Source:http://linkedlifedata.com/resource/pubmed/id/10385702
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
1
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| pubmed:dateCreated |
1999-7-22
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| pubmed:abstractText |
Basic fibroblast growth factor (FGF-2) interacts with high-affinity tyrosine-kinase fibroblast growth factor receptors (FGFRs) and low-affinity heparan sulfate proteoglycans (HSPGs) in target cells. Both interactions are required for FGF-2-mediated biological responses. Here we report the FGF-2 antagonist activity of novel synthetic sulfonic acid polymers with distinct chemical structures and molecular masses (MMs). PAMPS [poly(2-acrylamido-2-methyl-1-propanesulfonic acid)], (MM approximately 7,000-10,000), PAS [poly(anetholesulfonic acid)], (MM approximately 9,000-11,000), PSS [poly(4-styrenesulfonic acid)], (MM = 70,000), and poly(vinylsulfonic acid) (MM = 2,000), inhibited FGF-2 binding to HSPGs and FGFRs in fetal bovine aortic endothelial GM 7373 cells. They also abrogated the formation of the HSPG/FGF-2/FGFR ternary complex, as evidenced by their capacity to prevent FGF-2-mediated cell-cell attachment of FGFR-1-overexpressing, HSPG-deficient Chinese hamster ovary cells to wild-type HSPG-bearing cells. Direct interaction of the polysulfonates with FGF-2 was demonstrated by their ability to protect the growth factor from proteolytic cleavage. Accordingly, molecular modeling, based on the crystal structure of the interaction of FGF-2 with a heparin hexamer, showed the feasibility of docking PAMPS into the heparin-binding domain of FGF-2. In agreement with their FGF-2-binding capacity, PSS, PAS, and PAMPS inhibited FGF-2-induced cell proliferation in GM 7373 cells and murine brain microvascular endothelial cells. The antiproliferative activity of these compounds was associated with the abrogation of FGF-2-induced tyrosine phosphorylation of FGFR-1. Moreover, the polysulfonates PSS and PAS inhibited FGF-2-induced activation of mitogen-activated protein kinase-1/2, involved in FGF-2 signal transduction. In conclusion, sulfonic acid polymers bind FGF-2 by mimicking heparin interaction. These compounds may provide a tool to inhibit FGF-2-induced endothelial cell proliferation in angiogenesis and tumor growth.
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| pubmed:language |
eng
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| pubmed:journal | |
| pubmed:citationSubset |
IM
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| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Heparin,
http://linkedlifedata.com/resource/pubmed/chemical/Polymers,
http://linkedlifedata.com/resource/pubmed/chemical/Receptor, Fibroblast Growth...,
http://linkedlifedata.com/resource/pubmed/chemical/Receptor Protein-Tyrosine Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Fibroblast Growth Factor,
http://linkedlifedata.com/resource/pubmed/chemical/Sulfonic Acids,
http://linkedlifedata.com/resource/pubmed/chemical/Sulfur Compounds,
http://linkedlifedata.com/resource/pubmed/chemical/Trypsin,
http://linkedlifedata.com/resource/pubmed/chemical/poly(2-acrylamido-2-methyl-1-propane...,
http://linkedlifedata.com/resource/pubmed/chemical/poly(anetholesulfonic acid),
http://linkedlifedata.com/resource/pubmed/chemical/styrenesulfonic acid polymer
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| pubmed:status |
MEDLINE
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| pubmed:month |
Jul
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| pubmed:issn |
0026-895X
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| pubmed:author | |
| pubmed:issnType |
Print
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| pubmed:volume |
56
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| pubmed:owner |
NLM
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| pubmed:authorsComplete |
Y
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| pubmed:pagination |
204-13
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| pubmed:dateRevised |
2009-11-19
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| pubmed:meshHeading |
pubmed-meshheading:10385702-Animals,
pubmed-meshheading:10385702-Binding, Competitive,
pubmed-meshheading:10385702-CHO Cells,
pubmed-meshheading:10385702-Cattle,
pubmed-meshheading:10385702-Cells, Cultured,
pubmed-meshheading:10385702-Computer Simulation,
pubmed-meshheading:10385702-Cricetinae,
pubmed-meshheading:10385702-Endothelium,
pubmed-meshheading:10385702-Heparin,
pubmed-meshheading:10385702-Models, Molecular,
pubmed-meshheading:10385702-Molecular Mimicry,
pubmed-meshheading:10385702-Polymers,
pubmed-meshheading:10385702-Receptor, Fibroblast Growth Factor, Type 2,
pubmed-meshheading:10385702-Receptor Protein-Tyrosine Kinases,
pubmed-meshheading:10385702-Receptors, Fibroblast Growth Factor,
pubmed-meshheading:10385702-Signal Transduction,
pubmed-meshheading:10385702-Sulfonic Acids,
pubmed-meshheading:10385702-Sulfur Compounds,
pubmed-meshheading:10385702-Trypsin
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| pubmed:year |
1999
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| pubmed:articleTitle |
Modulation of fibroblast growth factor-2 receptor binding, signaling, and mitogenic activity by heparin-mimicking polysulfonated compounds.
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| pubmed:affiliation |
Rega Institute for Medical Research, University Hospital, Katholieke Universiteit Leuven, Leuven, Belgium. Liekens@rega.kuleuven.ac.be
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| pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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