Document Detail


Matrix metalloproteinase-1 and thrombin differentially activate gene expression in endothelial cells via PAR-1 and promote angiogenesis.
MedLine Citation:
PMID:  18988801     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Jessica S Blackburn; Constance E Brinckerhoff
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2008-11-06
Journal Detail:
Title:  The American journal of pathology     Volume:  173     ISSN:  1525-2191     ISO Abbreviation:  Am. J. Pathol.     Publication Date:  2008 Dec 
Date Detail:
Created Date:  2008-11-21     Completed Date:  2008-12-17     Revised Date:  2013-08-02    
Medline Journal Info:
Nlm Unique ID:  0370502     Medline TA:  Am J Pathol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1736-46     Citation Subset:  AIM; IM    
Affiliation:
Department of Biochemistry, Dartmouth Medical School, Lebanon, NH 03756, USA.
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MeSH Terms
Descriptor/Qualifier:
Antigens, CD31 / 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:
AR-26599/AR/NIAMS NIH HHS; CA-77267/CA/NCI NIH HHS; P30 CA023108/CA/NCI NIH HHS; R01 AR026599/AR/NIAMS NIH HHS; R01 CA077267/CA/NCI NIH HHS; T32 AI007363/AI/NIAID NIH HHS; T32-AI07363/AI/NIAID NIH HHS
Chemical
Reg. No./Substance:
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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