© 1999 American Heart Association, Inc.
Original Contribution |
Role of the Ets Transcription Factors in the Regulation of the Vascular-Specific Tie2 Gene
From the New England Baptist Bone and Joint Institute (A.D., Y.A., T.A.L. P.O.) and the Division of Cardiology (A.D., P.O.), Beth Israel Deaconess Medical Center, Boston, Mass; and the University of Texas Southwestern Medical Center (T.N.S.), Dallas, Texas.
Correspondence to Peter Oettgen, MD, Division of Cardiology, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Boston MA 02215. E-mail joettgen{at}BIDMC.harvard.edu
Abstract—The Tie2 gene encodes a vascular endothelium-specific receptor tyrosine kinase that is required for normal vascular development and is also upregulated during angiogenesis. The regulatory regions of the Tie2 gene that are required for endothelium-specific gene expression in vivo have been identified. However, the transcription factors required for Tie2 gene expression remain largely unknown. We have identified highly conserved binding sites for Ets transcription factors in the Tie2 promoter. Mutations in 2 particular binding sites lead to a 50% reduction in the endothelium-specific activity of the promoter. We have compared the ability of several members of the Ets family to transactivate the Tie2 promoter. Our results demonstrate that 1 of 3 distinct isoforms of the novel Ets transcription factor NERF, NERF2, is expressed in endothelial cells and can strongly transactivate the regulatory regions of the Tie2 gene in comparison to other Ets factors, which have little or no effect. NERF2 can bind to the Tie2 promoter Ets sites in electrophoretic mobility shift assays. These studies support a role for Ets factors in the regulation of vascular-specific gene expression and suggest that the novel Ets factor NERF2 may be a critical transcription factor in specifying the expression of the Tie2 gene in vascular endothelial cells.
Key Words: transcription • vasculogenesis • Tie2 • angiogenesis
This article has been cited by other articles:
 |
|
 |
|
  L. Yuan, V. Nikolova-Krstevski, Y. Zhan, M. Kondo, M. Bhasin, L. Varghese, K. Yano, C. V. Carman, W. C. Aird, and P. Oettgen Antiinflammatory Effects of the ETS Factor ERG in Endothelial Cells Are Mediated Through Transcriptional Repression of the Interleukin-8 Gene Circ. Res., May 8, 2009; 104(9): 1049 - 1057. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Okada, E. Jin, V. Nikolova-Krstevski, K. Yano, J. Liu, D. Beeler, K. Spokes, M. Kitayama, N. Funahashi, T. Doi, et al. A GABP-binding element in the Robo4 promoter is necessary for endothelial expression in vivo Blood, September 15, 2008; 112(6): 2336 - 2339. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Dutta, S. Ray, J. L. Vivian, and S. Paul Activation of the VEGFR1 Chromatin Domain: AN ANGIOGENIC SIGNAL-ETS1/HIF-2{alpha} REGULATORY AXIS J. Biol. Chem., September 12, 2008; 283(37): 25404 - 25413. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Okada, K. Yano, E. Jin, N. Funahashi, M. Kitayama, T. Doi, K. Spokes, D. L. Beeler, S.-C. Shih, H. Okada, et al. A Three-Kilobase Fragment of the Human Robo4 Promoter Directs Cell Type-Specific Expression in Endothelium Circ. Res., June 22, 2007; 100(12): 1712 - 1722. [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]
|
|
|
|
|
|
X. Huang, C. Brown, W. Ni, E. Maynard, A. C. Rigby, and P. Oettgen Critical role for the Ets transcription factor ELF-1 in the development of tumor angiogenesis Blood, April 15, 2006; 107(8): 3153 - 3160. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. E. Fish, C. C. Matouk, A. Rachlis, S. Lin, S. C. Tai, C. D'Abreo, and P. A. Marsden The Expression of Endothelial Nitric-oxide Synthase Is Controlled by a Cell-specific Histone Code J. Biol. Chem., July 1, 2005; 280(26): 24824 - 24838. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Arora, J. Kaur, C. Sharma, M. Mathur, S. Bahadur, N. K. Shukla, S. V.S. Deo, and R. Ralhan Stromelysin 3, Ets-1, and Vascular Endothelial Growth Factor Expression in Oral Precancerous and Cancerous Lesions: Correlation with Microvessel Density, Progression, and Prognosis Clin. Cancer Res., March 15, 2005; 11(6): 2272 - 2284. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Hegen, S. Koidl, K. Weindel, D. Marme, H. G. Augustin, and U. Fiedler Expression of Angiopoietin-2 in Endothelial Cells Is Controlled by Positive and Negative Regulatory Promoter Elements Arterioscler. Thromb. Vasc. Biol., October 1, 2004; 24(10): 1803 - 1809. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-Y. Cho, Y. Akbarali, L. F. Zerbini, X. Gu, J. Boltax, Y. Wang, P. Oettgen, D.-E. Zhang, and T. A. Libermann Isoforms of the Ets Transcription Factor NERF/ELF-2 Physically Interact with AML1 and Mediate Opposing Effects on AML1-mediated Transcription of the B Cell-specific blk Gene J. Biol. Chem., May 7, 2004; 279(19): 19512 - 19522. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Watanabe, H. Takagi, K. Suzuma, I. Suzuma, H. Oh, H. Ohashi, S. Kemmochi, A. Uemura, T. Ojima, E. Suganami, et al. Transcription Factor Ets-1 Mediates Ischemia- and Vascular Endothelial Growth Factor-Dependent Retinal Neovascularization Am. J. Pathol., May 1, 2004; 164(5): 1827 - 1835. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Morikawa and P. Cserjesi Extra-embryonic vasculature development is regulated by the transcription factor HAND1 Development, May 1, 2004; 131(9): 2195 - 2204. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Brown, J. Gaspar, A. Pettit, R. Lee, X. Gu, H. Wang, C. Manning, C. Voland, S. R. Goldring, M. B. Goldring, et al. ESE-1 Is a Novel Transcriptional Mediator of Angiopoietin-1 Expression in the Setting of Inflammation J. Biol. Chem., March 26, 2004; 279(13): 12794 - 12803. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Ryan and C. D. Sigmund HPRT Targeting: "Ets" A Powerful Tool For Investigating Endothelial-Cell Specific Gene Expression Arterioscler. Thromb. Vasc. Biol., November 1, 2003; 23(11): 1960 - 1962. [Full Text] [PDF]
|
|
|
|
|
|
T. Minami, J. A. Kuivenhoven, V. Evans, T. Kodama, R. D. Rosenberg, and W. C. Aird Ets Motifs Are Necessary for Endothelial Cell-Specific Expression of a 723-bp Tie-2 Promoter/Enhancer in Hprt Targeted Transgenic Mice Arterioscler. Thromb. Vasc. Biol., November 1, 2003; 23(11): 2041 - 2047. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. J. Favre, M. Mancuso, K. Maas, J. W. McLean, P. Baluk, and D. M. McDonald Expression of genes involved in vascular development and angiogenesis in endothelial cells of adult lung Am J Physiol Heart Circ Physiol, November 1, 2003; 285(5): H1917 - H1938. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y.-H. Chen, M. D. Layne, S. W. Chung, K. Ejima, R. M. Baron, S.-F. Yet, and M. A. Perrella Elk-3 Is a Transcriptional Repressor of Nitric-oxide Synthase 2 J. Biol. Chem., October 10, 2003; 278(41): 39572 - 39577. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. B. Rance, G. A. Follows, P. N. Cockerill, C. Bonifer, D. A. Lane, and R. E. Simmonds Regulation of the human endothelial cell protein C receptor gene promoter by multiple Sp1 binding sites Blood, June 1, 2003; 101(11): 4393 - 4401. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Elvert, A. Kappel, R. Heidenreich, U. Englmeier, S. Lanz, T. Acker, M. Rauter, K. Plate, M. Sieweke, G. Breier, et al. Cooperative Interaction of Hypoxia-inducible Factor-2alpha (HIF-2alpha ) and Ets-1 in the Transcriptional Activation of Vascular Endothelial Growth Factor Receptor-2 (Flk-1) J. Biol. Chem., February 21, 2003; 278(9): 7520 - 7530. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Lelievre, F. Lionneton, V. Mattot, N. Spruyt, and F. Soncin Ets-1 Regulates fli-1 Expression in Endothelial Cells. IDENTIFICATION OF ETS BINDING SITES IN THE fli-1 GENE PROMOTER J. Biol. Chem., July 5, 2002; 277(28): 25143 - 25151. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Gaspar, S. Thai, C. Voland, A. Dube, T. A. Libermann, M.L. Iruela-Arispe, and P. Oettgen Opposing Functions of the Ets Factors NERF and ELF-1 During Chicken Blood Vessel Development Arterioscler. Thromb. Vasc. Biol., July 1, 2002; 22(7): 1106 - 1112. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H.-D. Orzechowski, A. Gunther, S. Menzel, A. Zimmermann, H. Funke-Kaiser, R. Real, T. Subkowski, F. S. Zollmann, and M. Paul Transcriptional Mechanism of Protein Kinase C-Induced Isoform-Specific Expression of the Gene for Endothelin-Converting Enzyme-1in Human Endothelial Cells Mol. Pharmacol., December 1, 2001; 60(6): 1332 - 1342. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. McLaughlin, V. J. Ludbrook, J. Cox, I. von Carlowitz, S. Brown, and A. M. Randi Combined genomic and antisense analysis reveals that the transcription factor Erg is implicated in endothelial cell differentiation Blood, December 1, 2001; 98(12): 3332 - 3339. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Aitsebaomo, M. L. Kingsley-Kallesen, Y. Wu, T. Quertermous, and C. Patterson Vezf1/DB1 Is an Endothelial Cell-specific Transcription Factor That Regulates Expression of the Endothelin-1 Promoter J. Biol. Chem., October 12, 2001; 276(42): 39197 - 39205. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Oettgen Transcriptional Regulation of Vascular Development Circ. Res., August 31, 2001; 89(5): 380 - 388. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. D. Ramsden, H. C. Cocks, M. Shams, S. Nijjar, J. C. Watkinson, M. C. Sheppard, A. Ahmed, and M. C. Eggo Tie-2 Is Expressed on Thyroid Follicular Cells, Is Increased in Goiter, and Is Regulated by Thyrotropin through Cyclic Adenosine 3',5'-Monophosphate J. Clin. Endocrinol. Metab., June 1, 2001; 86(6): 2709 - 2716. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Dube, S. Thai, J. Gaspar, S. Rudders, T. A. Libermann, L. Iruela-Arispe, and P. Oettgen ELF-1 Is a Transcriptional Regulator of the Tie2 Gene During Vascular Development Circ. Res., February 2, 2001; 88(2): 237 - 244. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. M. Schwartz The Definition of Cell Type Circ. Res., May 28, 1999; 84(10): 1234 - 1235. [Full Text] [PDF]
|
|
|
|
 |
|
 F McLaughlin, V. Ludbrook, I Kola, C. Campbell, and A. Randi Characterisation of the tumour necrosis factor (TNF)-(alpha) response elements in the human ICAM-2 promoter J. Cell Sci., January 12, 1999; 112(24): 4695 - 4703. [Abstract] [PDF]
|
|
|
|
|
|
Y. Laumonnier, S. Nadaud, M. Agrapart, and F. Soubrier Characterization of an Upstream Enhancer Region in the Promoter of the Human Endothelial Nitric-oxide Synthase Gene J. Biol. Chem., December 22, 2000; 275(52): 40732 - 40741. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Rudders, J. Gaspar, R. Madore, C. Voland, F. Grall, A. Patel, A. Pellacani, M. A. Perrella, T. A. Libermann, and P. Oettgen ESE-1 Is a Novel Transcriptional Mediator of Inflammation That Interacts with NF-kappa B to Regulate the Inducible Nitric-oxide Synthase Gene J. Biol. Chem., January 26, 2001; 276(5): 3302 - 3309. [Abstract] [Full Text] [PDF]
|
|