Egr-1 Mediates Extracellular Matrix-driven Transcription of Membrane Type 1 Matrix Metalloproteinase in Endothelium*
- From the Department of Pathology, Yale University Medical School, New Haven, Connecticut 06520 and the ‡Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195
Abstract
Matrix metalloproteinase activity is instrumental in processes of cellular invasion. The interstitial invasion of endothelial cells during angiogenesis is accompanied by up-regulation of several matrix metalloproteinases, including membrane type 1 matrix metalloproteinase (MT1-MMP). In this study, we show that endothelial cells stimulated to undergo angiogenesis by a three-dimensional extracellular matrix environment increase production of the transcription factor Egr-1. Increased binding of Egr-1 to the MT1-MMP promoter correlates with enhanced transcriptional activity, whereas mutations in the Egr-1 binding site abrogate the increased transcription of MT1-MMP in the stimulated cells. These data identify Egr-1-mediated transcription of MT1-MMP as a mechanism by which endothelial cells can initiate an invasive phenotype in response to an alteration in extracellular matrix environment, thus functionally associating MT1-MMP with a growing number of proteins known to be up-regulated by Egr-1 in response to tissue injury or mechanical stress.
Footnotes
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↵* Supported in part by United States Public Health Service Grants RO1-HL5108 (to J. A. M.) and F23-HL09983 (to T. L. H.) and by funding from Cleveland Clinic Foundation (to S. S. A.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵§ To whom correspondence should be addressed: Dept. of Pathology, Yale University School of Medicine, 310 Cedar St., LH 115, New Haven, CT 06520. Tel.: 203-785-2763; Fax: 203-785-7303.
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↵2 T. L. Haas, D. Stitelman, S. J. Davis, S. S. Apte, and J. A. Madri, unpublished observations.
- Abbreviations:
- MMP
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matrix metalloproteinase
- MT
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membrane-type
- 3D
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three-dimensional
- 2D
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two-dimensional
- ActD
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actinomycin D
- EMSA
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electrophoretic mobility shift assay
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- Received March 26, 1999.
- The American Society for Biochemistry and Molecular Biology, Inc.
