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Blood, 15 September 2004, Vol. 104, No. 6, pp. 1760-1768. Prepublished online as a Blood First Edition Paper on June 8, 2004; DOI 10.1182/blood-2003-12-4244. This Article Full Text Full Text (PDF) All Versions of this Article: 2003-12-4244v1 104/6/1760    most recent 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 Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by MacKenzie, F. Articles by Karsan, A. Search for Related Content PubMed PubMed Citation Articles by MacKenzie, F. Articles by Karsan, A. Related Collections Cell Adhesion and Motility Gene Expression Hemostasis, Thrombosis, and Vascular Biology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Notch4-induced inhibition of endothelial sprouting requires the ankyrin repeats and involves signaling through RBP-J Farrell MacKenzie, Patrick Duriez, Bruno Larrivée, Linda Chang, Ingrid Pollet, Fred Wong, Calvin Yip, and Aly Karsan From the Department of Pathology and Laboratory Medicine, University of British Columbia; the Experimental Medicine Program, University of British Columbia, Vancouver, BC, Canada; the Department of Medical Biophysics, British Columbia Cancer Agency; and the Department of Pathology and Laboratory Medicine, British Columbia Cancer Agency, Vancouver, BC, Canada. Notch proteins comprise a family of transmembrane receptors. Ligand activation of Notch releases the intracellular domain of the receptor that translocates to the nucleus and regulates transcription through the DNA-binding protein RBP-J. Previously, it has been shown that the Notch4 intracellular region (N4IC) can inhibit endothelial sprouting and angiogenesis. Here, N4IC deletion mutants were assessed for their ability to inhibit human microvascular endothelial cell (HMEC) sprouting with the use of a quantitative endothelial sprouting assay. Deletion of the ankyrin repeats, but not the RAM (RBP-J associated module) domain or C-terminal region (CT), abrogated the inhibition of fibroblast growth factor 2 (FGF-2)- and vascular endothelial growth factor (VEGF)-induced sprouting by Notch4, whereas the ankyrin repeats alone partially blocked sprouting. The ankyrin repeats were also the only domain required for up-regulation of RBP-J-dependent gene expression. Interestingly, enforced expression of the ankyrin domain alone was sufficient to up-regulate some, but not all, RBP-J-dependent genes. Although N4IC reduced VEGF receptor-2 (VEGFR-2) and vascular endothelial (VE)-cadherin expression, neither of these events is necessary and sufficient to explain N4IC-mediated inhibition of sprouting. A constitutively active RBP-J mutant significantly inhibited HMEC sprouting but not as strongly as N4IC. Thus, Notch4-induced inhibition of sprouting requires the ankyrin repeats and appears to involve RBP-J-dependent and -independent signaling. (Blood. 2004;104:1760-1768) CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: C. Roca and R. H. Adams Regulation of vascular morphogenesis by Notch signaling Genes & Dev., October 15, 2007; 21(20): 2511 - 2524. [Abstract] [Full Text] [PDF] G. Kasper, N. Dankert, J. Tuischer, M. Hoeft, T. Gaber, J. D. Glaeser, D. Zander, M. Tschirschmann, M. Thompson, G. Matziolis, et al. Mesenchymal Stem Cells Regulate Angiogenesis According to Their Mechanical Environment Stem Cells, April 1, 2007; 25(4): 903 - 910. [Abstract] [Full Text] [PDF] J. Wu and E. H. Bresnick Glucocorticoid and Growth Factor Synergism Requirement for Notch4 Chromatin Domain Activation Mol. Cell. Biol., March 15, 2007; 27(6): 2411 - 2422. [Abstract] [Full Text] [PDF] S. Suchting, C. Freitas, F. le Noble, R. Benedito, C. Breant, A. Duarte, and A. Eichmann The Notch ligand Delta-like 4 negatively regulates endothelial tip cell formation and vessel branching PNAS, February 27, 2007; 104(9): 3225 - 3230. [Abstract] [Full Text] [PDF] S. Murphy, B. Larrivee, I. Pollet, K. S. Craig, D. E. Williams, X.-H. Huang, M. Abbott, F. Wong, C. Curtis, T. P. Conrads, et al. Identification of Sokotrasterol Sulfate As a Novel Proangiogenic Steroid Circ. Res., August 4, 2006; 99(3): 257 - 265. [Abstract] [Full Text] [PDF] K. G. Leong and A. Karsan Recent insights into the role of Notch signaling in tumorigenesis Blood, March 15, 2006; 107(6): 2223 - 2233. [Abstract] [Full Text] [PDF] C. Hu, A. Dievart, M. Lupien, E. Calvo, G. Tremblay, and P. Jolicoeur Overexpression of Activated Murine Notch1 and Notch3 in Transgenic Mice Blocks Mammary Gland Development and Induces Mammary Tumors Am. J. Pathol., March 1, 2006; 168(3): 973 - 990. [Abstract] [Full Text] [PDF] N. S. Patel, J.-L. Li, D. Generali, R. Poulsom, D. W. Cranston, and A. L. Harris Up-regulation of Delta-like 4 Ligand in Human Tumor Vasculature and the Role of Basal Expression in Endothelial Cell Function Cancer Res., October 1, 2005; 65(19): 8690 - 8697. [Abstract] [Full Text] [PDF] J. Wu, F. Iwata, J. A. Grass, C. S. Osborne, L. Elnitski, P. Fraser, O. Ohneda, M. Yamamoto, and E. H. Bresnick Molecular Determinants of NOTCH4 Transcription in Vascular Endothelium Mol. Cell. Biol., February 15, 2005; 25(4): 1458 - 1474. [Abstract] [Full Text] [PDF]

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