Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.30.1 (S1 nuclease)
 3,660 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The structure of the gene for human 70-kDa type IV collagenase (gelatinase) was determined. Three overlapping genomic clones were isolated and shown to contain 0.4 kilobase (kb) of the 5'-flanking region, the 27-kb structural gene, and 4.5 kb of the 3'-flanking region. The gene has 13 exons that vary in length from 110 to 901 base pairs (bp) and 12 introns that range from 175 to 4350 bp. Alignment of intron locations demonstrated that introns 1-4 and 8-12 of the type IV collagenase gene coincide with intron locations in the interstitial collagenase and stromelysin genes, indicating a close structural relationship of these metalloproteinase genes. Exons 5-7 are each 174 bp in size, and each codes for one complete internal repeat that resembles the collagen-binding domains of fibronectin. The transcription initiation site was determined by primer extension and S1 nuclease analyses. Analysis of the 0.4-kb 5'-flanking region of the gene showed that, in contrast to the genes of interstitial collagenease and stromelysin, there is no TATA box or 12-O-tetradecanoylphorbol-13-acetate-responsive element present in the promoter region, whereas there are two GC boxes. There is no CAAT box, but a potential binding site (CCCCAGGC) for the transcription factor AP-2 is located in the first exon.
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PMID:Structure of the human type IV collagenase gene. 216 31

This study examines endothelin-induced modulation of extracellular matrix synthesis and remodeling by fibroblasts, and its potential role in the pathogenesis of systemic sclerosis (scleroderma). Endothelin-1 promoted fibroblast synthesis of collagen types I and III, but not fibronectin, by a mechanism dependent upon both ETA and ETB receptors. Conversely, endothelin-1 inhibited both protein expression of matrix metalloproteinase 1 and zymographic activity exclusively via ETA receptors. A dual regulatory role for endothelin-1 in transcriptional regulation was suggested by the ability of endothelin-1 to enhance steady-state levels of collagen mRNA and activate the proalpha2(I) collagen (Col1a2) promoter, but in contrast to reduce matrix metalloproteinase 1 transcript expression and suppress transcription of a human matrix metalloproteinase 1 promoter reporter construct in transient transfection assays. Although endothelin-1 significantly enhanced remodeling of three-dimensional collagen lattices populated by normal fibroblasts, this was not observed for lattices populated by systemic sclerosis fibroblasts. Promotion of matrix remodeling was dependent upon ETA receptor expression and was blocked by specific inhibitors of tyrosine kinases or protein kinase C. Reverse transcriptase polymerase chain reaction, S1 nuclease, and functional cell surface binding studies showed that normal and systemic sclerosis fibroblasts express both ETA and ETB receptors (predominantly ETA), but that ETA receptor mRNA levels and ETA binding sites on fibroblasts cultured from systemic sclerosis skin biopsies are reduced by almost 50%. Endothelin-1 is thus able to induce a fibrogenic phenotype in normal fibroblasts that is similar to that of lesional systemic sclerosis fibroblasts. Moreover, reduced responsiveness to exogenous endothelin-1 in systemic sclerosis suggests that downstream pathways may have already been activated in vivo. These data further implicate dysregulated endothelin-receptor pathways in fibroblasts in the pathogenesis of connective tissue fibrosis.
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PMID:Fibroblast matrix gene expression and connective tissue remodeling: role of endothelin-1. 1123 16