Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.23 (MMP)
 4,246 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Stromelysin-3 (ST3) belongs to the matrix metalloproteinase (MMPs) family, a protease family involved in tissue remodeling. Although this family of enzymes is regulated by nuclear receptors, few hormone-responsive elements have been demonstrated in MMP promoters. In order to identify regulatory elements and/or factors that control the expression of the mouse st3 gene, we have analyzed genomic sequences encompassing 5 kilobase pairs of the ST3 promoter. Analysis of these sequences revealed several CCAAT/enhancer-binding proteins (C/EBP) and retinoic acid-responsive elements (RAREs), as well as one thyroid-responsive element. However, in contrast to most MMP promoters, no AP-1-binding sites were identified. Specific binding activities were demonstrated for all elements. Consistent with previous reports, retinoid X receptor is required for maximal binding to the ST3 RAREs and the TRE. The ST3-C/EBP element was shown to mediate dose-dependent promoter activation by C/EBPbeta. Among the RAREs, the proximal DR1-RARE was shown to be sufficient for ST3 promoter activation by ligand-bound retinoid receptors, whereas the two distal DR2-RAREs appear to be involved more in the control of base-line promoter activity. Accordingly, ST3 expression was induced by retinoic acid and was reduced in cells where specific retinoic acid receptors had been inactivated. The involvement of these conserved regulatory elements is discussed in the context of physiological or pathological situations associated with st3 expression. Our findings therefore assign to C/EBP, retinoids, and thyroid hormone important roles in the regulation of ST3 gene expression.
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PMID:Multiple regulatory elements in the murine stromelysin-3 promoter. Evidence for direct control by CCAAT/enhancer-binding protein beta and thyroid and retinoid receptors. 1099 3

The genetic background of rheumatoid arthritis (RA) is only partly understood, and several genes seem to be involved. The matrix metalloproteinases MMP1 (interstitial collagenase) and MMP3 (stromelysin 1) are thought to be important in destructive joint changes seen in RA. In the present study, functional relevant promoter polymorphisms of MMP1 and MMP3 were genotyped in 308 patients and in 110 controls, to test whether the polymorphisms contribute to the severity of the disease measured by radiographic progression of joint destruction. For comparison, the shared epitope of HLA DR4 and DR1 (SE) was determined by polymerase chain reaction. There was no association of MMP polymorphisms with susceptibility to RA. However, a strong linkage disequilibrium was observed between the 1G/2G (MMP1) and the 5A/6A (MMP3) polymorphisms (P << 10(-6); linkage disequilibrium index D' = 0.46). In factorial regression, the degree of radiographic joint destruction correlated significantly with the 1G-5A haplotype (P = 0.0001) and the interaction term 'estimated number of 1G-5A haplotypes x duration of disease' (P = 0.0007). This association was phasic, indicating that possession of the 1G-5A haplotype has a protective effect over a period of about 15 years of RA, but might be associated with a more pronounced radiographic progression later on. Similar results were also found with the 1G allele of MMP1 alone (P = 0.015) and with the interaction term 'estimated number of 1G alleles x duration of disease' (P = 0.014). The correlation of SE with the Ratingen score was comparable (0.044). The regression model of MMP haplotypes explained 35% of the variance of the radiographic score, whereas the SE explained 29%. The 1G-5A haplotype across the closely linked MMP1 and MMP3 gene loci is a newly described genetic factor strongly associated with the progression of joint damage in RA. Our findings suggest that there are haplotypes in a MMP cluster region that modify the joint destruction in RA in a phasic manner.
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PMID:Association of a specific haplotype across the genes MMP1 and MMP3 with radiographic joint destruction in rheumatoid arthritis. 1514 65