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)

The enzymes that comprise the family of matrix metalloproteinases (MMPs) share the capacity to degrade extracellular matrix components. A large body of evidence indicates that certain members of this metalloproteinase gene family play critical roles in determining the malignant phenotype of solid tumors. We previously have derived transformed cell lines with vastly different metastatic potentials by transfecting different combinations of oncogenes into primary rat embryo cells. Conditioned medium from those cell lines was assayed by Western blot analysis for the production of four separate matrix metalloproteinases to see whether a correlation could be found between protease expression and the metastatic phenotype. The transformed rat embryo cell lines with high metastatic potential were found to produce high levels of the stromelysin 1 (MMP-3) and stromelysin 2 (MMP-10) proteases, while the nonmetastatic lines produced low or undetectable levels of these two enzymes. No correlation was seen between the metastatic phenotype of the cell lines and the level of expression of two other matrix metalloproteinases, the M(r) 72,000 type IV collagenase (MMP-2) and the M(r) 92,000 gelatinase (MMP-9). These data suggest that the differential regulation of the stromelysin proteases may contribute to the difference seen in the metastatic potential of these cell lines.
Cancer Res 1992 Sep 15
PMID:Expression of matrix metalloproteinase genes in transformed rat cell lines of high and low metastatic potential. 132 87

The action of three matrix metalloproteinases (MMPs), 72- and 95-kDa gelatinases (MMP-2 and MMP-9) and PUMP (MMP-7), and a cysteine proteinase, cathepsin B, were investigated on aggrecan the major proteoglycan of cartilage. All the enzymes cleaved aggrecan although the activity of the 95-kDa gelatinase was very low. Specific cleavage sites were investigated following incubation with a purified aggrecan G1-G2 domain fragment (150 kDa). Both gelatinases produced 110-kDa G2 and 56-kDa G1 products by a single cleavage at an Asn-Phe bond within the interglobular domain close to the G1 domain. This was similar to the action of stromelysin (MMP-3) (Fosang, A. J., Neame, P. J., Hardingham, T. E., Murphy, G., and Hamilton, J. A. (1991) J. Biol. Chem. 266, 15579-15582). Cathepsin B also produced two fragments from a single cleavage at a Gly-Val bond only three amino acids C-terminal to the metalloproteinase cleavage site. PUMP cleaved at the metalloproteinase Asn-Phe site, but in addition produced a low yield of a smaller G2 fragment (56 kDa) corresponding to cleavage between Asp441 and Leu442 (human sequence), within the interglobular domain, close to the G2 domain. The apparent difference in size between the two G2 fragments released by PUMP (110 and 56 kDa) was much greater than predicted from the peptide length between the cleavage sites (100 amino acids). However, keratanase digestion greatly reduced the size of the 110-kDa G2 fragment, while producing only a small reduction in size of the 56-kDa product, showing that there was approximately 30-40 kDa of keratan sulfate attached to the interglobular domain between the PUMP cleavage sites. This new structural information on aggrecan may account for the previously observed stiffness of the interglobular domains when viewed by rotary shadowing electron microscopy (Paulsson, M., Morgelin, M., Wiedemann, H., Beardmore-Gray, M., Dunham, D. G., Hardingham, T. E., Heinegard, D., Timpl, R., and Engel, J. (1987) Biochem. J. 245, 763-772). These results show that in spite of a high keratan sulfate content the interglobular domain provides important sites for cleavage by different proteinases, including several members of the matrix metalloproteinase family.
J Biol Chem 1992 Sep 25
PMID:The interglobular domain of cartilage aggrecan is cleaved by PUMP, gelatinases, and cathepsin B. 132 52

The vEts oncoprotein and its progenitor cEts1(p68) belong to a growing family of transcription factors that are related by the conserved ets domain. We show here that the ets domain and adjacent COOH-terminal amino acids are required for DNA binding by cEts1(p68). vEts differs from cEts1(p68) in both the COOH-terminal sequence and an amino acid substitution in the ets domain. The change in the COOH-terminal sequence markedly decreases its affinity for specific DNA, and the ets domain mutation further diminishes binding. vEts does not trans-activate through the ets (PEA3) motif in vivo. Surprisingly, vEts still efficiently trans-activates the promoters of two genes, stromelysin and collagenase, that are found to be overexpressed in transformed cells. The AP1 motifs of both promoters are required for efficient activation. vEts does not bind to the AP1 motif, even in the presence of cJun and cFos. The DNA-binding domain of Ets1 is required for activation through the AP1 element. Activation is inhibited by the expression of the glucocorticoid and retinoic acid receptors, suggesting that activation by Ets does not involve reversal of negative regulators of AP1. We suggest that activation is by an indirect mechanism involving activation of endogenous genes. Our results show that vEts differs from its progenitor cEts1(p68) in its trans-activating properties. The findings suggest that activation of the Jun and Fos oncoprotein pathway is important for transformation by Ets.
Cell Growth Differ 1992 Sep
PMID:Oncogenic conversion alters the transcriptional properties of ets. 132 27

In basal cell carcinoma, release of proteolytic activity is implicated in extracellular matrix degradation and tumor infiltration. The stromelysin metalloproteinase family is a major candidate for the matrix proteolytic activity in infiltrative tumors. However, in murine models of basal cell carcinoma, neither stromelysin 1 nor 2 appears to play a role in tumor infiltration. We have analyzed the expression of the newly described stromelysin 3 in human basal cell carcinoma using Northern blot analysis and in situ hybridization. In 12 of 14 cases, levels of stromelysin 3 expression were more than tenfold above those observed in normal skin. In one of five cases of squamous cell carcinoma, stromelysin 3 expression was tenfold above levels seen in normal skin. Stromelysin 3 expression was either undetectable or extremely weak in all five cases of infiltrative malignant melanoma. In basal cell carcinoma, stromelysin 3 transcripts were localized by in situ hybridization to the stromal tissue immediately adjacent to basal cell carcinoma, the tumor cells themselves being negative. Therefore, expression of stromelysin 3 in stromal cells may be expected to play a significant role in destruction of the basal membrane zone and extracellular matrix in basal cell carcinoma invasion.
Diagn Mol Pathol 1992 Sep
PMID:Expression of stromelysin 3 in the stromal elements of human basal cell carcinoma. 134 67

Leukoregulin (LR), a product of activated T-cells, has been recently shown to modulate the metabolism of extracellular matrix components in human skin fibroblast cultures (Mauviel et al., J Cell Biol 113:1455-1462, 1991). In this study we focused our attention on the effects of LR on the expression of stromelysin-1 gene. This matrix metalloprotease has a broad spectrum of degradative activity and it is also required for maximal activation of interstitial collagenase. Incubation of skin fibroblast cultures with LR resulted in a dose- and time-dependent elevation of stromelysin-1 mRNA levels, the maximum enhancement being up to approximately sevenfold. This effect was abolished by cycloheximide, suggesting a requirement for ongoing protein synthesis. Transient cell transfections with a promoter/reporter gene construct containing 1.3 kb of 5' flanking DNA of the human stromelysin-1 gene linked to the chloramphenicol acetyl transferase (CAT) gene, indicated enhancement of promoter activity by LR. This enhancement was abolished by a single base substitution in the AP-1 binding site of the promoter. Furthermore, gel mobility shift assays demonstrated enhanced AP-1 binding activity in nuclear extracts from cells incubated with LR. However, LR did not alter the activity of a construct containing three AP-1 sequences in front of the thymidine kinase promoter linked to the CAT gene. These results collectively suggest that activation of stromelysin-1 gene expression by LR is mediated by AP-1 regulatory elements which are necessary, but not sufficient, for gene response.
J Cell Biochem 1992 Sep
PMID:Leukoregulin, a T-cell derived cytokine, upregulates stromelysin-1 gene expression in human dermal fibroblasts: evidence for the role of AP-1 in transcriptional activation. 142 74

Studies of aural and other body tissues suggest that otosclerosis represents the local manifestation of a general disorder of connective tissue. In particular, collagen abnormalities have been described. We have undertaken a pilot study of the in vivo messenger RNA (mRNA) transcription for procollagenase (precursor of collagenase), as well as for stromelysin and tissue inhibitor of metalloprotease (TIMP), an activator and a specific inhibitor of tissue collagenase activity, respectively. Human skin from individuals with surgically confirmed otosclerosis was compared to skin from their family members (clinically positive and clinically negative) and from unrelated normal controls. Preliminary data indicate that on average there are significantly lower levels of mRNA production for stromelysin among individuals with otosclerosis as compared to all others tested. Similar trends were demonstrated for TIMP and procollagenase, although these did not achieve statistical significance. In addition to suggesting a pathogenetic mechanism for the development of the disease, these data could serve as the basis of possible confirmatory tests for early diagnosis of otosclerosis and as a method for evaluating the genotype of offspring of affected individuals prior to their age of clinical manifestation. This could translate into the application of prophylactic treatment regimens in the future. The proposed abnormalities also suggest candidate genes for otosclerosis.
Am J Otol 1992 Sep
PMID:Aberration of the tissue collagenase system in association with otosclerosis. 144 74

Human cartilage link protein exists as three native components, while equine, bovine, and porcine cartilage link protein exist as two and Swarm rat chondrosarcoma link protein exists as only one component. These nonhuman link protein components represent intact protein structures, and there is little evidence for proteolytically modified forms in nonhuman tissues. In human cartilage, the proteolytic production of modified link proteins increases with age, whereas high amounts of such products were not seen in the nonhuman tissues. However, the small amounts of link protein fragments that were observed in the nonhuman cartilages were of a similar size to their human counterparts. On digestion of human proteoglycan aggregate with stromelysin, rapid modification of the link protein components occurred, whereas the aggregates from nonhuman cartilages showed incomplete cleavage of their link protein components. The relative resistance of nonhuman link protein to stromelysin may in part be due to a unique amino acid substitution present near the enzymic cleave site.
J Orthop Res 1992 Sep
PMID:Link protein shows species variation in its susceptibility to proteolysis. 150 Sep 76

Extracellular matrix (ECM) plays an important role in the maintenance of mammary epithelial differentiation in culture. We asked whether changes in mouse mammary specific function in vivo correlate with changes in the ECM. We showed, using expression of beta-casein as a marker, that the temporal expression of ECM-degrading proteinases and their inhibitors during lactation and involution are inversely related to functional differentiation. After a lactation period of 9 d, mammary epithelial cells maintained beta-casein expression up to 5 d of involution. Two metalloproteinases, 72-kD gelatinase (and its 62-kD active form), and stromelysin, and a serine proteinase tissue plasminogen activator were detected by day four of involution, and maintained expression until at least day 10. The expression of their inhibitors, the tissue inhibitor of metalloproteinases (TIMP) and plasminogen activator inhibitor-1, preceded the onset of ECM-degrading proteinase expression and was detected by day two of involution, and showed a sharp peak of expression centered on days 4-6 of involution. When involution was accelerated by decreasing lactation to 2 d, there was an accelerated loss of beta-casein expression evident by day four and a shift in expression of ECM-remodeling proteinases and inhibitors to a focus at 2-4 d of involution. To further extend the correlation between mammary-specific function and ECM remodeling we initiated involution by sealing just one gland in an otherwise hormonally sufficient lactating animal. Alveoli in the sealed gland contained casein for at least 7 d after sealing, and closely resembled those in a lactating gland. The relative expression of TIMP in the sealed gland increased, whereas the expression of stromelysin was much lower than that of a hormone-depleted involuting gland, indicating that the higher the ratio of TIMP to ECM-degrading proteinases the slower the process of involution. To test directly the functional role of ECM-degrading proteinases in the loss of tissue-specific function we artificially perturbed the ECM-degrading proteinase-inhibitor ratio in a normally involuting gland by maintaining high concentrations of TIMP protein with the use of surgically implanted slow-release pellets. In a concentration-dependent fashion, involuting mammary glands that received TIMP implants maintained high levels of casein and delayed alveolar regression. These data suggest that the balance of ECM-degrading proteinases and their inhibitors regulates the organization of the basement membrane and the tissue-specific function of the mammary gland.(ABSTRACT TRUNCATED AT 400 WORDS)
J Cell Biol 1992 Sep
PMID:Coordinated expression of extracellular matrix-degrading proteinases and their inhibitors regulates mammary epithelial function during involution. 151 97

The lapine synovial cell line HIG-82 secretes factors that activate cultures of articular chondrocytes. We showed that these "chondrocyte-activating factors" (CAF) also activate quiescent cultures of HIG-82 cells in an autocrine fashion. After exposure to partially purified preparations of CAF, HIG-82 cells increased their synthesis of prostaglandin E2 (PGE2) and the neutral proteinases collagenase, gelatinase, and stromelysin. CAF also induced their own synthesis. Both PGE2 synthesis and endogenous production of CAF started to increase between 1 and 3 h after treatment of cells with exogenous CAF, but the neutral proteolytic activity of the conditioned medium took approximately 12 h to increase. Induction of neutral proteinases by CAF was inversely related to the degree of cell confluency, whereas their induction by phorbol myristate acetate (PMA) was independent of this parameter. Both CAF and PMA provoked morphologic changes in subconfluent cultures of HIG-82 cells. Although the intracellular concentration of free Ca2+ increased rapidly in response to CAF, the results of experiments with calcium channel blockers and ionophores failed to support a role for Ca2+ fluxes in induction of neutral proteinases. In similar types of experiments, no evidence could be found to implicate fluxes in cyclic AMP or cyclic GMP in the induction of collagenase, gelatinase, or stromelysin. Because PMA is such a strong inducer of these enzymes, protein kinase C may be involved in signal transduction, but further work is needed to determine whether this is so.
J Orthop Res 1991 Sep
PMID:Studies on the autocrine activation of a synovial cell line. 165 86

The proenzyme fragment of the 72 kDa type IV collagenase contains a conserved amino acid sequence, MRKPRCGN(V)PDV, that is shared with other members of the matrix metalloproteinase family, such as interstitial collagenase and stromelysin. This sequence is lost upon the autocatalytic removal of the 80-84 amino acids from the amino terminus of these proenzymes following enzyme activation. The loss of this profragment converts the latent proenzyme species into a stable active enzyme species. In the present study, we demonstrate that this conserved prosegment sequence is an inhibitor of these enzymes and plays a critical role in maintenance of the latent state of the matrix metalloproteinases. Peptides containing the conserved sequence, MRKPRCGNPDV, were capable of inhibiting activated enzyme. Free cysteine was also an effective inhibitor, whereas reduced glutathione was a less effective inhibitor. Oxidized glutathione was not inhibitory. The 72 kDa type IV collagenase holoproenzyme preparations did not contain a free cysteinyl side chain that reacted with the sulfhydryl substitution reagent 5,5'-dithiobis(2-nitrobenzoic acid) (Ellman's reagent). However, addition of ethylenediaminetetraacetic acid to the reaction mixture to generate the apoenzyme form resulted in the detection of titrable sulfhydryl side chains. Based on these data, we postulate that in the latent enzyme state the conserved profragment sequence interacts with the metal atom at the active site through a sulfhydryl-metal atom coordination that is further stabilized by the amino acyl residues surrounding the essential 73Cys residue. Disturbance of this interaction results in enzyme activation.(ABSTRACT TRUNCATED AT 250 WORDS)
Am J Med Sci 1991 Sep
PMID:Inhibition of human type IV collagenase by a highly conserved peptide sequence derived from its prosegment. 165 51


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