| Matrix metalloproteinase-1 and thrombin differentially activate gene expression in endothelial cells via PAR-1 and promote angiogenesis. | |
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MedLine Citation:
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PMID: 18988801 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Many tumor types express matrix metalloproteinase-1 (MMP-1); its collagenase activity facilitates both tumor cell invasion and metastasis. MMP-1 expression is also associated with increased angiogenesis; however, the exact mechanism by which this occurs is not clear. MMP-1 proteolytically activates protease activated receptor-1 (PAR-1), a thrombin receptor that is highly expressed in endothelial cells. Thrombin is also present in the tumor microenvironment, and its activation of PAR-1 is pro-angiogenic. It is currently unknown whether MMP-1 activation of PAR-1 induces angiogenesis in a similar or different manner compared with thrombin. We sought to determine the mechanism by which MMP-1 promotes angiogenesis and to compare the effects of MMP-1 with those of thrombin. Our results demonstrate that via PAR-1, MMP-1 activates mitogen-activated protein kinase signaling cascades in microvessel endothelial cells. Although thrombin activation of PAR-1 also induces signaling through these pathways, the time-course of activation appears to vary. Gene expression analysis revealed a possible consequence of these signaling differences as MMP-1 and thrombin induce expression of different subsets of pro-angiogenic genes. Furthermore, the combination of thrombin and MMP-1 is more angiogenic than either protease alone. These data demonstrate that MMP-1 acts directly on endothelial cells as a pro-angiogenic signaling molecule and also suggest that the effects of MMP-1 may complement the activity of thrombin to better facilitate angiogenesis and promote tumor progression. |
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Authors:
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Jessica S Blackburn; Constance E Brinckerhoff |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2008-11-06 |
Journal Detail:
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Title: The American journal of pathology Volume: 173 ISSN: 1525-2191 ISO Abbreviation: Am. J. Pathol. Publication Date: 2008 Dec |
Date Detail:
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Created Date: 2008-11-21 Completed Date: 2008-12-17 Revised Date: 2009-11-18 |
Medline Journal Info:
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Nlm Unique ID: 0370502 Medline TA: Am J Pathol Country: United States |
Other Details:
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Languages: eng Pagination: 1736-46 Citation Subset: AIM; IM |
Affiliation:
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Department of Biochemistry, Dartmouth Medical School, Lebanon, NH 03756, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Antigens, CD31
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metabolism Biocompatible Materials / metabolism Cell Line Collagen / metabolism Drug Combinations Endothelial Cells / cytology, physiology* Enzyme Activation Gene Expression* Humans Laminin / metabolism MAP Kinase Signaling System / physiology Matrix Metalloproteinase 1 / genetics, metabolism* Molecular Sequence Data Neovascularization, Physiologic / physiology* Proteoglycans / metabolism Receptor, PAR-1 / genetics, metabolism* Thrombin / genetics, metabolism* |
| Grant Support | |
ID/Acronym/Agency:
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AR-26599/AR/NIAMS NIH HHS; CA-77267/CA/NCI NIH HHS; T32-AI07363/AI/NIAID NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Antigens, CD31; 0/Biocompatible Materials; 0/Drug Combinations; 0/Laminin; 0/Proteoglycans; 0/Receptor, PAR-1; 119978-18-6/matrigel; 9007-34-5/Collagen; EC 3.4.21.5/Thrombin; EC 3.4.24.7/Matrix Metalloproteinase 1 |
| Comments/Corrections | |
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