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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 (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 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. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted December 15, 2003 Accepted May 17, 2004 Notch4-induced inhibition of endothelial sprouting requires the ankyrin repeats and involves signaling through RBP-J Farrell MacKenzie, Patrick Duriez, Bruno Larrivee, Linda Chang, Ingrid Pollet, Fred Wong, Calvin Yip, and Aly Karsan* Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada; Medical Biophysics, British Columbia Cancer Agency, Vancouver, BC, Canada Experimental Medicine, University of British Columbia, Vancouver, BC, Canada; Medical Biophysics, British Columbia Cancer Agency, Vancouver, BC, Canada Medical Biophysics, British Columbia Cancer Agency, Vancouver, BC, Canada Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada; Experimental Medicine, University of British Columbia, Vancouver, BC, Canada; Pathology and Laboratory Medicine, British Columbia Cancer Agency, Vancouver, BC, Canada * Corresponding author; email: akarsan{at}bccrc.ca. 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 using a quantitative endothelial sprouting assay. Deletion of the ankyrin repeats, but not the RAM domain or C-terminal region (CT), abrogated the inhibition of FGF-2- and VEGF-induced sprouting by Notch4, while the ankyrin repeats alone partially blocked sprouting. The ankyrin repeats were also the only domain required for upregulation of RBP-J-dependent gene expression. Interestingly, enforced expression of the ankyrin domain alone was sufficient to upregulate some, but not all, RBP-J-dependent genes. Although N4IC reduced VEGF receptor-2 (VEGFR-2) and 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. 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] 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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