. Higgins, S. Liu, M. Abdelrahim, K. Vanderlaag, X. Liu, W. Porter, R. Metz, and S. Safe Vascular Endothelial Growth Factor Receptor-2 Expression Is Down-Regulated by 17{beta}-Estradiol in MCF-7 Breast Cancer Cells by Estrogen Receptor {alpha}/Sp Proteins Mol. Endocrinol., February 1, 2008; 22(2): 388 - 402. [Abstract] [Full Text] [PDF]

				S. U. Mertens-Talcott, S. Chintharlapalli, X. Li, and S. Safe The Oncogenic microRNA-27a Targets Genes That Regulate Specificity Protein Transcription Factors and the G2-M Checkpoint in MDA-MB-231 Breast Cancer Cells Cancer Res., November 15, 2007; 67(22): 11001 - 11011. [Abstract] [Full Text] [PDF]

				J.-M. Sun, H. Y. Chen, and J. R. Davie Differential Distribution of Unmodified and Phosphorylated Histone Deacetylase 2 in Chromatin J. Biol. Chem., November 9, 2007; 282(45): 33227 - 33236. [Abstract] [Full Text] [PDF]

				S. Khan, F. Wu, S. Liu, Q. Wu, and S. Safe Role of specificity protein transcription factors in estrogen-induced gene expression in MCF-7 breast cancer cells J. Mol. Endocrinol., October 1, 2007; 39(4): 289 - 304. [Abstract] [Full Text] [PDF]

				P. Kundu, A. Alioua, E. Stefani, and L. Toro Regulation of Mouse Slo Gene Expression: MULTIPLE PROMOTERS, TRANSCRIPTION START SITES, AND GENOMIC ACTION OF ESTROGEN J. Biol. Chem., September 14, 2007; 282(37): 27478 - 27492. [Abstract] [Full Text] [PDF]

				A. Shatnawi, T. Tran, and M. Ratnam R5020 and RU486 Act as Progesterone Receptor Agonists to Enhance Sp1/Sp4-Dependent Gene Transcription by an Indirect Mechanism Mol. Endocrinol., March 1, 2007; 21(3): 635 - 650. [Abstract] [Full Text] [PDF]