Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.24.35 (matrix metalloproteinase 9)
 2,207 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Members of the gelatinase subclass of the matrix metalloproteinase family have the capacity to degrade denatured collagens of all types and native types IV, V, and VII collagens. The authors identified the metalloproteinase species of the gelatinase class produced by the cells of rabbit corneal tissue. Two different molecular forms of gelatinase, visualized as enzymatic activities, that undergo electrophoresis with different mobilities on gelatin zymograms are synthesized by corneal cells in serum-free organ culture. The enzyme species that has the slower mobility is biochemically and immunologically related to a gelatinase synthesized by macrophages and neutrophils which has been called both type IV and type V collagenase. The second gelatinase species is related to a second enzyme, the product of a different gene, which has also been called type IV collagenase. The electrophoretic mobilities of these enzymes on polyacrylamide gels indicate the inactive proenzyme forms. The authors refer to these enzymes as 92-kilodalton (kD) gelatinase and 72-kD gelatinase based on their electrophoretic mobilities under sulfhydryl-reducing conditions. In primary cell culture, corneal epithelial cells were found to synthesize predominantly the 92-kD gelatinase species whereas the 72-kD gelatinase is synthesized mostly by stromal fibroblasts. However, each cell type can produce small amounts of the other enzyme. The 72-kD gelatinase, mostly in the proenzyme form, can be extracted from the normal corneal stroma without culturing, but expression of 92-kD gelatinase can only be detected in cell or organ culture. The substrate specificities of these enzymes suggests that they may be of central importance in the degradation of the epithelial basement membrane and in formation of the epithelial defect that precedes corneal ulceration.
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PMID:Expression of collagenolytic/gelatinolytic metalloproteinases by normal cornea. 217 Feb 94

We have reported that SV40-transformed human lung fibroblasts secrete a 92-kDa metalloprotease which is not detectable in the parental cell line IMR-90. We now present the complete structure of this enzyme along with the evidence that it is identical to the 92-kDa metalloprotease secreted by normal human alveolar macrophages, phorbol ester-differentiated monocytic leukemia U937 cells, fibrosarcoma HT1080 cells, and cultured human keratinocytes. A similar, perhaps identical, enzyme can be released by polymorphonuclear cells. The preproenzyme is synthesized as a polypeptide of predicted Mr 78,426 containing a 19 amino-acid-long signal peptide and secreted as a single 92,000 glycosylated proenzyme. The purified proenzyme complexes noncovalently with the tissue inhibitor of metalloproteases (TIMP) and can be activated by organomercurials. Activation with phenylmercuric chloride results in removal of 73 amino acids from the NH2 terminus of the proenzyme, yielding an active form capable of digesting native types IV and V collagen. The in vitro substrate specificity of the enzyme using these substrates was indistinguishable from that of the 72-kDa type IV collagenase. The 92-kDa type IV collagenase consists of five domains; the amino-terminal and zinc-binding domains shared by all members of the secreted metalloprotease gene family, the collagen-binding fibronectin-like domain also present in the 72-kDa type IV collagenase, a carboxyl-terminal hemopexin-like domain shared by all known enzymes of this family with the exception of PUMP-1, and a unique 54-amino-acid-long proline-rich domain homologous to the alpha 2 chain of type V collagen.
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PMID:SV40-transformed human lung fibroblasts secrete a 92-kDa type IV collagenase which is identical to that secreted by normal human macrophages. 255 98

Simian virus 40 (SV40)-transformed human lung fibroblasts secrete both 72-kDa type IV collagenase and a closely related 92-kDa type IV collagenase that was not detected in the parental cell line. The 92-kDa type IV procollagenase purified from these cells exists in a noncovalent complex with the tissue inhibitor of metalloproteases, TIMP. Here we report that the 72-kDa type IV procollagenase purified from HRAS-transformed human bronchial epithelial cells, SV40-transformed lung fibroblasts, and normal skin fibroblasts exists in a stable but noncovalent stoichiometric complex with a 24-kDa inhibitor referred to here as "TIMP-2." TIMP-2 is closely related to TIMP, as demonstrated by comparison of the partial amino acid sequence of this protein to that of TIMP, although it does not cross-react with TIMP-specific antibody. The TIMP-2 inhibitor interacts with the 72-kDa type IV collagenase in preference to the 92-kDa type IV collagenase that forms a complex exclusively with TIMP. The 72-kDa type IV collagenase-TIMP-2 complex can be activated with organomercurials to yield a catalytically competent enzyme. Activation occurs concomitantly with autoproteolytic cleavage of the amino terminus of the protein and does not require dissociation of the complex. Both activity and activation of the complex can be completely inhibited by further addition of stoichiometric quantities of purified TIMP-2 or recombinant TIMP.
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PMID:Human 72-kilodalton type IV collagenase forms a complex with a tissue inhibitor of metalloproteases designated TIMP-2. 255 4

Collagenase type IV degradation activity was examined in metastatic and nonmetastatic clones of the Lewis lung carcinoma (3LL) and of the T10 sarcoma. Conditioned media prepared from cells of both tumors grown in vitro contained low degradation activities, whereas conditioned media from organ cultures of the same clones grown as solid tumors in animals exhibited higher degradation activities. Analysis of subcellular fractions of tumor cells showed that collagenase type IV activity was localized mainly in the cytoplasmic fraction. Crude homogenates or detergent lysates manifested low degradation activities. Little activity was associated with purified plasma membrane preparations and endoplasmic reticular fractions. However, addition of plasma membrane to conditioned media and to cytoplasmic fractions reduced the degradation activities of the cytoplasmic fractions. Possibly a factor that inhibits collagenase type IV exists in the cells in a vesicular form. No correlation between degradation activity and metastatic capacity was demonstrated in the models used in this study. Both metastatic and nonmetastatic clones of the same tumor similarly could degrade basement membrane components.
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PMID:Proteolytic enzymes in tumor metastasis. II. Collagenase type IV activity in subcellular fractions of cloned tumor cell populations. 298 56

The expression of a basement membrane (BM) collagen-degrading metalloprotease (Type IV collagenase) was studied in a herpes simplex virus (HSV)-2 transformed hamster fibrosarcoma and its in vivo derived sublines and in vitro derived clones of varying metastatic potential. The primary parent tumor was shown to release more or less Type IV collagenolytic activity compared with its sublines (derived from lung nodules that developed after resection of the primary tumor). Normal baby hamster kidney and hamster embryo fibroblasts did not secrete detectable amounts of BM collagenase, whereas normal hamster lung fibroblast secreted intermediate levels of Type IV collagenase activity. The collagenase IV activity of the parent tumor and its in vivo and in vitro derived sublines was assayed in vitro and compared with the ability of the cells lines to spontaneously metastasize in vivo. No correlation between the ability to secrete type IV collagenase and metastatic propensity was detected. Although all cell lines secreted type IV collagenase, the highest activity was recorded for a nonmetastatic variant.
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PMID:Type IV collagenase activity of a primary HSV-2-induced hamster fibrosarcoma and its in vivo metastases and in vitro clones. 304 Feb 11

Proteolytic enzymes like collagenase type IV are relevant to the destruction of matrix-components within the scope of invasive tumor growth. Preneoplastic lesions of the bronchial mucosa and early squamous cell carcinomas were investigated immunohistochemically using anti-human-collagenase type IV monoclonal antibodies due to the question of enzymatic proteolysis of basement membrane structures. With increasing malignant epithelial transformation an increase of collagenase type IV expression was observed in single atypical cells of severe dysplasia, carcinoma in situ and early cancer of the bronchus. Collagenase type IV expression can be evaluated as enhanced proteolytic potency for degradation of matrix structures of the basement membrane as one factor for early infiltration in preneoplastic lesions up to early squamous cell carcinomas of the lung.
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PMID:[Anti-human collagenase type IV expression in preneoplastic lesions and early squamous cell lung carcinoma]. 751 Dec 99

Human umbilical vein endothelial cells (HUVECs) invade collagen gels and establish vascular-like structures within the gel following stimulation with phorbol esters. This process was quantitated by measuring release of radioactivity from gels composed of [3H]collagen. Collagen was steadily degraded over the period of several weeks by phorbol ester-treated cells while little collagenolysis by cells not receiving phorbol ester was noted. Examination of matrix metalloproteinases (MMPs) secreted by HUVECs revealed a prominent induction of interstitial collagenase. Production of the mature forms of gelatinase A was also stimulated, as was the secretion of gelatinase B. Stromelysin was not detected. Two inhibitors of MMPs, the naturally occurring tissue inhibitor of metalloproteinases (TIMP; 10 micrograms/ml) and the synthetic, peptide inhibitor BB-94 (1 microM) were both effective at blocking HUVEC-mediated collagen degradation. Morphological examination of control, PMA-treated HUVECs, as well as PMA-treated HUVECs receiving TIMP or BB-94, revealed that MMP inhibition resulted in a block to invasion and tubule formation within the collagen gels. Similar results for MMP expression and inhibition of tubule formation in vitro were obtained with human dermal microvascular endothelial cells. Examination of collagen proteolytic fragments revealed that both BB-94 and TIMP blocked cleavage of the alpha 1 and alpha 2 chains of type I collagen and the appearance of tropocollagen fragments A and B, demonstrating that the inhibitors were acting directly upon interstitial collagenase. Our results demonstrate that interstitial collagenase is required for angiogenesis in vitro.
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PMID:Interstitial collagenase is required for angiogenesis in vitro. 751 58

The anthracycline antibiotics, daunorubicin, doxorubicin, and epirubicin, which are widely used for treatment of malignancies, have been evaluated for their effect on angiogenesis in relation to the inhibition of collagenase type IV reported previously. In the chick chorioallantoic membrane (CAM) system of angiogenesis, anthracyclines inhibited vascular density at doses of 5-20 micrograms/disc as well as collagenous protein biosynthesis, which is a reliable index of angiogenesis. Similarly, all three anthracyclines inhibited tube formation in the in vitro system of angiogenesis using human umbilical vein endothelial cells (HUVECs) plated on Matrigel. The inhibition was dose-dependent and caused 50% inhibition at concentrations of 2.5-15 micrograms/mL. At concentrations of anthracyclines which prevented tube formation and angiogenesis, there were no cytotoxic effects, as evidenced by methylene blue uptake, and the growth of these endothelial cells was not inhibited. The experimental antitumor agent titanocene dichloride inhibited collagenase type IV from Walker 256 carcinosarcoma with IC50 approximately 0.2 mM. Titanocene also prevented angiogenesis in the CAM and tube formation by HUVECs on Matrigel at concentrations that were without effect on growth or cytotoxicity of endothelial cells or Walker 256 cells in culture. The antiangiogenic effect of the aforementioned antitumor agents at therapeutically attainable concentrations may explain, at least in part, their antitumor properties because angiogenesis is an essential process for tumor growth and metastasis. The antiangiogenic effect is, however, unrelated to metalloproteinase inhibition because higher concentrations are required for that effect than for inhibition of angiogenesis.
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PMID:Inhibition of angiogenesis by anthracyclines and titanocene dichloride. 752 59

In the initial phases of angiogenesis, endothelial cells must degrade and cross the vessel basement membrane, as do tumor cells during invasion and metastasis formation. Various metalloproteinases have been implicated in tumor cell invasion, in particular MMP-2 (72 kDa collagenase IV, gelatinase A), which has been demonstrated to be associated with tumor metastasis formation. Supernatants from AIDS-Kaposi sarcoma (KS) cells induce normal endothelial cells to invade through a reconstituted basement membrane (Matrigel) in vitro, which correlates with the angiogenic potential of KS cells in vivo. Here we demonstrate that two specific inhibitors of MMP-2, TIMP-2 and a peptide from the MMP-2 propeptide region (peptide 74), inhibit endothelial cell invasion induced by AIDS-KS cell supernatants. Smooth muscle cells were much less sensitive to these inhibitors. These data suggest that MMP-2 activation is a key event in endothelial cell invasion, the initial phase of tumor-associated neoangiogenesis. Inhibition of this enzyme could be an effective treatment for KS and tumor-associated angiogenesis.
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PMID:Inhibition of AIDS-Kaposi's sarcoma cell induced endothelial cell invasion by TIMP-2 and a synthetic peptide from the metalloproteinase propeptide: implications for an anti-angiogenic therapy. 753 74

Incubation of progelatinase B, isolated from human polymorphonuclear leukocytes, with TIMP-1 leads to the formation of the progelatinase B/TIMP-1 complex. This complex behaves like a Janus in a similar manner as we previously described for the progelatinase A/TIMP-2 complex. It shows the properties of TIMP-1 and is a better inhibitor for gelatinase A than for gelatinase B. Treatment with trypsin leads to activation of the binary complex. The activity, however, amounts only to slightly more than 10% of the activity of free gelatinase B, not complexed with TIMP-1. When the progelatinase B/TIMP-1 complex inhibits an active matrix metalloproteinase, a ternary complex is generated that after activation displays a distinct higher proteolytic activity than the active binary complex. The active binary complex cannot be transformed into the active ternary complex.
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PMID:Generation and activity of the ternary gelatinase B/TIMP-1/LMW-stromelysin-1 complex. 757 48


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