Gelatinase B/lacZ transgenic mice, a model for mapping gelatinase B expression during developmental and injury-related tissue remodeling.
Matrix metalloproteinases (MMPs) drive normal tissue remodeling and are implicated in a wide range of pathologies. Although MMP activity is controlled at multiple levels, the primary regulation of MMP activity is transcriptional. The transcriptional promoter elements required for MMP gene expression in cultured cells have been defined, but this has not been extended to the in vivo situation. In this paper, we show that the DNA sequences between -522 and +19 of the rabbit gelatinase B gene (MMP-9) (as characterized in the transgenic mouse line 3445) constitute a minimal promoter that drives appropriate developmental and injury-induced reporter gene expression in transgenic mice. We further show that the expression and activity of three transcription factors (NF-kappaB, AP-2, and Sp1) that control the activity of the gelatinase B promoter are selectively induced in the epithelium migrating to heal a wound. Although promoter activity parallels expression of the endogenous gene in cell cultures, we show by several criteria that cell cultures cannot model many aspects of promoter regulation in vivo. This study reveals that the transgenic mouse line 3445 might be a useful model for investigating the regulation of gelatinase B expression in vivo and for identifying and characterizing new drugs that can control gelatinase B gene transcription.
Mohan
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Vision Research Laboratories, New England Medical Center, and the Departments of Ophthalmology, Anatomy, and Cell Biology, Tufts University School of Medicine, Boston, Massachusetts 02111, USA.
Rinehart
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Bargagna-Mohan
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Fini
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D000818:Animals; D002460:Cell Line; D017364:Collagenases / Q000235:genetics*; D003315:Cornea / Q000166:cytology; D004268:DNA-Binding Proteins / Q000235:genetics; D004195:Disease Models, Animal; D005314:Embryonic and Fetal Development / Q000235:genetics; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D017930:Genes, Reporter / Q000235:genetics; D006651:Histocytochemistry; D007763:Lac Operon / Q000235:genetics*; D020780:Matrix Metalloproteinase 9; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D016329:Sp1 Transcription Factor / Q000235:genetics; D050656:Transcription Factor AP-2; D014157:Transcription Factors / Q000235:genetics; D014945:Wound Healing / Q000502:physiology*
D004268:DNA-Binding Proteins; D016328:NF-kappa B; D016329:Sp1 Transcription Factor; D050656:Transcription Factor AP-2; D014157:Transcription Factors; D017364:Collagenases; D020780:Matrix Metalloproteinase 9