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The minimal active domain of endostatin is a heparin-binding motif that mediates inhibition of tumor vascularization
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
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2004 (English)In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 64, no 24, 9012-9017 p.Article in journal (Refereed) Published
Abstract [en]

Endostatin constitutes the COOH-terminal 20,000 Da proteolytic fragment of collagen XVIII and has been shown to possess antiangiogenic and antitumorigenic properties. In the present study, we have investigated the role of the heparin-binding sites in the in vivo mechanism of action of endostatin. The majority of the heparin binding is mediated by arginines 155/158/184/270 in endostatin, but there is also a minor site constituted by arginines 193/194. Using endostatin mutants lacking either of these two sites, we show that inhibition of fibroblast growth factor-2-induced angiogenesis in the chicken chorioallantoic membrane requires both heparin-binding sites. In contrast, inhibition of vascular endothelial growth factor-A-induced chorioallantoic membrane angiogenesis by endostatin was only dependent on the minor heparin-binding site (R193/194). These arginines were also required for endostatin to inhibit fibroblast growth factor-2- and vascular endothelial growth factor-A-induced chemotaxis of primary endothelial cells. Moreover, we show that a synthetic peptide corresponding to amino acids 180-199 of human endostatin (which covers the minor heparin-binding site) inhibits endothelial cell chemotaxis and reduces tumor vascularization in vivo. Substitution of arginine residues 193/194 for alanine attenuates the antiangiogenic effects of the peptide. These data show an essential role for heparin binding in the antiangiogenic action of endostatin.

Place, publisher, year, edition, pages
2004. Vol. 64, no 24, 9012-9017 p.
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Medical and Health Sciences
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URN: urn:nbn:se:uu:diva-13081DOI: 10.1158/0008-5472.CAN-04-2172PubMedID: 15604266OAI: oai:DiVA.org:uu-13081DiVA: diva2:40851
Available from: 2008-08-01 Created: 2008-08-01 Last updated: 2017-12-11Bibliographically approved

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Olsson, Anna-KarinJohansson, IrjaÅkerud, HelenaEinarsson, BarbroChristofferson, RolfClaesson-Welsh, Lena

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Olsson, Anna-KarinJohansson, IrjaÅkerud, HelenaEinarsson, BarbroChristofferson, RolfClaesson-Welsh, Lena
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