Endothelial Transcriptional Networks in the Control of Angiogenesis: the ETS Factor

  • Anna M. RandiEmail author


Endothelial gene expression is controlled by a few families of transcription factors (TF) which form regulatory networks. Amongst the most important are the ETS factors, a large family of which at least 19 members are expressed in human endothelial cells at some point throughout development. Through interaction with other TF families and co-regulators, ETS factors control most aspects of endothelial biology, from early differentiation in the embryo to homeostasis, angiogenesis and inflammation in the adult. Several ETS family members have been shown to be essential for vascular development and angiogenesis and to regulate processes from cell migration to survival and growth. Amongst the list of ETS targets genes involved in angiogenic pathways are growth factor receptors for vascular endothelial growth factor and angiopoietins. ETS factors also control cell adhesion, matrix remodelling and cytoskeletal dynamics, processes essential for tissue homeostasis, which therefore influence the viability and stability of new vascular networks. Most ETS proteins have been shown to activate transcription; however, a few can also act as transcriptional repressors. Several ETS factors can control the same target genes, raising the question of possible redundancy in the system. Data from a variety of in vivo models are shedding new light on the different roles of ETS factors in vascular development, adult angiogenesis and endothelial homeostasis. In this review some general properties of ETS factors in the endothelium are discussed and then two of the best characterised ETS proteins in endothelial cells, Ets-1 and Erg, which exemplify the complex picture of distinct and overlapping targets and functions, are presented.


ETS transcription factors Angiogenesis Endothelial homeostasis Ets-1 Erg 



The unpublished work mentioned in this chapter has been supported by grants from the British Heart Foundation. My thanks to Dr. Graeme Birdsey (Imperial College London, UK) for his invaluable contribution to my laboratory over many years, to Prof. Dorian Haskard (Imperial College London, UK) for his support and encouragement and to Prof. Justin Mason (Imperial College London, UK) for his continuous support and for critical reading of the manuscript.


  1. 1.
    Bartel FO, Higuchi T, Spyropoulos DD (2000) Mouse models in the study of the Ets family of transcription factors. Oncogene 19:6443–6454PubMedGoogle Scholar
  2. 2.
    Seth A, Watson DK (2005) ETS transcription factors and their emerging roles in human cancer. Eur J Cancer 41:2462–2478PubMedGoogle Scholar
  3. 3.
    Oettgen P (2010) The role of ets factors in tumor angiogenesis. J Oncol 2010:767384PubMedCentralPubMedGoogle Scholar
  4. 4.
    Dittmer J, Nordheim A (1998) Ets transcription factors and human disease. Biochim Biophys Acta 1377:F1–F11PubMedGoogle Scholar
  5. 5.
    Oettgen P (2006) Regulation of vascular inflammation and remodeling by ETS factors. Circ Res 99:1159–1166PubMedGoogle Scholar
  6. 6.
    Randi AM, Sperone A, Dryden NH, Birdsey GM (2009) Regulation of angiogenesis by ETS transcription factors. Biochem Soc Trans 37:1248–1253PubMedGoogle Scholar
  7. 7.
    Vrieseling E, Arber S (2006) Target-induced transcriptional control of dendritic patterning and connectivity in motor neurons by the ETS gene Pea3. Cell 127:1439–1452PubMedGoogle Scholar
  8. 8.
    Leprince D, Gegonne A, Coll J, de Taisne C, Schneeberger A, Lagrou C, Stehelin D (1983) A putative second cell-derived oncogene of the avian leukaemia retrovirus E26. Nature 306:395–397PubMedGoogle Scholar
  9. 9.
    Hollenhorst PC, Shah AA, Hopkins C, Graves BJ (2007) Genome-wide analyses reveal properties of redundant and specific promoter occupancy within the ETS gene family. Genes Dev 21:1882–1894PubMedGoogle Scholar
  10. 10.
    Bult CJ, Eppig JT, Kadin JA, Richardson JE, Blake JA (2008) The mouse genome database (MGD): mouse biology and model systems. Nucleic Acids Res 36:D724–D728PubMedCentralPubMedGoogle Scholar
  11. 11.
    Sharrocks AD (2001) The ETS-domain transcription factor family. Nat Rev Mol Cell Biol 2:827–837PubMedGoogle Scholar
  12. 12.
    Batchelor AH, Piper DE, de la Brousse FC, McKnight SL, Wolberger C (1998) The structure of GABPalpha/beta: an ETS domain- ankyrin repeat heterodimer bound to DNA. Science 279:1037–1041PubMedGoogle Scholar
  13. 13.
    Lamber EP, Vanhille L, Textor LC, Kachalova GS, Sieweke MH, Wilmanns M (2008) Regulation of the transcription factor Ets-1 by DNA-mediated homo-dimerization. EMBO J 27:2006–2017PubMedGoogle Scholar
  14. 14.
    Hollenhorst PC, McIntosh LP, Graves BJ (2011) Genomic and biochemical insights into the specificity of ETS transcription factors. Annu Rev Biochem 80:437–471PubMedGoogle Scholar
  15. 15.
    Yang L, Xia L, Wu DY, Wang H, Chansky HA, Schubach WH, Hickstein DD, Zhang Y (2002) Molecular cloning of ESET, a novel histone H3-specific methyltransferase that interacts with ERG transcription factor. Oncogene 21:148–152PubMedGoogle Scholar
  16. 16.
    Mackereth CD, Scharpf M, Gentile LN, MacIntosh SE, Slupsky CM, McIntosh LP (2004) Diversity in structure and function of the Ets family PNT domains. J Mol Biol 342:1249–1264PubMedGoogle Scholar
  17. 17.
    Carrere S, Verger A, Flourens A, Stehelin D, Duterque-Coquillaud M (1998) Erg proteins, transcription factors of the Ets family, form homo, heterodimers and ternary complexes via two distinct domains. Oncogene 16:3261–3268PubMedGoogle Scholar
  18. 18.
    Reddy SY, Obika S, Bruice TC (2003) Conformations and dynamics of Ets-1 ETS domain-DNA complexes. Proc Natl Acad Sci USA 100:15475–15480PubMedGoogle Scholar
  19. 19.
    Obika S, Reddy SY, Bruice TC (2003) Sequence specific DNA binding of Ets-1 transcription factor: molecular dynamics study on the Ets domain–DNA complexes. J Mol Biol 331:345–359PubMedGoogle Scholar
  20. 20.
    Hsu T, Trojanowska M, Watson DK (2004) Ets proteins in biological control and cancer. J Cell Biochem 91:896–903PubMedCentralPubMedGoogle Scholar
  21. 21.
    Wei GH, Badis G, Berger MF, Kivioja T, Palin K, Enge M, Bonke M, Jolma A, Varjosalo M, Gehrke AR, Yan J, Talukder S, Turunen M, Taipale M, Stunnenberg HG, Ukkonen E, Hughes TR, Bulyk ML, Taipale J (2010) Genome-wide analysis of ETS-family DNA-binding in vitro and in vivo. EMBO J 29:2147–2160PubMedGoogle Scholar
  22. 22.
    Basuyaux JP, Ferreira E, Stehelin D, Buttice G (1997) The Ets transcription factors interact with each other and with the c-Fos/c-Jun complex via distinct protein domains in a DNA-dependent and -independent manner. J Biol Chem 272:26188–26195PubMedGoogle Scholar
  23. 23.
    Green SM, Coyne HJ III, McIntosh LP, Graves BJ (2010) DNA binding by the ETS protein TEL (ETV6) is regulated by autoinhibition and self-association. J Biol Chem 285:18496–18504PubMedGoogle Scholar
  24. 24.
    Li R, Pei H, Watson DK (2000) Regulation of Ets function by protein–protein interactions. Oncogene 19:6514–6523PubMedGoogle Scholar
  25. 25.
    Seidel JJ, Graves BJ (2002) An ERK2 docking site in the Pointed domain distinguishes a subset of ETS transcription factors. Genes Dev 16:127–137PubMedGoogle Scholar
  26. 26.
    Foulds CE, Nelson ML, Blaszczak AG, Graves BJ (2004) Ras/mitogen-activated protein kinase signaling activates Ets-1 and Ets-2 by CBP/p300 recruitment. Mol Cell Biol 24:10954–10964PubMedCentralPubMedGoogle Scholar
  27. 27.
    Lopez RG, Carron C, Oury C, Gardellin P, Bernard O, Ghysdael J (1999) TEL is a sequence-specific transcriptional repressor. J Biol Chem 274:30132–30138PubMedGoogle Scholar
  28. 28.
    Lelievre E, Lionneton F, Soncin F, Vandenbunder B (2001) The Ets family contains transcriptional activators and repressors involved in angiogenesis. Int J Biochem Cell Biol 33:391–407PubMedGoogle Scholar
  29. 29.
    Leprivier G, Baillat D, Begue A, Hartmann B, Aumercier M (2009) Ets-1 p51 and p42 isoforms differentially modulate Stromelysin-1 promoter according to induced DNA bend orientation. Nucleic Acids Res 37:4341–4352PubMedCentralPubMedGoogle Scholar
  30. 30.
    Sarrazin S, Starck J, Gonnet C, Doubeikovski A, Melet F, Morle F (2000) Negative and translation termination-dependent positive control of FLI-1 protein synthesis by conserved overlapping 5' upstream open reading frames in Fli-1 mRNA. Mol Cell Biol 20:2959–2969PubMedCentralPubMedGoogle Scholar
  31. 31.
    Coutte L, Monte D, Imai K, Pouilly L, Dewitte F, Vidaud M, Adamski J, Baert JL, de Launoit Y (1999) Characterization of the human and mouse ETV1/ER81 transcription factor genes: role of the two alternatively spliced isoforms in the human. Oncogene 18:6278–6286PubMedGoogle Scholar
  32. 32.
    DuterqueCoquillaud M, Niel C, Plaza S, Stehelin D (1993) New human erg isoforms generated by alternative splicing are transcriptional activators. Oncogene 8:1865–1873Google Scholar
  33. 33.
    Owczarek CM, Portbury KJ, Hardy MP, O’Leary DA, Kudoh J, Shibuya K, Shimizu N, Kola I, Hertzog PJ (2004) Detailed mapping of the ERG-ETS2 interval of human chromosome 21 and comparison with the region of conserved synteny on mouse chromosome 16. Gene 324:65–77PubMedGoogle Scholar
  34. 34.
    Sasaki K, Nakamura Y, Maki K, Waga K, Nakamura F, Arai H, Imai Y, Hirai H, Mitani K (2004) Functional analysis of a dominant-negative DeltaETS TEL/ETV6 isoform. Biochem Biophys Res Commun 317:1128–1137PubMedGoogle Scholar
  35. 35.
    De Haro L, Janknecht R (2005) Cloning of the murine ER71 gene (Etsrp71) and initial characterization of its promoter. Genomics 85:493–502PubMedGoogle Scholar
  36. 36.
    Lee GM, Donaldson LW, Pufall MA, Kang HS, Pot I, Graves BJ, McIntosh LP (2005) The structural and dynamic basis of Ets-1 DNA binding autoinhibition. J Biol Chem 280:7088–7099PubMedGoogle Scholar
  37. 37.
    Pufall MA, Graves BJ (2002) Ets-1 flips for new partner Pax-5. Structure 10:11–14PubMedGoogle Scholar
  38. 38.
    Laitem C, Leprivier G, Choul-Li S, Begue A, Monte D, Larsimont D, Dumont P, Duterque-Coquillaud M, Aumercier M (2009) Ets-1 p27: a novel Ets-1 isoform with dominant-negative effects on the transcriptional properties and the subcellular localization of Ets-1 p51. Oncogene 28:2087–2099PubMedGoogle Scholar
  39. 39.
    Zammarchi F, Boutsalis G, Cartegni L (2013) 5' UTR control of native ERG and of Tmprss2:ERG variants activity in prostate cancer. PLoS One 8:e49721PubMedCentralPubMedGoogle Scholar
  40. 40.
    Vijayaraj P, Le BA, Mitchell N, Kondo M, Juliao S, Wasserman M, Beeler D, Spokes K, Aird WC, Baldwin HS, Oettgen P (2012) Erg is a crucial regulator of endocardial-mesenchymal transformation during cardiac valve morphogenesis. Development 139:3973–3985PubMedGoogle Scholar
  41. 41.
    Clark J, Merson S, Jhavar S, Flohr P, Edwards S, Foster CS, Eeles R, Martin FL, Phillips DH, Crundwell M, Christmas T, Thompson A, Fisher C, Kovacs G, Cooper CS (2007) Diversity of TMPRSS2-ERG fusion transcripts in the human prostate. Oncogene 26:2667–2673PubMedGoogle Scholar
  42. 42.
    Sun C, Dobi A, Mohamed A, Li H, Thangapazham RL, Furusato B, Shaheduzzaman S, Tan SH, Vaidyanathan G, Whitman E, Hawksworth DJ, Chen Y, Nau M, Patel V, Vahey M, Gutkind JS, Sreenath T, Petrovics G, Sesterhenn IA, Mcleod DG, Srivastava S (2008) TMPRSS2-ERG fusion, a common genomic alteration in prostate cancer activates C-MYC and abrogates prostate epithelial differentiation. Oncogene 27:5348–5353PubMedGoogle Scholar
  43. 43.
    Tomlins SA, Rhodes DR, Perner S, Dhanasekaran SM, Mehra R, Sun XW, Varambally S, Cao XH, Tchinda J, Kuefer R, Lee C, Montie JE, Shah RB, Pienta KJ, Rubin MA, Chinnaiyan AM (2005) Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science 310:644–648PubMedGoogle Scholar
  44. 44.
    Tomlins SA, Mehra R, Rhodes DR, Smith LR, Roulston D, Helgesson BE, Cao XH, Wei JT, Rubin MA, Shah RB, Chinnaiyan AM (2006) TMPRSS2: ETV4 gene fusions define a third molecular subtype of prostate cancer. Cancer Res 66:3396–3400PubMedGoogle Scholar
  45. 45.
    Hu Y, Dobi A, Sreenath T, Cook C, Tadase AY, Ravindranath L, Cullen J, Furusato B, Chen Y, Thangapazham RL, Mohamed A, Sun C, Sesterhenn IA, Mcleod DG, Petrovics G, Srivastava S (2008) Delineation of TMPRSS2-ERG splice variants in prostate cancer. Clin Cancer Res 14:4719–4725PubMedGoogle Scholar
  46. 46.
    Santen RJ, Song RX, McPherson R, Kumar R, Adam L, Jeng MH, Yue W (2002) The role of mitogen-activated protein (MAP) kinase in breast cancer. J Steroid Biochem Mol Biol 80:239–256PubMedGoogle Scholar
  47. 47.
    Yang BS, Hauser CA, Henkel G, Colman MS, Van BC, Stacey KJ, Hume DA, Maki RA, Ostrowski MC (1996) Ras-mediated phosphorylation of a conserved threonine residue enhances the transactivation activities of c-Ets1 and c-Ets2. Mol Cell Biol 16:538–547PubMedCentralPubMedGoogle Scholar
  48. 48.
    Fowles LF, Martin ML, Nelsen L, Stacey KJ, Redd D, Clark YM, Nagamine Y, McMahon M, Hume DA, Ostrowski MC (1998) Persistent activation of mitogen-activated protein kinases p42 and p44 and ets-2 phosphorylation in response to colony-stimulating factor 1/c-fms signaling. Mol Cell Biol 18:5148–5156PubMedCentralPubMedGoogle Scholar
  49. 49.
    Smith JL, Schaffner AE, Hofmeister JK, Hartman M, Wei G, Forsthoefel D, Hume DA, Ostrowski MC (2000) ets-2 is a target for an akt (Protein kinase B)/jun N-terminal kinase signaling pathway in macrophages of motheaten-viable mutant mice. Mol Cell Biol 20:8026–8034PubMedCentralPubMedGoogle Scholar
  50. 50.
    Yordy JS, Muise-Helmericks RC (2000) Signal transduction and the Ets family of transcription factors. Oncogene 19:6503–6513PubMedGoogle Scholar
  51. 51.
    Rabault B, Roussel MF, Quang CT, Ghysdael J (1996) Phosphorylation of Ets1 regulates the complementation of a CSF-1 receptor impaired in mitogenesis. Oncogene 13:877–881PubMedGoogle Scholar
  52. 52.
    Elvert G, Kappel A, Heidenreich R, Englmeier U, Lanz S, Acker T, Rauter M, Plate K, Sieweke M, Breier G, Flamme I (2003) 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 278:7520–7530PubMedGoogle Scholar
  53. 53.
    Simon MP, Tournaire R, Pouyssegur J (2008) The angiopoietin-2 gene of endothelial cells is up-regulated in hypoxia by a HIF binding site located in its first intron and by the central factors GATA-2 and Ets-1. J Cell Physiol 217:809–818PubMedGoogle Scholar
  54. 54.
    Wasylyk C, Gutman A, Nicholson R, Wasylyk B (1991) The c-Ets oncoprotein activates the stromelysin promoter through the same elements as several non-nuclear oncoproteins. EMBO J 10:1127–1134PubMedGoogle Scholar
  55. 55.
    Logan SK, Garabedian MJ, Campbell CE, Werb Z (1996) Synergistic transcriptional activation of the tissue inhibitor of metalloproteinases-1 promoter via functional interaction of AP-1 and Ets-1 transcription factors. J Biol Chem 271:774–782PubMedGoogle Scholar
  56. 56.
    Buttice G, DuterqueCoquillaud M, Basuyaux JP, Carrere S, Kurkinen M, Stehelin D (1996) Erg, an Ets-family member, differentially regulates human collagenase1 (MMP1) and stromelysin1 (MMP3) gene expression by physically interacting with the Fos/Jun complex. Oncogene 13:2297–2306PubMedGoogle Scholar
  57. 57.
    Birdsey GM, Dryden NH, Shah AV, Hanna RL, Hall MD, Haskard DO, Parsons M, Mason JC, Zvelebil M, Gottgens B, Ridley AJ, Randi AM (2012) The transcription factor Erg regulates expression of histone deacetylase 6 and multiple pathways involved in endothelial cell migration and angiogenesis. Blood 119:894–903, Ref Type: GenericPubMedGoogle Scholar
  58. 58.
    Yuan L, Sacharidou A, Stratman AN, Le Bras A, Zwiers PJ, Spokes K, Bhasin M, Shih SC, Nagy JA, Molema G, Aird WC, Davis GE, Oettgen P (2011) RhoJ is an endothelial cell-restricted Rho GTPase that mediates vascular morphogenesis and is regulated by the transcription factor ERG. Blood 118:1145–1153PubMedGoogle Scholar
  59. 59.
    Iljin K, Dube A, Kontusaari S, Korhonen J, Lahtinen I, Oettgen P, Alitalo K (1999) Role of ets factors in the activity and endothelial cell specificity of the mouse Tie gene promoter. FASEB J 13:377–386PubMedGoogle Scholar
  60. 60.
    Dube A, Akbarali Y, Sato TN, Libermann TA, Oettgen P (1999) Role of the Ets transcription factors in the regulation of the vascular-specific Tie2 gene. Circ Res 84:1177–1185PubMedGoogle Scholar
  61. 61.
    Huang X, Brown C, Ni W, Maynard E, Rigby AC, Oettgen P (2006) Critical role for the Ets transcription factor ELF-1 in the development of tumor angiogenesis. Blood 107:3153–3160PubMedGoogle Scholar
  62. 62.
    Wakiya K, Begue A, Stehelin D, Shibuya M (1996) A cAMP response element and an Ets motif are involved in the transcriptional regulation of flt-1 tyrosine kinase (vascular endothelial growth factor receptor 1) gene. J Biol Chem 271:30823–30828PubMedGoogle Scholar
  63. 63.
    Meadows SM, Salanga MC, Krieg PA (2009) Kruppel-like factor 2 cooperates with the ETS family protein ERG to activate Flk1 expression during vascular development. Development 136:1115–1125PubMedGoogle Scholar
  64. 64.
    Kappel A, Schlaeger TM, Flamme I, Orkin SH, Risau W, Breier G (2000) Role of SCL/Tal-1, GATA, and ets transcription factor binding sites for the regulation of flk-1 expression during murine vascular development. Blood 96:3078–3085PubMedGoogle Scholar
  65. 65.
    Teruyama K, Abe M, Nakano T, Takahashi S, Yamada S, Sato Y (2001) Neurophilin-1 is a downstream target of transcription factor Ets-1 in human umbilical vein endothelial cells. FEBS Lett 504:1–4PubMedGoogle Scholar
  66. 66.
    Zheng H, Wasylyk C, Ayadi A, Abecassis J, Schalken JA, Rogatsch H, Wernert N, Maira SM, Multon MC, Wasylyk B (2003) The transcription factor Net regulates the angiogenic switch. Genes Dev 17:2283–2297PubMedGoogle Scholar
  67. 67.
    Hasegawa Y, Abe M, Yamazaki T, Niizeki O, Shiiba K, Sasaki I, Sato Y (2004) Transcriptional regulation of human angiopoietin-2 by transcription factor Ets-1. Biochem Biophys Res Commun 316:52–58PubMedGoogle Scholar
  68. 68.
    Roukens MG, Alloul-Ramdhani M, Baan B, Kobayashi K, Peterson-Maduro J, van Dam H, Schulte-Merker S, Baker DA (2010) Control of endothelial sprouting by a Tel-CtBP complex. Nat Cell Biol 12:933–942PubMedGoogle Scholar
  69. 69.
    Birdsey GM, Dryden NH, Amsellem V, Gebhardt F, Sahnan K, Haskard DO, Dejana E, Mason JC, Randi AM (2008) Transcription factor Erg regulates angiogenesis and endothelial apoptosis through VE-cadherin. Blood 111:3498–3506PubMedGoogle Scholar
  70. 70.
    Lelievre E, Mattot V, Huber P, Vandenbunder B, Soncin F (2000) ETS1 lowers capillary endothelial cell density at confluence and induces the expression of VE-cadherin. Oncogene 19:2438–2446PubMedGoogle Scholar
  71. 71.
    McLaughlin F, Ludbrook VJ, Kola I, Campbell CJ, Randi AM (1999) Characterisation of the tumour necrosis factor (TNF)-(alpha) response elements in the human ICAM-2 promoter. J Cell Sci 112(Pt 24):4695–4703PubMedGoogle Scholar
  72. 72.
    Okada Y, Jin E, Nikolova-Krstevski V, Yano K, Liu J, Beeler D, Spokes K, Kitayama M, Funahashi N, Doi T, Janes L, Minami T, Oettgen P, Aird WC (2008) A GABP-binding element in the Robo4 promoter is necessary for endothelial expression in vivo. Blood 112:2336–2339PubMedGoogle Scholar
  73. 73.
    Oda N, Abe M, Sato Y (1999) ETS-1 converts endothelial cells to the angiogenic phenotype by inducing the expression of matrix metalloproteinases and integrin beta3. J Cell Physiol 178:121–132PubMedGoogle Scholar
  74. 74.
    McLaughlin F, Ludbrook VJ, Cox J, von Carlowitz I, Brown S, Randi AM (2001) Combined genomic and antisense analysis reveals that the transcription factor Erg is implicated in endothelial cell differentiation. Blood 98:3332–3339PubMedGoogle Scholar
  75. 75.
    Heo SH, Choi YJ, Ryoo HM, Cho JY (2010) Expression profiling of ETS and MMP factors in VEGF-activated endothelial cells: role of MMP-10 in VEGF-induced angiogenesis. J Cell Physiol 224:734–742PubMedGoogle Scholar
  76. 76.
    Petrovic N, Bhagwat SV, Ratzan WJ, Ostrowski MC, Shapiro LH (2003) CD13/APN transcription is induced by RAS/MAPK-mediated phosphorylation of Ets-2 in activated endothelial cells. J Biol Chem 278:49358–49368PubMedGoogle Scholar
  77. 77.
    Pimanda JE, Chan WY, Donaldson IJ, Bowen M, Green AR, Gottgens B (2006) Endoglin expression in the endothelium is regulated by Fli-1, Erg, and Elf-1 acting on the promoter and a −8-kb enhancer. Blood 107:4737–4745PubMedGoogle Scholar
  78. 78.
    Deramaudt BM, Remy P, Abraham NG (1999) Upregulation of human heme oxygenase gene expression by Ets-family proteins. J Cell Biochem 72:311–321PubMedGoogle Scholar
  79. 79.
    Wei G, Srinivasan R, Cantemir-Stone CZ, Sharma SM, Santhanam R, Weinstein M, Muthusamy N, Man AK, Oshima RG, Leone G, Ostrowski MC (2009) Ets1 and Ets2 are required for endothelial cell survival during embryonic angiogenesis. Blood 114:1123–1130PubMedGoogle Scholar
  80. 80.
    Karantzoulis-Fegaras F, Antoniou H, Lai SLM, Kulkarni G, D’Abreo C, Wong GKT, Miller TL, Chan Y, Atkins J, Wang Y, Marsden PA (1999) Characterization of the human endothelial nitric-oxide synthase promoter. J Biol Chem 274:3076–3093PubMedGoogle Scholar
  81. 81.
    Zhan Y, Brown C, Maynard E, Anshelevich A, Ni W, Ho IC, Oettgen P (2005) Ets-1 is a critical regulator of Ang II-mediated vascular inflammation and remodeling. J Clin Invest 115:2508–2516PubMedCentralPubMedGoogle Scholar
  82. 82.
    Yuan L, Nikolova-Krstevski V, Zhan Y, Kondo M, Bhasin M, Varghese L, Yano K, Carman CV, Aird WC, Oettgen P (2009) Antiinflammatory effects of the ETS factor ERG in endothelial cells are mediated through transcriptional repression of the interleukin-8 gene. Circ Res 104:1049–1057PubMedCentralPubMedGoogle Scholar
  83. 83.
    Dryden NH, Sperone A, Martin-Almedina S, Hannah RL, Birdsey GM, Khan ST, Layhadi JA, Mason JC, Haskard DO, Gottgens B, Randi AM (2012) The transcription factor Erg controls endothelial cell quiescence by repressing activity of nuclear factor (NF)-kappaB p65. J Biol Chem 287:12331–12342PubMedGoogle Scholar
  84. 84.
    Yockell-Lelievre J, Spriet C, Cantin P, Malenfant P, Heliot L, de Launoit Y, Audette M (2009) Functional cooperation between Stat-1 and ets-1 to optimize icam-1 gene transcription. Biochem Cell Biol 87:905–918PubMedGoogle Scholar
  85. 85.
    de Launoit Y, Audette M, Pelczar H, Plaza S, Baert JL (1998) The transcription of the intercellular adhesion molecule-1 is regulated by Ets transcription factors. Oncogene 16:2065–2073PubMedGoogle Scholar
  86. 86.
    Sperone A, Dryden NH, Birdsey GM, Madden L, Johns M, Evans PC, Mason JC, Haskard DO, Boyle JJ, Paleolog EM, Randi AM (2011) The transcription factor Erg inhibits vascular inflammation by repressing NF-kappaB activation and proinflammatory gene expression in endothelial cells. Arterioscler Thromb Vasc Biol 31:142–150PubMedGoogle Scholar
  87. 87.
    Ayadi A, Zheng H, Sobieszczuk P, Buchwalter G, Moerman P, Alitalo K, Wasylyk B (2001) Net-targeted mutant mice develop a vascular phenotype and up-regulate egr-1. EMBO J 20:5139–5152PubMedGoogle Scholar
  88. 88.
    Lelievre E, Lionneton F, Mattot V, Spruyt N, Soncin F (2002) Ets-1 regulates fli-1 expression in endothelial cells. Identification of ETS binding sites in the fli-1 gene promoter. J Biol Chem 277:25143–25151PubMedGoogle Scholar
  89. 89.
    Majerus MA, Bibollet-Ruche F, Telliez JB, Wasylyk B, Bailleul B (1992) Serum, AP-1 and Ets-1 stimulate the human ets-1 promoter. Nucleic Acids Res 20:2699–2703PubMedCentralPubMedGoogle Scholar
  90. 90.
    Coffer P, de Jonge M, Mettouchi A, Binetruy B, Ghysdael J, Kruijer W (1994) junB promoter regulation: Ras mediated transactivation by c-Ets-1 and c-Ets-2. Oncogene 9:911–921PubMedGoogle Scholar
  91. 91.
    Landry JR, Kinston S, Knezevic K, Donaldson IJ, Green AR, Gottgens B (2005) Fli1, Elf1, and Ets1 regulate the proximal promoter of the LMO2 gene in endothelial cells. Blood 106:2680–2687PubMedGoogle Scholar
  92. 92.
    Schwachtgen JL, Janel N, Barek L, Duterque-Coquillaud M, Ghysdael J, Meyer D, Kerbiriou-Nabias D (1997) Ets transcription factors bind and transactivate the core promoter of the von Willebrand factor gene. Oncogene 15:3091–3102PubMedGoogle Scholar
  93. 93.
    von der Ahe D, Nischan C, Kunz C, Otte J, Knies U, Oderwald H, Wasylyk B (1993) Ets transcription factor binding site is required for positive and TNF alpha-induced negative promoter regulation. Nucleic Acids Res 21:5636–5643PubMedCentralPubMedGoogle Scholar
  94. 94.
    Ginsberg M, James D, Ding BS, Nolan D, Geng F, Butler JM, Schachterle W, Pulijaal VR, Mathew S, Chasen ST, Xiang J, Rosenwaks Z, Shido K, Elemento O, Rabbany SY, Rafii S (2012) Efficient direct reprogramming of mature amniotic cells into endothelial cells by ETS factors and TGFbeta suppression. Cell 151:559–575PubMedCentralPubMedGoogle Scholar
  95. 95.
    Rasmussen TL, Shi X, Wallis A, Kweon J, Zirbes KM, Koyano-Nakagawa N, Garry DJ (2012) VEGF/Flk1 signaling cascade transactivates Etv2 gene expression. PLoS One 7:e50103PubMedCentralPubMedGoogle Scholar
  96. 96.
    De Val S (2011) Key transcriptional regulators of early vascular development. Arterioscler Thromb Vasc Biol 31:1469–1475PubMedGoogle Scholar
  97. 97.
    Patterson LJ, Patient R (2006) The “Ets” factor: vessel formation in zebrafish – the missing link? PLoS Biol 4:21–24Google Scholar
  98. 98.
    De Val S, Black BL (2009) Transcriptional control of endothelial cell development. Dev Cell 16:180–195PubMedCentralPubMedGoogle Scholar
  99. 99.
    Liu F, Patient R (2008) Genome-wide analysis of the zebrafish ETS family identifies three genes required for hemangioblast differentiation or angiogenesis. Circ Res 103:1147–1154PubMedGoogle Scholar
  100. 100.
    Ellett F, Kile BT, Lieschke GJ (2009) The role of the ETS factor erg in zebrafish vasculogenesis. Mech Dev 126:220–229PubMedCentralPubMedGoogle Scholar
  101. 101.
    Meadows SM, Myers CT, Krieg PA (2011) Regulation of endothelial cell development by ETS transcription factors. Semin Cell Dev Biol 22:976–984PubMedCentralPubMedGoogle Scholar
  102. 102.
    Ristevski S, Tam PP, Hertzog PJ, Kola I (2002) Ets2 is expressed during morphogenesis of the somite and limb in the mouse embryo. Mech Dev 116:165–168PubMedGoogle Scholar
  103. 103.
    Yamamoto H, Flannery ML, Kupriyanov S, Pearce J, McKercher SR, Henkel GW, Maki RA, Werb Z, Oshima RG (1998) Defective trophoblast function in mice with a targeted mutation of Ets2. Genes Dev 12:1315–1326PubMedGoogle Scholar
  104. 104.
    De Val S, Chi NC, Meadows SM, Minovitsky S, Anderson JP, Harris IS, Ehlers ML, Agarwal P, Visel A, Xu SM, Pennacchio LA, Dubchak I, Krieg PA, Stainier DY, Black BL (2008) Combinatorial regulation of endothelial gene expression by ets and forkhead transcription factors. Cell 135:1053–1064PubMedCentralPubMedGoogle Scholar
  105. 105.
    Bories JC, Willerford DM, Grevin D, Davidson L, Camus A, Martin P, Stehelin D, Alt FW (1995) Increased T-cell apoptosis and terminal B-cell differentiation induced by inactivation of the Ets-1 proto-oncogene. Nature 377:635–638PubMedGoogle Scholar
  106. 106.
    Muthusamy N, Barton K, Leiden JM (1995) Defective activation and survival of T cells lacking the Ets-1 transcription factor. Nature 377:639–642PubMedGoogle Scholar
  107. 107.
    Vlaeminck-Guillem V, Carrere S, Dewitte F, Stehelin D, Desbiens X, Duterque-Coquillaud M (2000) The Ets family member Erg gene is expressed in mesodermal tissues and neural crests at fundamental steps during mouse embryogenesis. Mech Dev 91:331–335PubMedGoogle Scholar
  108. 108.
    Mohamed AA, Tan SH, Mikhalkevich N, Ponniah S, Vasioukhin V, Bieberich CJ, Sesterhenn IA, Dobi A, Srivastava S, Sreenath TL (2010) Ets family protein, erg expression in developing and adult mouse tissues by a highly specific monoclonal antibody. J Cancer 1:197–208PubMedCentralPubMedGoogle Scholar
  109. 109.
    Oikawa M, Abe M, Kurosawa H, Hida W, Shirato K, Sato Y (2001) Hypoxia induces transcription factor ETS-1 via the activity of hypoxia-inducible factor-1. Biochem Biophys Res Commun 289:39–43PubMedGoogle Scholar
  110. 110.
    Hashiya N, Jo N, Aoki M, Matsumoto K, Nakamura T, Sato Y, Ogata N, Ogihara T, Kaneda Y, Morishita R (2004) In vivo evidence of angiogenesis induced by transcription factor Ets-1: Ets-1 is located upstream of angiogenesis cascade. Circulation 109:3035–3041PubMedGoogle Scholar
  111. 111.
    Pourtier-Manzanedo A, Vercamer C, Van BE, Mattot V, Mouquet F, Vandenbunder B (2003) Expression of an Ets-1 dominant-negative mutant perturbs normal and tumor angiogenesis in a mouse ear model. Oncogene 22:1795–1806PubMedGoogle Scholar
  112. 112.
    Nakano T, Abe M, Tanaka K, Shineha R, Satomi S, Sato Y (2000) Angiogenesis inhibition by transdominant mutant Ets-1. J Cell Physiol 184:255–262PubMedGoogle Scholar
  113. 113.
    Watanabe D, Takagi H, Suzuma K, Suzuma I, Oh H, Ohashi H, Kemmochi S, Uemura A, Ojima T, Suganami E, Miyamoto N, Sato Y, Honda Y (2004) Transcription factor Ets-1 mediates ischemia- and vascular endothelial growth factor-dependent retinal neovascularization. Am J Pathol 164:1827–1835PubMedGoogle Scholar
  114. 114.
    Lefter LP, Dima S, Sunamura M, Furukawa T, Sato Y, Abe M, Chivu M, Popescu I, Horii A (2009) Transcriptional silencing of ETS-1 efficiently suppresses angiogenesis of pancreatic cancer. Cancer Gene Ther 16:137–148PubMedGoogle Scholar
  115. 115.
    Wernert N, Stanjek A, Kiriakidis S, Hugel A, Jha HC, Mazitschek R, Giannis A (1999) Inhibition of angiogenesis in vivo by ets-1 antisense oligonucleotides-inhibition of Ets-1 transcription factor expression by the antibiotic fumagillin. Angew Chem Int Ed Engl 38:3228–3231PubMedGoogle Scholar
  116. 116.
    Yoon KC, Bae JA, Park HJ, Im SK, Oh HJ, Lin XH, Kim MY, Lee JH, Lee SE, Ahn KY, Kim KK (2009) Subconjunctival gene delivery of the transcription factor GA-binding protein delays corneal neovascularization in a mouse model. Gene Ther 16:973–981PubMedGoogle Scholar
  117. 117.
    Man AK, Young LJ, Tynan JA, Lesperance J, Egeblad M, Werb Z, Hauser CA, Muller WJ, Cardiff RD, Oshima RG (2003) Ets2-dependent stromal regulation of mouse mammary tumors. Mol Cell Biol 23:8614–8625PubMedCentralPubMedGoogle Scholar
  118. 118.
    Iwasaka C, Tanaka K, Abe M, Sato Y (1996) Ets-1 regulates angiogenesis by inducing the expression of urokinase-type plasminogen activator and matrix metalloproteinase-1 and the migration of vascular endothelial cells. J Cell Physiol 169:522–531PubMedGoogle Scholar
  119. 119.
    Stamatovic SM, Keep RF, Mostarica-Stojkovic M, Andjelkovic AV (2006) CCL2 regulates angiogenesis via activation of Ets-1 transcription factor. J Immunol 177:2651–2661PubMedGoogle Scholar
  120. 120.
    Arderiu G, Pena E, Aledo R, Espinosa S, Badimon L (2012) Ets-1 transcription is required in tissue factor driven microvessel formation and stabilization. Angiogenesis 15:657–669PubMedGoogle Scholar
  121. 121.
    Mattot V, Vercamer C, Soncin F, Calmels T, Huguet C, Fafeur V, Vandenbunder B (2000) Constitutive expression of the DNA-binding domain of Ets1 increases endothelial cell adhesion and stimulates their organization into capillary-like structures. Oncogene 19:762–772PubMedGoogle Scholar
  122. 122.
    Dejana E, Taddei A, Randi AM (2007) Foxs and Ets in the transcriptional regulation of endothelial cell differentiation and angiogenesis. Biochim Biophys Acta 1775:298–312PubMedGoogle Scholar
  123. 123.
    Wernert N, Raes MB, Lassalle P, Dehouck MP, Gosselin B, Vandenbunder B, Stehelin D (1992) c-Ets1 proto-oncogene is a transcription factor expressed in endothelial cells during tumor vascularization and other forms of angiogenesis in humans. Am J Pathol 140:119–127PubMedGoogle Scholar
  124. 124.
    Tokuhara K, Ogata Y, Nakagawa M, Shirouzu K (2003) Ets-1 expression in vascular endothelial cells as an angiogenic and prognostic factor in colorectal carcinoma. Int Surg 88:25–33PubMedGoogle Scholar
  125. 125.
    Tomlins SA, Bjartell A, Chinnaiyan AM, Jenster G, Nam RK, Rubin MA, Schalken JA (2009) ETS gene fusions in prostate cancer: from discovery to daily clinical practice. Eur Urol 56:275–286PubMedGoogle Scholar
  126. 126.
    Nikolova-Krstevski V, Bhasin M, Otu HH, Libermann T, Oettgen P (2008) Gene expression analysis of embryonic stem cells expressing VE-cadherin (CD144) during endothelial differentiation. BMC Genomics 9:240PubMedCentralPubMedGoogle Scholar
  127. 127.
    Loughran SJ, Kruse EA, Hacking DF, de Graaf CA, Hyland CD, Willson TA, Henley KJ, Ellis S, Voss AK, Metcalf D, Hilton DJ, Alexander WS, Kile BT (2008) The transcription factor Erg is essential for definitive hematopoiesis and the function of adult hematopoietic stem cells. Nat Immunol 9:810–819PubMedGoogle Scholar
  128. 128.
    Hollenhorst PC, Jones DA, Graves BJ (2004) Expression profiles frame the promoter specificity dilemma of the ETS family of transcription factors. Nucleic Acids Res 32:5693–5702PubMedCentralPubMedGoogle Scholar
  129. 129.
    Hewett PW, Nishi K, Daft EL, Murray JC (2001) Selective expression of erg isoforms In human endothelial cells. Int J Biochem Cell Biol 33:347–355PubMedGoogle Scholar
  130. 130.
    Yuan L, Le BA, Sacharidou A, Itagaki K, Zhan Y, Kondo M, Carman CV, Davis GE, Aird WC, Oettgen P (2012) ETS-related gene (ERG) controls endothelial cell permeability via transcriptional regulation of the claudin 5 (CLDN5) gene. J Biol Chem 287:6582–6591PubMedGoogle Scholar
  131. 131.
    Song KS, Yoon JH, Kim KS, Ahn DW (2012) c-Ets1 inhibits the interaction of NF-kappaB and CREB, and downregulates IL-1beta-induced MUC5AC overproduction during airway inflammation. Mucosal Immunol 5:207–215PubMedCentralPubMedGoogle Scholar
  132. 132.
    Le Bras A, Lionneton F, Mattot V, Lelièvre E, Caetano B, Spruyt N, Soncin F (2007) HIF-2 specifically activates the VE-cadherin promoter independently of hypoxia and in synergy with Ets-1 through two essential ETS-binding sites. Oncogene 26:7480–7489PubMedGoogle Scholar
  133. 133.
    Dutta D, Ray S, Vivian JL, Paul S (2008) Activation of the VEGFR1 chromatin domain: an angiogenic signal-ETS1/HIF-2alpha regulatory axis. J Biol Chem 283(37):25404–25413PubMedGoogle Scholar
  134. 134.
    Linnemann AK, O’Geen H, Keles S, Farnham PJ, Bresnick EH (2011) Genetic framework for GATA factor function in vascular biology. Proc Natl Acad Sci U S A 108(33):13641–13646PubMedCentralPubMedGoogle Scholar
  135. 135.
    Mollica LR, Crawley JT, Liu K, Rance JB, Cockerill PN, Follows GA, Landry JR, Wells DJ, Lane DA (2006) Role of a 5′-enhancer in the transcriptional regulation of the human endothelial cell protein C receptor gene. Blood 108(4):1251–1259PubMedGoogle Scholar
  136. 136.
    Wisdom R (1999) AP-1: one switch for many signals. Exp Cell Res 253(1):180–185PubMedGoogle Scholar
  137. 137.
    Westermarck J, Kähäri VM (1999) Regulation of matrix metalloproteinase expression in tumor invasion. FASEB J 13(8):781–792PubMedGoogle Scholar
  138. 138.
    Bassuk AG, Leiden JM (2007) A direct physical association between ETS and AP-1 transcription factors in normal human T cells. Immunity 27(4):561–571Google Scholar
  139. 139.
    Gottschalk LR, Giannola DM, Emerson SG (1995) Molecular regulation of the human IL-3 gene: inducible T cell-restricted expression requires intact AP-1 and Elf-1 nuclear protein binding sites. Immunity 3(2):223–237Google Scholar
  140. 140.
    Crawford HC, Matrisian LM (1996) Mechanisms controlling the transcription of matrix metalloproteinase genes in normal and neoplastic cells. Enzyme Protein 49(1–3):20–37PubMedGoogle Scholar

Copyright information

© Springer-Verlag Wien 2013

Authors and Affiliations

  1. 1.Vascular Sciences UnitNational Heart and Lung Institute (NHLI), Imperial College London, Hammersmith HospitalLondonUK

Personalised recommendations