Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.73 (urokinase-type plasminogen activator)
 10,685 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

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

Current hypotheses suggest that the degradation of cervical collagen and elastin leads to cervical effacement and dilation during labor. The collagenolytic activity is thought to be initiated through the conversion of latent (pro)collagenase to active collagenase by the plasmin formed from plasminogen or by other proteases similarly formed from their inactive zymogens. We presently demonstrate that meperidine stimulates the activity of several enzymes in the proteolytic cascade leading toward proteolysis of connective tissue proteins. Meperidine in its therapeutic concentration range produces a 26% stimulation of urokinase activity on substrate S-2444, a 39% stimulation of plasmin activity on substrate S-2551, and a 33% stimulation of collagenase activity on 14C-labeled globin substrate. These direct effects on the enzyme activities are noted in vitro with the purified enzymes and were confirmed with several small molecular weight chromogenic substrates and with 14C-globin protein substrate. Oxytocin at levels found during active labor fails to stimulate the in vitro activity of purified urokinase, plasmin, collagenase, trypsin, or tissue-type plasminogen activator. The effect of meperidine on the proteolytic enzymes suggests that its ability to promote cervical effacement and distention during labor may be at least partially due to a meperidine-induced stimulation of cervical proteases.
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PMID:Direct stimulation of urokinase, plasmin, and collagenase by meperidine: a possible mechanism for the ability of meperidine to enhance cervical effacement and dilation. 847 75

The regulation of microvessel formation and the expression of CNS-specific endothelial properties are attributed to perivascular astroglia. Specific proteolytic pathways mediate processes such as tissue remodeling, differentiation, invasion, and metastasis. We used a co-culture system in which C6 glial cells induce CNS microvascular endothelial cells to form capillary-like structures to examine the role of plasminogen activators and collagenases in CNS microvessel morphogenesis. Fibrin zymography revealed the presence of high-molecular weight urokinase-type plasminogen activator (uPA), low-molecular weight uPA, and uPA/inhibitor complexes within endothelial cultures and cocultures. Gelatin zymography revealed the presence of 92-, 72-, and 62-kDa type IV collagenases within endothelial cultures and cocultures. uPA activity was confirmed by incubating the extracts with amiloride, an inhibitor of uPA. Collagenase activity was confirmed by incubating the gels with EDTA, an inhibitor of metalloproteinases. Quantitative densitometry showed a six- to eightfold decrease in coculture uPA during capillary-like structure formation. Substantially less change in type IV 72-kDa procollagenase activity was seen in cocultures during capillary-like structure formation, but active type IV 62-kDa collagenase activity was significantly increased during capillary-like structure formation. These findings establish that uPA and activated type IV collagenase activity specifically regulates morphogenic endothelial responses to glial interactions and suggest mechanisms by which microvessels respond within the CNS.
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PMID:Modulation of serine proteinases and metalloproteinases during morphogenic glial-endothelial interactions. 862 23

Matrix proteases and the transcription factor c-Ets-1, which regulates in vitro stromelysin 1, collagenase 1, and urokinase type plasminogen activator gene promoters, are frequently expressed in invasive carcinomas. Using in situ hybridization and immunohistochemistry, we analyzed collagenase 1, stromelysins 1 and 3, matrilysin, urokinase type plasminogen activator, and c-Ets-1 gene expression on serial frozen sections of 39 intraepithelial bronchial lesions, including areas of hyperplasia, metaplasia, dysplasia, carcinoma in situ, and corresponding lung carcinomas in 13 patients. In intraepithelial lesions, expression of all matrix proteases was detected in epithelial cells. Conversely, in microinvasive or invasive lesions, a fibroblastic expression was observed. Collagenase 1 and matrilysin were expressed seldomly in intraepithelial lesions and frequently in carcinomas (p = 0.0016 and p < 0.0001, respectively). Stromelysin 1 was expressed inconsistently in 31% of intraepithelial lesions of all grades and in 50% of carcinomas. Stromelysin 3 and urokinase type plasminogen activator were expressed only, but frequently, in preinvasive lesions (dysplasia, carcinoma in situ) and in carcinomas. The expression of stromelysin 3 in fibroblasts started with dysplasia and carcinoma in situ, but was more frequent in invasive than preinvasive lesions (p = 0.0012). c-Ets-1 was more often expressed in carcinomas than in intraepithelial lesions (p < 0.0001) and was always expressed in fibroblasts. Comparing preinvasive lesions adjacent to or at a distance from squamous lung carcinoma, stromelysin 3 epithelial expression was more frequent in preinvasive lesions adjacent to invasive foci than in others (p = 0.036). We conclude that (a) both epithelial expression of matrix proteases in intraepithelial bronchial lesions and their stromal expression in microinvasive and invasive lesions suggest their role in lung tumor development; (b) c-Ets-1 does not act as a transcriptional activator for matrix proteases genes in preinvasion, although it might regulate collagenase 1 gene during lung tumor progression; and (c) matrix proteases might offer new therapeutic targets for chemoprevention of lung cancer.
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PMID:Changes in the expression of matrix proteases and of the transcription factor c-Ets-1 during progression of precancerous bronchial lesions. 868 34

To investigate the regulation of promoters containing classical phorbol ester response sequences (PEA-3/12-O-tetradecanoylphorbol-13-acetate response element motifs) by protein kinase C (PKC) isozymes, co-transfections were performed in human dermal fibroblasts with a plasmid containing either the human collagenase promoter or the porcine urokinase plasminogen activator (uPA) promoter linked to the chloramphenicol acetyltransferase gene and a plasmid expressing an individual PKC isozyme. Using this experimental design, seven PKC isozymes were analyzed for their ability to trans-activate the collagenase and uPA promoters. Our results demonstrate that only PKC delta, epsilon, and eta trans-activated the collagenase promoter and that binding of Ap-1 family members to the collagenase 12-O-tetradecanoylphorbol-13-acetate response element (TRE) was not responsible for the isozyme-specific trans-activation. In contrast, the uPA promoter was stimulated by all of the PKC isozymes examined (PKC alpha, betaII, gamma, delta, epsilon, zeta, and eta). These results indicate that PKC isozymes differentially regulate promoters containing PEA-3/TRE motifs and suggest that individual isozymes play unique roles within the cell.
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PMID:Protein kinase C isozymes differentially regulate promoters containing PEA-3/12-O-tetradecanoylphorbol-13-acetate response element motifs. 870 56

Sections of tissue biopsies obtained from advanced, destructive periodontitis were compared with minimally inflamed periodontal tissues in relation to the distribution of type I (interstitial) collagenase. Immunohistochemistry using a highly specific antiserum showed weak staining of occasional vessels in minimally inflamed specimens but widespread reactivity, localized to the vasculature, in advanced disease. In situ hybridization confirmed the vascular source of type I collagenase. Minimally inflamed tissues did not react with antibody to urokinase-type plasminogen activator, a potential activator of pro-collagenase, but there was a consistent strong reaction in advanced disease. Antibody to tissue inhibitor of metalloproteinase (TIMP)-1 did not react with minimally inflamed tissues, but gave intense, widespread vascular staining in advanced disease, whereas antibody to TIMP-2 produced localized connective tissue staining. These results indicate that upregulation of proteinases and inhibitors related to the vasculature is an integral component of destructive periodontitis.
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PMID:Vascular co-localization of proteolytic enzymes and proteinase inhibitors in advanced periodontitis. 877 91

The present study was carried out to characterize the patterns of expression of matrix metalloproteinases or their tissue inhibitor (TIMP-1) in normally healing, acute vs. chronic, skin wounds. In situ hybridization was performed to localize collagenase, stromelysin-1, stromelysin-2, matrilysin, urokinase plasminogen activator (uPA) and TIMP-1 mRNAs in 14 chronic venous ulcers and 10 normally healing wounds, representing different time points after wounding. Surgical wounds, made in piglets harvested at several time points, were studied as controls. Collagenase, stromelysin-1 and -2, as well as uPa, were expressed in keratinocytes in both acute and chronic wounds, while epithelial TIMP-1 mRNA was not detected in any chronic wound biopsies studied. However, TIMP-1 was expressed at the epithelial edges of both acute human and pig wounds. Our results suggest that the balance between metalloenzymes and their inhibitor TIMP-1, is disturbed, in poorly healing wounds.
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PMID:Patterns of matrix metalloproteinase and TIMP-1 expression in chronic and normally healing human cutaneous wounds. 877 59

Does the c-ets 1 protooncogene take part in the regulation of tumor angiogenesis? The formation of new blood vessels is an essential process in embryonic development and wound healing, for tumor growth and metastasis. In situ hybridization studies have revealed that the protooncogene c-ets 1 is expressed in endothelial cells at the beginning of blood vessel formation, in normal and pathological conditions. C-ets 1 encodes a transcription factor, a protein which binds specifically to DNA and which regulates the transcription of genes containing these specific binding sequences in their promotors. Thus in vitro experiments suggest that c-ets 1 may activate the transcription of genes encoding collagenase 1, stromelysine 1 and urokinase plasminogen activator, proteases involved in extracellular matrix degradation. A working hypothesis is that c-ets 1 takes part in regulating angiogenesis by controlling the transcription of these genes whose activity is necessary for the migration of endothelial cells from preexisting capillaries. This hypothesis is discussed with respect to current experimental evidences and to the complexity of the regulatory network controlling gene transcription and extracellular matrix degradation.
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PMID:[Does the c-ets 1 oncogene participate in the regulation of tumor angiogenesis?]. 880 51

The invasive character of squamous cell carcinoma of the head and neck represents a major challenge to the clinician since most often these tumors require extensive surgical resection impairing important physiological functions including speech and swallowing. Additionally, in many cases costly reconstructive surgery is required to repair the adverse cosmetic effects of the resective surgery. Thus, there is an urgent need to understand the molecular mechanism(s) which underlie the local and regional spread of this disease. Since the ability of tumor cells to invade into surrounding structures requires hydrolytic action much effort has been spent on identifying the hydrolases involved in this process. Some of the enzymes which have been implicated in the spread of head and neck cancer include the urokinase-type plasminogen activator and several members of the collagenase family such as type I and IV collagenases and the stromelysins synthesized either by the tumor cells or in the surrounding fibroblasts. More recent studies have addressed the mechanism(s) by which these hydrolases are overexpressed in invasive cancer. In the tumor cells themselves, work has focused on defining the transcriptional requirements for enzyme synthesis and addressing how the appropriate transcription factors are activated by signal transduction pathways. In contrast, where the hydrolases (e.g. stromelysin-2 and stromelysin-3) are produced by the fibroblasts, current investigations are directed at identifying tumor-derived growth factors which lead to the inducible expression of the enzymes in the stromal cells. The ultimate goal of these studies is to develop novel therapeutic interventions which decrease the invasive capacity of head and neck cancer leading to longer survival times and enhanced quality of life for patients afflicted with this disease.
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PMID:Invasion and metastasis. 884 80


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