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)

SV-40 transformed human lung fibroblasts and HT 1080 fibrosarcoma cells secrete a 92-kDa type IV collagenase (in addition to 72-kDa type IV collagenase identical to that found in macrophages, phorbol ester differentiated U937 cells, and keratinocytes. The expression of this protease is induced by the tumor promoter TPA, and interleukin-1 and was not detected in the parental human lung fibroblast. The 92-kDa preproenzyme has a predicted Mr of 78,426, including a 19 amino acid long hydrophobic signal peptide. The apparent discrepancy between the predicted molecular weight and the molecular weight of the secreted protein is due to a post-translational modification of the enzyme through glycosylation. The 92-kDa type IV collagenase consists of five distinct domains, including a unique 54 amino acid long collagen--like domain, and is a member of the secreted ECM metalloprotease gene family. Both the 72 and 92-kDa type IV collagenase contain a fibronectin-like collagen binding domain. The mosaic structure of the secreted ECM metalloproteases is a result of a recruitment of the functional units from ECM structural macromolecules into an enzyme protein in the process of evolution. The 92-kDa and 72-kDa type IV collagenase proenzymes form a noncovalent complex with inhibitors, which is activatable by APMA, yielding an enzymes with similar if not identical substrate specificity profile. Our results demonstrate that while the 92-kDa type IV collagenase forms a stoichiometric complex with TIMP, the 72-kDa type IV collagenase, purified from the same starting material, contains a novel 24-kDa inhibitor-TIMP-2.
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PMID:Mosaic structure of the secreted ECM metalloproteases and interaction of the type IV collagenases with inhibitors. 133 9

Transformed human fibroblasts secrete two structurally and functionally related inhibitors of matrix metalloproteinases, tissue inhibitor of metalloproteinases (TIMP) 1 and 2. In assays measuring the relative inhibitory capability of TIMP-1 and TIMP-2 against autoactivated 72-kDa gelatinase, which consists of two major active peptides and several inactive fragments, TIMP-2 was more effective than TIMP-1. The isolated 42.5-kDa active fragment that formed as a result of the autoactivation of 72-kDa gelatinase showed the greatest preference for TIMP-2; at half-maximal inhibition, TIMP-2 was greater than 10-fold more effective than TIMP-1. TIMP-2 was also greater than 2-fold more effective than TIMP-1 at inhibiting 72-kDa gelatinase-TIMP-2 complexes activated with 4-aminophenylmercuric acetate, and greater than 7-fold more effective than TIMP-1 at inhibiting 92-kDa gelatinase activated with 4-aminophenylmercuric acetate. Furthermore, these active gelatinases preferentially bound 125I-TIMP-2 when incubated with equal amounts of radiolabeled TIMP-1 and TIMP-2. The ratios of 125I-TIMP-2/125I-TIMP-1 binding to 92-kDa gelatinase, autoactivated 72-kDa gelatinase, and 42.5-kDa fragment were 4.4, 10, and 33, respectively. On the other hand, interstitial collagenase was inhibited by TIMP-1 greater than 2-fold more effectively than TIMP-2 in assays measuring cleavage of loose collagen fibrils.
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PMID:Preferential inhibition of 72- and 92-kDa gelatinases by tissue inhibitor of metalloproteinases-2. 164 75

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

HIV infection of monocytes resulted in twofold elevation of adhesion molecule LFA-1 (both alpha L/CD11a and beta 2/CD18 subunits) and LFA-3 (CD58), with no apparent increase in LFA-2 (CD2) or various beta 1-integrins. Homotypic aggregation of monocytes was evident 2 h after exposure to virus and was inhibited by mAbs to both the alpha L- and beta 2-subunits of LFA-1. HIV-infected monocytes also showed a marked increase in adherence to human capillary endothelial cell monolayers derived from brain, lung, and skin. This adherence was inhibited by mAb to either LFA-1 subunit and by mAb to the counter-receptor intercellular adhesion molecule-1. Cocultivation of HIV-infected monocytes with endothelial cells increased permeability of endothelial cell monolayers to 125I albumin in transwell assay systems. The increased endothelial permeability induced by HIV-infected monocytes was associated with a substantial disruption of the endothelial cell monolayer. Morphologic disruption was not a direct toxic effect on endothelial cells, but appeared to be secondary to changes in endothelial cell-cell or cell-matrix interactions. Northern blot analysis showed increased expression of gelatinase B (92-kDa gelatinase), tissue inhibitor of metalloproteinase TIMP-1, and TIMP-2 in the HIV-infected monocytes. Consistent with these Northern analyses, secretion of gelatinase activity in culture fluids of HIV-infected monocytes was also increased and was dependent on the stage of virus replication. Incubation of HIV-infected monocytes with the proteinase inhibitors TIMP-1 and TIMP-2 inhibited the increased permeability of endothelial cell monolayers to 125I albumin. These results suggest possible mechanisms for extravasation of HIV-infected monocytes through vascular endothelium into tissue in early stages of HIV disease.
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PMID:HIV-1 infection alters monocyte interactions with human microvascular endothelial cells. 752 19

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

Matrix metalloproteinases (MMPs) are a family of inducible enzymes that degrade extracellular matrix components, allowing cells to traverse connective tissue structures efficiently. Specific tissue inhibitors (TIMPs) function as physiologic inhibitors of MMP activity. Because neovascularization may require various proteinases, we characterized the profile of metalloenzyme production by microvascular endothelial cells (MEC) and the modulation of expression by phorbol esters (PMA) and by the physiologically relevant cytokines tumor necrosis factor-alpha (TNF-alpha), basic fibroblast growth factor, and interferon-gamma. MMP expression by MEC and large-vessel human umbilical vein endothelial cells (HUVEC) was determined by enzyme-linked immunosorbent assay, immunoprecipitation, Northern hybridization, and transfection assays. Constitutive expression of MMPs by endothelial cells was low. PMA stimulated the production of collagenase, stromelysin, 92-kDa gelatinase, and TIMP-1 in both endothelial cell types. TIMP-2 was constitutively expressed by MEC and HUVEC, but was down-regulated by PMA. TNF-alpha induced an endothelial-cell-specific up-regulation of collagenase with a concomitant inhibition of PMA-induced TIMP-1 up-regulation, a response that is distinct from that of fibroblasts. Interferon-gamma up-regulated TIMP-1 production by MEC and blocked PMA and TNF-induced up-regulation of collagenase. Northern hybridization assays showed pretranslational control of PMA-, basic fibroblast growth factor-, and TNF-alpha-induced MMP expression. Collagenase-promoter CAT constructs containing 2.28 kb of the 5' region of the collagenase gene demonstrated transcriptional regulation. The potential physiologic relevance of such regulation was shown in an in vitro migration assay. MEC were stimulated to migrate by wounding and exposure to TNF-alpha. Collagenase mRNA was prominently expressed by the migrating cells, as shown by in situ hybridization. In sum, MEC have a unique profile of MMP expression and regulation compared with other cell types, which may be important for wound healing and angiogenesis, particularly during the early phase of migration.
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PMID:Human dermal microvascular endothelial cells produce matrix metalloproteinases in response to angiogenic factors and migration. 754 47

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

The gene expression of five matrix metalloproteinases (MMPs) and two tissue inhibitors of metalloproteinases (TIMPs) was studied in human gliomas in vivo and in vitro to evaluate their roles in glioma invasion. Simultaneous expression of one to four MMP genes and two TIMP genes was found in 17 surgical glioma specimens, and one MMP (gelatinase A) gene and two TIMP genes were simultaneously expressed in tissue of three brains. The concomitant overexpression of gelatinase A, gelatinase B, and occasional matrilysin genes was associated with the malignancy of gliomas and accompanied by overexpression of the TIMP-1 gene. In five human glioma cell lines, gelatinase A, TIMP-1, and TIMP-2 genes were constitutively expressed in alll cell lines: the matrilysin gene in three cell lines; the stromelysin gene in two cell lines; and the interstitial collagenase gene in one cell line. There was a clear difference in the expression of gelatinase B and stromelysin genes between surgical glioma specimens and glioma cell lines: the gelatinase B gene was not expressed constitutively in vitro but was overexpressed in vivo, whereas the stromelysin gene was not expressed in vivo but was expressed in some cell lines. To find the cause of that difference in vivo and in vitro, the transcriptional regulations of MMP and TIMP genes by tumor promoter, growth factors, or cytokines were studied in vitro. Interstitial collagenase, gelatinase B, stromelysin, and TIMP-1 genes were upregulated in many cell lines by phorbol-12-myristate-13-acetate (PMA) and in some cell lines by epidermal growth factor, tumor necrosis factor-alpha, or interleukin-1 beta. Transforming growth factor-beta 1 (TGF beta 1) upregulated gelatinase A and matrilysin genes in some cell lines, and there were no clear responses from any MMP and TIMP genes to interleukin-6. Thus, the transcriptional modulation of MMP genes by these growth factors and cytokines seemed insufficient to explain the difference in gelatinase B and stromelysin gene expressions in vivo and in vitro and was suggestive of the genetic alteration of glioma cells in vitro, the heterogeneous cell population in glioma tissues, or both. Furthermore, the in vitro invasion of glioma cells through Matrigel in response to PMA, TGF beta 1, or TIMP-1 was assessed by chemoinvasion assay. In most cell lines, invasion was significantly stimulated by PMA or TGF beta 1 but suppressed by TIMP-1.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Matrix metalloproteinases and tissue inhibitors of metalloproteinases in human gliomas. 761 76

The adult mammalian temporomandibular joint (TM) disc is a fibrocartilaginous tissue that undergoes normal developmental remodeling, requiring removal of the existing extracellular matrix and its replacement by new matrix macromolecules. This remodeling is probably mediated by matrix-degrading enzymes, but to date none has been demonstrated in association with the TMJ disc. We characterized, identified, and determined the regulation of proteinases and proteinase inhibitor (PIs) synthesized by TMJ disc cells in organ and cell cultures. TMJ discs were retrieved from 14-week-old male NZW rabbits and both tissue- and disc-derived cells were cultured in serum-free medium. The conditioned media were retrieved at 12-hour intervals and assayed for proteinases and PIs in gelatin- and casein-impregnated polyacrylamide gels. Three proteinases with gelatinolytic activities at 92 kDa, 72 kDa, and 42/57 kDa and one caseinolytic activity at 51/54 kDa were detected. All were inhibited by 1,10-1 phenanthroline, thus characterizing these enzymes as matrix metalloproteinases (MMPs), most likely 92-kDa gelatinase (proMMP-9), 72-kDa gelatinase (proMMP-2), procollagenase (proMMP-1), and prostromelysin (proMMP-3). The identity of the latter two MMPs was confirmed by Western blots. Two PIs and 30 kDa and 20 kDa, probably tissue inhibitors of metalloproteinase (TIMP) and TIMP-2, were observed on reverse zymograms. TPA, a protein kinase-C agonist, increased the expression of 92-kDa gelatinase and 30-kDa PI by both explanted discs and isolated disc cells. The profile of MMPs constitutively expressed by disc cells is similar to that of synovial fibroblasts but different from that of chondrocytes.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Characterization and identification of proteinases and proteinase inhibitors synthesized by temporomandibular joint disc cells. 762 41

Malignant glioma is a local invasive tumor in the central nervous system. The mRNA expression of five matrix metalloproteinases (MMPs) and two tissue inhibitors of metalloproteinases (TIMPs) was examined in surgical specimens of three brain tissues, two astrocytomas, four anaplastic astrocytomas and eleven glioblastomas, including recurrent one anaplastic astrocytoma and two glioblastomas. In the control brain tissues, mRNA expression was high for TIMP-2, low for gelatinase A and TIMP-1, and undetectable for gelatinase B, interstitial collagenase, stromelysin and matrilysin. Gelatinase B and TIMP-1 were concomitantly overexpressed in primary glioblastomas. In addition, the average expression level of gelatinase A increased 3.0 fold in astrocytomas and anaplastic astrocytomas and 6.0 fold in glioblastomas, compared to the brain tissues. Matrilysin was induced variably in more than half of the primary glioblastomas, and interstitial collagenase was slightly induced in some primary and recurrent glioblastomas. Stromelysin was characteristically not expressed in any gliomas, and the expression level of TIMP-2 did not significantly change in the gliomas. These results suggest that the concomitant increased expression of gelatinase A, gelatinase B and occasional matrilysin genes is associated with the malignancy of gliomas and accompanied by the increased expression of TIMP-1 gene.
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PMID:[Increased expression of gelatinases A and B, matrilysin and TIMP-1 genes in human malignant gliomas ]. 763 25


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