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Blood, 15 April 2004, Vol. 103, No. 8, pp. 3005-3012. Prepublished online as a Blood First Edition Paper on December 11, 2003; DOI 10.1182/blood-2003-07-2459. This Article Full Text Full Text (PDF) All Versions of this Article: 2003-07-2459v1 103/8/3005    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 Spagnuolo, R. Articles by Dejana, E. Search for Related Content PubMed PubMed Citation Articles by Spagnuolo, R. Articles by Dejana, E. Related Collections Hemostasis, Thrombosis, and Vascular Biology Apoptosis Cell Adhesion and Motility Gene Expression Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Gas1 is induced by VE-cadherin and vascular endothelial growth factor and inhibits endothelial cell apoptosis Raffaella Spagnuolo, Monica Corada, Fabrizio Orsenigo, Lucia Zanetta, Ulrich Deuschle, Peter Sandy, Claudio Schneider, Christopher J. Drake, Ferruccio Breviario, and Elisabetta Dejana From the Italian Foundation for Cancer Research (FIRC) Institute of Molecular Oncology, Milan, Italy; Mario Negri Institute for Pharmacological Research, Milan, Italy; LION Bioscience AG, Heidelberg, Germany; Laboratorio Nazionale Consorzio Interuniversitario per le Biotecnologie (CIB), Area Science Park, Padriciano, Trieste, Italy; Department of Cell Biology, Medical University of South Carolina, Charleston, SC; and Department of Biomolecular and Biotechnological Sciences, University of Milan, School of Sciences, Milan, Italy. The junctional membrane protein vascular endothelial (VE)–cadherin mediates contact inhibition of growth and inhibits apoptosis of endothelial cells. In this article we show that VE-cadherin induces expression of growth arrest–specific 1 (Gas1), an integral membrane protein up-regulated in nonproliferating cells. By comparing syngenic endothelial cell lines, we found that Gas1 mRNA was increased by 3-fold in VE-cadherin–positive cells in comparison to VE-cadherin–null cells. Ectopic expression of Gas1 in endothelial or 293 cells strongly reduced apoptosis without affecting cell growth. Addition of vascular endothelial growth factor (VEGF) also up-regulated Gas1 and this effect was augmented more so in confluent nonproliferating cells than in sparse cultures. VE-cadherin–blocking antibody partially inhibited VEGF-induced Gas1, suggesting that VE-cadherin clustering is required for an optimal response to this stimulus. Inhibition of phosphoinositole-3-OH kinase (PI3-kinase) pathway by Wortmannin prevented Gas1 synthesis and the antiapoptotic effect of VEGF, but, in cells ectopically expressing Gas1, Wortmannin was ineffective. Furthermore, inhibition of Gas1 expression by short interfering RNA (siRNA) both in vitro and in allantois organ cultures made endothelial cells refractory to the antiapoptotic effect of VEGF. Overall these data indicate that Gas1 induction by VE-cadherin and VEGF in endothelial cells requires activation of PI3-kinase. Gas1 expression positively correlates with inhibition of endothelial cell apoptosis and may contribute to the integrity of resting endothelium. (Blood. 2004;103:3005-3012) CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Gas up and live! Victoria L. Bautch Blood 2004 103: 2865. [Full Text] [PDF] This article has been cited by other articles: G. M. Birdsey, N. H. Dryden, V. Amsellem, F. Gebhardt, K. Sahnan, D. O. Haskard, E. Dejana, J. C. Mason, and A. M. Randi Transcription factor Erg regulates angiogenesis and endothelial apoptosis through VE-cadherin Blood, April 1, 2008; 111(7): 3498 - 3506. [Abstract] [Full Text] [PDF] D. Viemann, K. Barczyk, T. Vogl, U. Fischer, C. Sunderkotter, K. Schulze-Osthoff, and J. Roth MRP8/MRP14 impairs endothelial integrity and induces a caspase-dependent and -independent cell death program Blood, March 15, 2007; 109(6): 2453 - 2460. [Abstract] [Full Text] [PDF] K. Xiao, J. Garner, K. M. Buckley, P. A. Vincent, C. M. Chiasson, E. Dejana, V. Faundez, and A. P. Kowalczyk p120-Catenin Regulates Clathrin-dependent Endocytosis of VE-Cadherin Mol. Biol. Cell, November 1, 2005; 16(11): 5141 - 5151. [Abstract] [Full Text] [PDF] X. Luo, L. Ding, J. Xu, and N. Chegini Gene Expression Profiling of Leiomyoma and Myometrial Smooth Muscle Cells in Response to Transforming Growth Factor-{beta} Endocrinology, March 1, 2005; 146(3): 1097 - 1118. [Abstract] [Full Text] [PDF] S. Liebner, A. Cattelino, R. Gallini, N. Rudini, M. Iurlaro, S. Piccolo, and E. Dejana {beta}-Catenin is required for endothelial-mesenchymal transformation during heart cushion development in the mouse J. Cell Biol., August 2, 2004; 166(3): 359 - 367. [Abstract] [Full Text] [PDF]

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