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Blood, 15 August 2007, Vol. 110, No. 4, pp. 1168-1177. Prepublished online as a Blood First Edition Paper on April 10, 2007; DOI 10.1182/blood-2007-01-066282. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2007-01-066282v1 110/4/1168    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 Boosani, C. S. Articles by Sudhakar, A. Search for Related Content PubMed PubMed Citation Articles by Boosani, C. S. Articles by Sudhakar, A. Related Collections Hemostasis, Thrombosis, and Vascular Biology Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Regulation of COX-2–mediated signaling by 3 type IV noncollagenous domain in tumor angiogenesis Chandra Shekhar Boosani1, Arjuna P. Mannam2, Dominic Cosgrove3, Rita Silva4, Kairbaan M. Hodivala-Dilke4, Venkateshwar G. Keshamouni5, and Akulapalli Sudhakar1,6,7 1 Cell Signaling and Tumor Angiogenesis Laboratory, Department of Genetics, Boys Town National Research Hospital, Omaha, NE; 2 Department of Neurology, University of Connecticut School of Medicine, Hartford Hospital; 3 Gene Expression Laboratory, Department of Genetics, Boys Town National Research Hospital, Omaha, NE; 4 Cancer Research UK, Cell Adhesion and Disease Laboratory, Richard Dimbleby Department of Cancer Research, St Thomas' Hospital, London, United Kingdom; 5 Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor; 6 Department of Biomedical Sciences, Creighton University School of Medicine, Omaha, NE; 7 Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha Human 3 chain, a noncollagenous domain of type IV collagen [3(IV)NC1], inhibits angiogenesis and tumor growth. These biologic functions are partly attributed to the binding of 3(IV)NC1 to Vß3 and 3ß1 integrins. 3(IV)NC1 binds Vß3 integrin, leading to translation inhibition by inhibiting focal adhesion kinase/phosphatidylinositol 3-kinase/Akt/mTOR/4E-BP1 pathways. In the present study, we evaluated the role of 3ß1 and Vß3 integrins in tube formation and regulation of cyclooxygenase-2 (COX-2) on 3(IV)NC1 stimulation. We found that although both integrins were required for the inhibition of tube formation by 3(IV)NC1 in endothelial cells, only 3ß1 integrin was sufficient to regulate COX-2 in hypoxic endothelial cells. We show that binding of 3(IV)NC1 to 3ß1 integrin leads to inhibition of COX-2–mediated pro-angiogenic factors, vascular endothelial growth factor, and basic fibroblast growth factor by regulating IB/NFB axis, and is independent of Vß3 integrin. Furthermore, ß3 integrin–null endothelial cells, when treated with 3(IV)NC1, inhibited hypoxia-mediated COX-2 expression, whereas COX-2 inhibition was not observed in 3 integrin–null endothelial cells, indicating that regulation of COX-2 by 3(IV)NC1 is mediated by integrin 3ß1. Our in vitro and in vivo findings demonstrate that 3ß1 integrin is critical for 3(IV)NC1-mediated inhibition of COX-2–dependent angiogenic signaling and inhibition of tumor progression. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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