Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.17 (MMP-3)
 3,419 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chronic pancreatitis is characterized by proliferation of the extracellular matrix and by increased deposition of interstitial extracellular matrix proteins (collagens type I and III, fibronectin). In this study we analyzed the balance of expression of mRNAs encoding extracellular matrix components (collagens I, III and IV, laminin, fibronectin), extracellular matrix degrading metalloproteinases (MMP-1, -2 and -3) and tissue inhibitors of metalloproteinases (TIMP-1 and -2) in chronic pancreatitis (n = 8) and control pancreas (n = 7) by northern blot analysis. Transcripts for MMP-1 (interstitial collagenase), MMP-3 (stromelysin) and TIMP-1 were not detectable in chronic pancreatitis and control tissues. Steady-state levels of transcripts encoding extracellular matrix proteins, MMP-2 (72 kDa collagenase IV) and TIMP-2 were enhanced in 7 out of 8 chronic pancreatitis tissue samples and showed a large degree of variation between individual patients. Transcript levels could not be correlated to the histologically detectable degree of inflammation and fibrosis or to the total amount of deposited collagen protein, which was high in all chronic pancreatitis tissue samples as determined by a standard colorimetric procedure. Increased steady state levels of transcripts encoding extracellular matrix proteins or extracellular matrix degrading proteases may thus reflect the activity of processes involved in the remodeling of the gland during chronic inflammation. The precise role of overexpression of MMP-2 and its inhibitor TIMP-2 will have to be elucidated in further studies.
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PMID:Balance of expression of genes coding for extracellular matrix proteins and extracellular matrix degrading proteases in chronic pancreatitis. 801 97

An inhibitory activity toward matrix metalloproteinases such as interstitial collagenase, 72-kDa gelatinase/type IV collagenase, and stromelysin-1 was detected in an EDTA extract of pulverized roots of human teeth, and identified as TIMP-1 by sodium dodecyl sulphate-polyacrylamide gel electrophoresis and immunoblotting. Distribution of TIMP-1 in human cementum and dentine was investigated by a sandwich enzyme immunoassay in combination with an abrasive microsampling technique. TIMP-1 could not be detected in cementum from some teeth but in others decreased from a fairly low value at the surface towards the cementodentinal junction. TIMP-1 concentrations in the dentine increased consistently from the cementodentinal junction toward the predentine. The average TIMP-1 concentration in the dentine (54.1 +/- 18.5 pg/mg +/- SE) was significantly (P < 0.05) higher than that (9.6 +/- 6.0 pg/mg +/- SE) in the cementum.
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PMID:Identification of tissue inhibitor of metalloproteinases-1 (TIMP-1) in human teeth and its distribution in cementum and dentine. 802 99

Wound repair involves cell migration and tissue remodeling, and these ordered and regulated processes are facilitated by matrix-degrading proteases. We reported that interstitial collagenase is invariantly expressed by basal keratinocytes at the migrating front of healing epidermis (Saarialho-Kere, U. K., E. S. Chang, H. G. Welgus, and W. C. Parks, 1992. J. Clin. Invest. 90:1952-1957). Because of the limited substrate specificity of collagenase, principally for interstitial fibrillar collagens, other enzymes must also be produced in the wound environment to effectively restructure tissues with a complex matrix composition. Stromelysins-1 and -2 are closely related, yet distinct metalloproteinases, and both can degrade many noncollagenous connective tissue macromolecules. Using in situ hybridization and immunohistochemistry, we found that both stromelysins are produced by distinct populations of keratinocytes in a variety of chronic ulcers. Stromelysin-1 mRNA and protein were detected in basal keratinocytes adjacent to but distal from the wound edge in what probably represents the sites of proliferating epidermis. In contrast, stromelysin-2 mRNA was seen only in basal keratinocytes at the migrating front, in the same epidermal cell population that expresses collagenase. Stromelysin-1-producing keratinocytes resided on the basement membrane, whereas stromelysin-2-producing keratinocytes were in contact with the dermal matrix. Furthermore, stromelysin-1 expression was prominent in dermal fibroblasts, whereas no signal for stromelysin-2 was seen in any dermal cell. These findings demonstrate that stromelysins-1 and -2 are produced by different populations of basal keratinocytes in response to wounding and suggest that these two matrix metalloproteinases serve distinct roles in tissue repair.
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PMID:Distinct populations of basal keratinocytes express stromelysin-1 and stromelysin-2 in chronic wounds. 804 Feb 94

Matrix metalloproteinases (MMPs) together degrade virtually all the components of the extracellular matrix and are likely to play a role in remodeling of endometrial tissue during the normal menstrual cycle. Primary cultures of human endometrial stromal cells secreted a number of MMPs. MMP-1 (interstitial collagenase) and MMP-3 (stromelysin-1) were measured in culture medium by specific enzyme assays. Production of the enzymes did not correlate with the time of the menstrual cycle at which the tissue was collected. Identities of MMP-1 and MMP-3 were confirmed by Western blots, by comparison of mol wt with those of purified enzymes on casein zymography, and by inhibition of these activities with EDTA and 1,10-phenanthroline. Northern analysis demonstrated specific messenger ribonucleic acid for pro-MMP-1 and pro-MMP-3 in phorbol myristate acetate-stimulated stromal cells. Two gelatinases were detected by gelatin zymography: MMP-2 (gelatinase-A) was present in two forms (72 and 67 kilodaltons), and MMP-9 (gelatinase-B) was present as a homodimer with a mol wt of approximately 180 kilodaltons. MMP-9, but not MMP-2, secretion was stimulated by phorbol myristate acetate. All enzymes could be activated in vitro by (4-aminophenyl)mercuric acetate. Both interleukin-1 alpha and tumor necrosis factor-alpha stimulated the secretion of MMP-1, MMP-3, and MMP-9, but not MMP-2, from the cells in a concentration-dependent manner. MMP production by endometrial stromal cells has a potentially important role in the processes of menstruation and implantation.
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PMID:Matrix metalloproteinase production by cultured human endometrial stromal cells: identification of interstitial collagenase, gelatinase-A, gelatinase-B, and stromelysin-1 and their differential regulation by interleukin-1 alpha and tumor necrosis factor-alpha. 804 73

Members of the matrix metalloproteinase (MMP) family have been implicated in disease states such as arthritis, periodontal disease, and tumor cell invasion and metastasis. Stromelysin 1 (MMP-3) has a broad substrate specificity and participates in the activation of several MMP zymogens. We examined known sequences of MMP-3 cleavage sites in natural peptides and proteins and compared sequence specificities of MMP-3 and interstitial collagenase (MMP-1) in order to design fluorogenic substrates that (i) would be hydrolyzed rapidly by MMP-3, (ii) would discriminate between MMP-3 and MMP-1, and (iii) could be monitored continuously without interference from MMP amino acid residues. Designed substrates were then screened for activity toward MMP-1, gelatinase A (MMP-2), MMP-3, and gelatinase B (MMP-9). The first of these substrates, NFF-1 (Mca-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Lys-(Dnp)-Gly, where Mca is (7-methoxycoumarin-4-yl)acetyl and Dnp is 2,4-dinitrophenyl), was hydrolyzed equally well by MMP-3 and MMP-2 (kcat/Km approximately 11,000 s-1 M-1). MMP-1 had 25% of the activity of MMP-3 toward NFF-1. The second substrate, NFF-2 (Mca-Arg-Pro-Lys-Pro-Tyr-Ala-Nva-Trp-Met-Lys(Dnp)-NH2, where Nva is norvaline), was hydrolyzed 60 times more rapidly by MMP-3 (kcat/Km = 59,400 s-1 M-1) than MMP-1. Unfortunately, NFF-2 showed little discrimination between MMP-3, MMP-2 (kcat/Km = 54,000 s-1 M-1), and MMP-9 (kcat/Km = 55,300 s-1 M-1). The third substrate, NFF-3 (Mca-Arg-Pro-Lys-Pro-Val-Glu-Nva-Trp-Arg-Lys(Dnp)-NH2), was hydrolyzed rapidly by MMP-3 (kcat/Km = 218,000 s-1 M-1) and very slowly by MMP-9 (kcat/Km = 10,100 s-1 M-1), but there was no significant hydrolysis by MMP-1 and MMP-2. NFF-3 is the first documented synthetic substrate hydrolyzed by only certain members of the MMP family and thus has important application for the discrimination of MMP-3 activity from that of other MMPs. Although NFF-3 was designed by assuming that substrate subsites were independent and hence free energy changes derived from single mutation experiments were additive, we found discrepancies between predicted and experimental kcat/Km values, one on the order of 2000-5000. Thus, the design of additional discriminatory MMP substrates may require approaches other than assuming additive free energy changes, such as screening synthetic libraries and consideration of secondary and tertiary structures of substrates and the enzyme.
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PMID:Design and characterization of a fluorogenic substrate selectively hydrolyzed by stromelysin 1 (matrix metalloproteinase-3). 806 13

The metalloproteinase matrilysin is widely expressed in the epithelial tumor cells of malignant colorectal adenocarcinomas. Approximately 50% of benign adenomas also express low levels of matrilysin that is focally localized. The expression of stromelysin-1, stromelysin-3, and gelatinase A was observed in the stromal component of several carcinomas and was not present in adenomatous tissue. The expression of interstitial collagenase and gelatinase B was observed in occasional adenomas and carcinomas. Stromelysin-2 transcripts were not detectable in any of the samples examined. Tissue inhibitor of metalloproteinase-1 gene expression was widespread and was observed in both epithelial and stromal cells of adenomas and carcinomas. These results indicate that matrilysin gene expression is an early event in colorectal tumorigenesis and that the expression of stromelysin-1, stromelysin-3, and gelatinase A is primarily a late event. The observed gene expression patterns suggest that matrilysin may participate in early events in tumor progression and that multiple members of the metalloproteinase family may work in concert to facilitate late-stage tumor invasion and metastasis.
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PMID:Expression and localization of matrix-degrading metalloproteinases during colorectal tumorigenesis. 806 80

Death from cancer results from the development of metastases or local progression of tumour. Metastasis and local progression may result from the inappropriate activity of metalloproteinases released by tumour cells or of their regulatory peptides. We have developed quantitative assays for interstitial collagenase, stromelysin 1 and tissue inhibitors of metalloproteinase (TIMP) 1 and 2, which have allowed the study of serum levels of these proteins. Sera from 40 patients with prostatic cancer, stored prior to and after 6 and 12 months' treatment with a gonadotrophin-releasing hormone agonist and an anti-androgen were analysed. Levels were compared with two control groups, comprising 21 patients with active rheumatoid arthritis and 56 age-matched hospital attenders without arthritis or cancer. Contrasting levels have been found in patients with prostatic cancer as compared with hospital controls without cancer and patients with rheumatoid arthritis. Patients with prostatic cancer had higher levels of TIMP-1 and collagenase (P = 0.0001) and lower levels of TIMP-2 (P = 0.003) than controls. Patients with metastatic cancer had significantly higher levels of collagenase than those without metastases (P = 0.02). Patients with rheumatoid arthritis had significantly higher levels of stromelysin than either controls (P = 0.002) or patients with cancer (P = 0.008). Serum tissue inhibitor of metalloproteinase 1 in combination with collagenase levels was as sensitive as prostate-specific antigen as a marker of metastatic disease. These findings provide a basis for the investigation of the role of metalloproteinases and their inhibitors in other malignancies.
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PMID:Serum metalloproteinases and their inhibitors: markers for malignant potential. 808 Jul 38

Recessive dystrophic epidermolysis bullosa (RDEB) is a mutilating disease of the skin characterized by recurrent blistering and erosions that result from compromised integrity of the basement membrane zone. In this study, fibroblasts derived from the skin of RDEB patients were characterized for expression of the major metalloproteinases, particularly interstitial collagenase. Consistent with previous reports on increased collagenase protein levels in fibroblasts from some RDEB patients, we found that steady-state levels of collagenase mRNA were significantly increased in fibroblast strains derived from three of five RDEB patients compared to fibroblasts obtained from normal donors. Stromelysin mRNA was elevated in the same three fibroblast strains, whereas expression of neither the 72- nor the 92-kDa type IV collagenases was different from that of controls. Tissue inhibitor of metalloproteinases was expressed in RDEB fibroblasts at levels similar to those observed in normal fibroblasts. To investigate the mechanism behind the steady-state elevation in collagenase and stromelysin expression, AP-1 expression and activation were studied. Although levels of Jun expression were not different from those seen in normal fibroblasts, AP-1 activity, as assessed by ability to bind to a TPA response element-containing oligonucleotide, was endogenously elevated in RDEB fibroblasts compared to normal fibroblasts. Transfection studies using a plasmid construct containing the collagenase promoter linked to a CAT reporter gene demonstrated that RDEB fibroblasts were able to support active transcription of the promoter compared to normal fibroblasts. These studies support the hypothesis that RDEB fibroblasts contain chronically activated AP-1, and perhaps other transactivating factors, that contribute to the cellular phenotype of collagenase and stromelysin overexpression.
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PMID:Constitutive activation of the collagenase promoter in recessive dystrophic epidermolysis bullosa fibroblasts: role of endogenously activated AP-1. 814 67

Synthetic inhibitors of interstitial collagenase, tri- and tetrapeptidyl hydroxamic acids, have been developed and tested for their inhibitory activities against human matrix metalloproteinases. A water soluble inhibitor, p-NH2-Bz-Gly-Pro-D-Leu-D-Ala-NHOH (FN-439) inhibited interstitial and granulocyte collagenases, granulocyte gelatinase and skin fibroblast stromelysin with IC50 of 1 x 10(-6) M, 3.0 x 10(-5) M and 1.5 x 10(-4), respectively, but not thermolysin and serine proteinases. FN-439 was found to retain its inhibitory activity against matrix metalloproteinases even after prolonged incubation with pronase or human granulocyte elastase, indicating a favorite candidate of the inhibitor to modulate metalloproteinase activities in vivo.
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PMID:Inhibition of matrix metalloproteinases by peptidyl hydroxamic acids. 814 88

In this study, we have used high resolution gel-filtration chromatography and measurements of Ki to compare the capacity of full-length native stromelysin, C-terminal truncated stromelysin (Phe100-Pro273), and matrilysin (the only metalloproteinase spontaneously lacking a C-terminal hemopexin-like domain) to bind to the tissue inhibitor of metalloproteinases (TIMP). While prostromelysin failed to bind TIMP, active stromelysin bound to the inhibitor avidly, exhibiting an affinity for TIMP (Ki = 8.3 x 10(-10) M) essentially identical to that of active interstitial collagenase as determined by competition experiments. C-terminal truncated stromelysin also formed a higher M(r) complex with TIMP which survived gel filtration. However, when truncated stromelysin was forced to compete with its full-length parent molecule for limiting amounts of TIMP, the full-length enzyme preferentially bound to the inhibitor. Indeed, binding studies indicated a Ki of 5.95 x 10(-9) M for the truncated variant's interaction with TIMP, only 14% as tight as that of full-length stromelysin. We also examined the interaction between TIMP and matrilysin, the only metalloproteinase which naturally lacks a C-terminal domain. Promatrilysin failed to bind the inhibitor. However, active matrilysin readily bound TIMP, forming a complex that resisted separation by gel filtration. When active matrilysin was forced to compete with truncated stromelysin for limiting amounts of TIMP, both enzymes appeared to complex the inhibitor with nearly equivalent efficacy. Indeed, active matrilysin exhibited a Ki for TIMP of 4.5 x 10(-9) M, essentially identical to that of truncated stromelysin. These data indicate that, as is true for collagenase, the C-terminal domain of stromelysin contributes significantly to its capacity to bind the physiologic inhibitor, TIMP. Furthermore, since stromelysin readily processes in vitro to a C-terminal truncated form, this enzyme species, as well as the full-length metalloproteinase matrilysin, may resist inhibition by TIMP in areas of active inflammation in vivo.
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PMID:Contribution of the C-terminal domain of metalloproteinases to binding by tissue inhibitor of metalloproteinases. C-terminal truncated stromelysin and matrilysin exhibit equally compromised binding affinities as compared to full-length stromelysin. 817 79


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