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Blood, 5 February 2009, Vol. 113, No. 6, pp. 1383-1390. Prepublished online as a Blood First Edition Paper on October 23, 2008; DOI 10.1182/blood-2008-06-164210. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2008-06-164210v1 113/6/1383    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 CrossRef Citing Articles via Google Scholar Google Scholar Articles by Prager, G. W. Articles by Binder, B. R. Search for Related Content PubMed PubMed Citation Articles by Prager, G. W. Articles by Binder, B. R. Related Collections Vascular Biology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  VASCULAR BIOLOGY Urokinase mediates endothelial cell survival via induction of the X-linked inhibitor of apoptosis protein Gerald W. Prager1,2, Judit Mihaly1, Patrick M. Brunner1, Yuri Koshelnick1, Gunilla Hoyer-Hansen3, and Bernd R. Binder1 1 Department of Vascular Biology and Thrombosis Research, Centre for Bio-Molecular Medicine and Pharmacology, and 2 Clinical Division of Oncology, Department of Medicine I and Cancer Center, Medical University Vienna, Vienna, Austria; and 3 Finsen Laboratory, Copenhagen Biocenter, Copenhagen, Denmark Urokinase-type plasminogen activator (uPA) additionally elicits a whole array of pro-angiogenic responses, such as differentiation, proliferation, and migration. In this study, we demonstrate that in endothelial cells uPA also protects against apoptosis by transcriptional up-regulation and partially by mRNA stabilization of inhibitor of apoptosis proteins, most prominently the X-linked inhibitor of apoptosis protein (XIAP). The antiapoptotic activity of uPA was dependent on its protease activity, the presence of uPA receptor (uPAR) and low-density lipoprotein receptor-related protein (LRP), but independent of the phosphatidylinositol 3 (PI3) kinase pathway, whereas vascular endothelial growth factor (VEGF)–induced antiapoptosis was PI3 kinase dependent. uPA-induced cell survival involved phosphorylation of p21-activated kinase 1 (Pak1) and the IB kinase that leads to nuclear factor B (NF-B) p52 activation. Indeed, blocking NF-B activation by using specific NF-B inhibitors abolished uPA-induced cell survival as it blocked uPA-induced XIAP up-regulation. Furthermore, down-regulating XIAP expression by small interfering RNA (siRNA) significantly reduced uPA-dependent endothelial cell survival. This mechanism is also important for VEGF-induced antiapoptosis because VEGF-dependent up-regulation of XIAP was found defective in uPA–/– endothelial cells. This led us to conclude that uPA is part of a novel NF-B–dependent cell survival pathway. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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