Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.3 (collagenase)
 18,340 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Many bacteria that spread in the skin produce enzymes that digest extracellular matrix components. Borrelia burgdorferi spreads from a skin inoculation site to form the characteristic erythema migrans skin lesion. It was determined that B. burgdorferi does not produce collagenase, elastase, hyaluronidase, or other enzymes that digest extracellular matrix components. However, B. burgdorferi bound human plasmin, plasminogen (Pgn), and urokinase-type plasminogen activator (uPA). When spirochetes were sequentially incubated with Pgn and uPA, bioactive plasmin was generated on the surface of B. burgdorferi. B. burgdorferi did not produce an endogenous Pgn activator. Fluorochrome-conjugated uPA and Pgn colocalized to the terminus of the spirochete. In a mouse model, uPA-treated B. burgdorferi were more infectious than control spirochetes. Binding of host uPA and Pgn to form a bioactive extracellular matrix protease on B. burgdorferi represents a mechanism that could facilitate dissemination and localization of spirochetes to sites of vascular injury.
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PMID:Binding of human plasminogen and urokinase-type plasminogen activator to the Lyme disease spirochete, Borrelia burgdorferi. 775 1

Evidence indicates that breakdown of articular cartilage resulting in the loss of normal joint function is the distinctive feature of osteoarthritis. Degradation of cartilage extracellular matrix components involves the action of at least 2 classes of proteinases: serine proteinases and metalloproteinases. Receptors have been described on a wide range of cell lines for many such proteinases [urokinase-type plasminogen activator (u-PA), plasminogen/plasmin, collagenase], which subsequently activate each other on the solid phase of the cell surface, leading to cartilage destruction. We review the leading role of u-PA and its receptor (u-PAR) in cartilage degradation.
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PMID:Plasminogen activator and receptor in osteoarthritis. 775 14

Concomitant expression of urokinase type plasminogen activator (uPA) and its surface receptor (uPAR) has been shown to correlate strongly with a more invasive tumor cell phenotype. A highly malignant human epidermoid carcinoma cell line (HEp3) was transfected with a vector capable of expressing an antisense transcript complementary to 300 bases of the 5' end of uPAR, including the ATG codon. Six stably transfected antisense (AS-2, 3, 5, 9, 10, 12) and eight control clones were characterized. All clones produced high levels of uPA activity. Examination of collagenase production and doubling time showed that all of the clones tested produced similar activities. The antisense clones showed a 20-74% reduction in the uPAR sites; the uPAR mRNA level was also reduced. A test of the invasive ability of all clones in a modified chorioallantoic membrane (CAM) showed that invasiveness of the antisense-inhibited clones was directly proportional to the density of surface uPAR. The AS-2 clone, which expressed the lowest number of uPARs showed a significantly reduced level of invasion. The invasiveness of additional AS-inhibited clones was also reduced. Seven control and four AS-inhibited clones were tested for tumorigenicity on CAMs of chick embryos. Inoculation of control cells produced large tumors, while the As clones were non-tumorigenic. AS-2 did not produce tumors even if kept in vivo for up to 10 weeks.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The effect of antisense inhibition of urokinase receptor in human squamous cell carcinoma on malignancy. 807 94

Inflammatory cytokines like interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) are linked to abnormal cartilage and bone loss in a variety of pathological conditions. We have investigated the effect of TNF-alpha on the synthesis and/or steady-state mRNA levels of collagen, alkaline phosphatase (ALP), plasminogen activators (PAs) and their inhibitor PAI-1, and collagenases (MMPs) and their inhibitor TIMP-1 by human osteoblastic, HOS TE85, cells in monolayer cultures. HOS TE85 cells possess approximately 2000 TNF-alpha receptors per cell with a Kd value of 0.67 nM and receptor of approximately 60 kDa. TNF-alpha enhances urokinase-plasminogen activator (u-PA) activity and steady-state mRNA levels twofold without affecting tissue-plasminogen activator (t-PA) or PAI-1. The increase in u-PA mRNA is due to enhanced transcription of this gene. mRNA levels or activities of collagenase 1 (MMP-1), 72- and 92-kDa gelatinases (MMP-2 and MMP-9) are also nearly doubled with little change in the level of expression of TIMP-1. TNF-alpha does not significantly affect the activity or mRNA levels of ALP. TNF-alpha decreases collagen as well as general protein synthesis. However, the steady-state mRNA for the alpha 2 chain of collagen type I is increased three- to fourfold. These results show that TNF-alpha may increase pathological bone turnover by enhancing the rate of transcription of proteases capable of degrading the nonmineralized osteoid layer and decelerating the maturation of the extracellular matrix formed by osteoblasts.
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PMID:Modulation of proteases and their inhibitors in immortal human osteoblast-like cells by tumor necrosis factor-alpha in vitro. 808 23

The enzymatic activities of uPA, and a collagenase-like proteinase in the post-nuclear fraction of cell homogenates of a metastatic carcinomatous cell line following X-ray irradiation were examined by the use of chromogenic substrates and by casein- or gelatin-containing zymographies and electrophoretic gel stained with avidin-conjugated peroxidase. Enhanced activities were observed in these cells, while those of 5'nucleotidase and Na(+)-K(+)-ATPase were attenuated. A partial purification and characterization of the collagenase showed that it was able to hydrolyze the heat-denatured type-I collagen more efficiently than the native one. The activation of both uPA and collagenase enables an efficient degradation of matrix barrier proteins. These findings suggest that following a certain dose range of X-ray irradiation, tumor cells may increase their ability to migrate and invade through the enhancement of uPA and collagenase activities.
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PMID:The concomitant augmentation of urokinase-type plasminogen activator and collagenase-like proteinase activities in X-ray irradiated cells of a human metastatic carcinomatous line. 809

The neutral protease, plasmin, is generated by plasminogen activators, and is ascribed an important role in several physiological and pathological circumstances characterized by tissue remodelling and cell motility. The two types of plasminogen activator, tissue-type (tPA) and urokinase-type (uPA), are produced by osteoblasts, as is the specific PA inhibitor, PAI-1. Some hormones which activate bone resorption increase PA activity produced by osteoblasts, by decreasing the production of PAI-1. The increased PA activity has been suggested to facilitate bone resorption by activating latent collagenase, thus preparing the bone surface for osteoclastic resorption. Targeted and regulated production of plasmin might also contribute to the coupling of bone formation to resorption, by activating latent TGF beta in bone, and activating IGF-1 by freeing it from association with inhibitory binding protein. TGF beta itself is a powerful inhibitor of PA activity, an effect achieved by enhancing mRNA and protein for PAI-1. Thus the PA system is a potentially important regulatory system in bone remodelling, whose local activity is controlled through concerted actions of hormones and locally generated growth factors and cytokines.
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PMID:The plasminogen activator and inhibitor system in bone remodelling. 813 Jul 29

Many of the Ets proteins have been shown to be transcription activators. In vitro, Ets 1 proteins are involved in the transcriptional induction of genes such as stromelysin 1, collagenase 1 or urokinase type plasminogen activator, which are proteases responsible for extracellular matrix degradation. In vivo, c-ets 1 is expressed in a wide variety of embryonic tissues in migrating cells, especially in endothelial cells during blood vessel formation. C-ets 1 is also expressed in stromal cells of invasive carcinomas. In the present work, we have investigated the expression of both c-ets 1 and u-PA, a putative target gene of the Ets 1 proteins, within a biological model which includes both embryonic and tumoral aspects. Implantation and placentation of the mouse embryo display migration of the trophoblastic cells, which invade the stroma of the uterine endometrium and trigger the establishment of a new vascular frame. Using in situ hybridization, we show that the overlapping of expression of c-ets 1 and u-PA is restricted to some maternal cell populations from the invasive front and to the endothelial cells of the endometrial vasculature. C-ets 1 is never expressed in trophoblasts. In contrast, u-PA expression in trophoblasts is strong and coincides with the embryo invasive phase. In the embryo proper, c-ets 1 displays a spatio-temporal expression pattern similar to that described in the chick embryo. Until E 10.5, u-PA is expressed neither in embryonic nor in extra-embryonic structures. The respective roles of c-ets 1 and u-PA and their relationship during mammalian placentation are discussed.
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PMID:Involvement of the proto-oncogene c-ets 1 and the urokinase plasminogen activator during mouse implantation and placentation. 817 96

Murine leukemic cells from the WEHI-3B line, present in the cell surface a latent collagenase activity which is activated proteolytically. In this paper we show that this enzyme is activated by plasmin generated by the activity of a urokinase-like plasminogen activator (u-PA) also present in the surface of these cells. Using a reverse fibrin autography method we found that u-PA is the major proteolytic activity present in the cell membranes. This fact suggests that u-PA could represent a normal activating system for this collagenase.
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PMID:Membrane-associated procollagenase of leukemic cells is activated by urokinase-type plasminogen activator. 824 9

Trophoblast cells of the blastocyst and of the first trimester placenta penetrate the endometrial basement membrane during the process of implantation and placental development. However, this invasive capacity seems to be restricted to the fetomaternal interface, as few trophoblast cells can be identified in the decidua, and trophoblasts rarely penetrate the maternal blood vessels. We have shown that the high invasive ability of first trimester human trophoblasts in vitro depends on collagenase activated by plasmin generation. In our study we used invasive first trimester trophoblast cells in conjunction with as in vitro amnion invasion assay to assess the role of hCG in the invasive process. hCG inhibited trophoblast invasion capacity in a dose-dependent fashion but exerted no effect on the ability of the trophoblasts to attach to the basement membrane. The activity of collagenase by trophoblasts (determined by zymography) was down-regulated by hCG, again in a dose-dependent manner. In contrast, hCG had no effect on production of the tissue inhibitor of metalloproteinases. Similar inhibitory effects of hCG on urokinase-plasminogen activator (uPA) and the activity of trophoblast-conditioned media were shown (measured by degradation of S-2444). The hCG effect on collagenase production was not mediated by the expression of procollagenase messenger RNA (mRNA), the expression of the mRNA encoding tissue inhibitor of metalloproteinase, or the expression of uPA mRNA, suggesting posttranscriptional control of hCG action. High levels of hCG attenuated the activity of commercial uPA but had no effect on commercial collagenase activity. These observations suggest that hCG may play a role in the trophoblast invasion process by inhibition of uPA activity, in turn decreasing collagenase activity and thereby reducing trophoblast cell invasion.
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PMID:High levels of human chorionic gonadotropin retard first trimester trophoblast invasion in vitro by decreasing urokinase plasminogen activator and collagenase activities. 826 34

Plasmin was found to degrade the fibronectin (Fn) mesh produced by cultures of normal rabbit corneal fibroblasts, cause breakdown of F-actin-containing microfilament bundles ("stress fibers"), and increase levels of active type I interstitial collagenase (MMP-1) in the medium. Fibroblast cultures derived from alkali-burned, ulcerating rabbit corneas also responded to plasmin by secreting collagenase, detected only in active form. Moreover, harvests from organ cultures of ulcerating corneas not only had higher levels of urokinase-like plasminogen activator (uPA) than normal cultures but also had higher levels of Fn degradation fragments. The results are consistent with reports that indicate that perturbation of the alpha 5 beta 1 integrin (Fn) receptor by proteolytic fragments of Fn causes the increased synthesis and secretion of MMP-1. The uPA/plasmin system, therefore, might have an important role in regulating collagenase synthesis, secretion, and activation during wound remodelling and stromal ulceration.
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PMID:Regulation of corneal fibroblast MMP-1 collagenase secretion by plasmin. 830 64


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