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Transgenic or tumor-induced expression of heparanase upregulates sulfation of heparan sulfate
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
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2007 (English)In: Nature Chemical Biology, ISSN 1552-4450, Vol. 3, no 12, 773-778 p.Article in journal (Refereed) Published
Abstract [en]

Heparan sulfate proteoglycans (HSPGs) interact with numerous proteins of importance in animal development and homeostasis. Heparanase, which is expressed in normal tissues and upregulated in angiogenesis, cancer and inflammation, selectively cleaves β-glucuronidic linkages in HS chains. In a previous study, we transgenically overexpressed heparanase in mice to assess the overall effects of heparanase on HS metabolism. Metabolic labeling confirmed extensive fragmentation of HS in vivo. In the current study we found that in liver showing excessive heparanase overexpression, HSPG turnover is accelerated along with upregulation of HS N- and O-sulfation, thus yielding heparin-like chains without the domain structure typical of HS. Heparanase overexpression in other mouse organs and in human tumors correlated with increased 6-O-sulfation of HS, whereas the domain structure was conserved. The heavily sulfated HS fragments strongly promoted formation of ternary complexes with fibroblast growth factor 1 (FGF1) or FGF2 and FGF receptor 1. Heparanase thus contributes to regulation of HS biosynthesis in a way that may promote growth factor action in tumor angiogenesis and metastasis.

Place, publisher, year, edition, pages
2007. Vol. 3, no 12, 773-778 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-15718DOI: 10.1038/nchembio.2007.41ISI: 000251028600011PubMedID: 17952066OAI: oai:DiVA.org:uu-15718DiVA: diva2:43489
Available from: 2008-03-05 Created: 2008-03-05 Last updated: 2011-01-18Bibliographically approved
In thesis
1. Structure and functions of heparan sulfate/heparin – Importance of glucuronyl C5-epimerase and heparanase
Open this publication in new window or tab >>Structure and functions of heparan sulfate/heparin – Importance of glucuronyl C5-epimerase and heparanase
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Heparan sulfate (HS) and heparin are linear polysaccharide chains covalently O-linked to serine residues within the core proteins, so called HS proteoglycans (PGs) or heparin PG. HSPGs are produced by almost all mammalian cells and known to play important roles in developmental processes, physiological and pathological conditions; whereas heparin PG is produced by mast cells and best known as an anticoagulant in clinic.

Biosynthesis of HS/heparin occurs in Golgi compartment and involves many enzymes, one of which is glucuronyl C5-epimerase (Hsepi) that catalyzes the conversion of D-glucuronic acid (GlcA) to L-iduronic acid (IdoA). Heparanase is an enzyme involved in metabolism of HS; it cleaves the linkage between GlcA and glucosamine residues in HS/heparin chains. Heparanase is expressed essentially by all cells and found up-regulated in many metastatic tumors.

This thesis focuses on the structure and functions of HS/heparin through studies on the implications of Hsepi and heparanase. My study demonstrated that the modification catalyzed by Hsepi is critical for HS-dependent function of growth factors, especially FGF2; heparanase is involved in regulation of HS biosynthesis and matrix metalloproteinases expression; moreover, my experimental data demonstrated the functions of heparin in mast cells, showing cleavage of heparin by heparanase contributes to modulation of protease storage in mast cells.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2009. 46 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 470
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Research subject
Biochemistry
Identifiers
urn:nbn:se:uu:diva-107202 (URN)978-91-554-7571-0 (ISBN)
Public defence
2009-09-11, C10:301, BMC, Husargatan 3, Uppsala, 09:00 (English)
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Supervisors
Available from: 2009-08-20 Created: 2009-07-28 Last updated: 2009-08-20Bibliographically approved

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Jia, JuanZhang, XiaoJastrebova, NadjaSpillmann, DorotheGottfridsson, EvaLindahl, UlfLi, Jin-Ping

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