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)

The enzyme responsible for the metalloproteinase activity which cleaves the Glu143-Leu144 bond of (pro)urokinase has been isolated from the conditioned medium of cultured normal human kidney cells. Using S-Sepharose and Cibacron Blue-agarose chromatography, then C-4 reversed phase high pressure liquid chromatography, a protein of about 20,000 Da was isolated. Through an identical amino-terminal sequence, the protein was shown to be the matrix metalloproteinase previously referred to in the literature as "pump-1" (putative metalloproteinase). When aprotinin was added during the course of the purification, the major species isolated was the zymogen form (28,000 Da) of pump-1. Pump-1 has been shown to efficiently cleave the susceptible bond of both pro-urokinase (single-chain) and active (two-chain) urokinase and thereby produce the corresponding low molecular weight forms. The amino-terminal sequences of the A and B chains of low molecular weight urokinase prepared by action of pump-1 on recombinant high molecular weight urokinase are identical to those of the low molecular weight urokinase isolated from human kidney cell culture. Since the reaction of urokinase with this metalloproteinase results in separation of its serine proteinase region from the domain which mediates binding to the urokinase receptor, it may be of importance in the regulation of the functional activity of the plasminogen activator in cellular processes.
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PMID:The matrix metalloproteinase pump-1 catalyzes formation of low molecular weight (pro)urokinase in cultures of normal human kidney cells. 162 80

Because dermatitis herpetiformis is characterized by neutrophilic inflammation and destructive changes in the basement membrane zone, we studied the in situ expression of interstitial collagenase and stromelysin-1 in 11 lesions. A prominent signal for collagenase mRNA was consistently detected in the basal keratinocytes of rete ridges surrounding the neutrophilic abscesses in 10 of 11 lesions, and the expression was independent of the age of the lesion and the migratory state of the basal keratinocytes. Expression of stromelysin-1 was detected in seven of 11 lesions and co-localized with collagenase. No expression of the 92-kDa gelatinase mRNA or matrilysin protein was found in the vicinity of neutrophilic accumulations or the damaged basement membrane. Urokinase-type plasminogen activator mRNA was found in basal keratinocytes in seven of nine samples. Collagenase, stromelysin-1, and urokinase-type plasminogen activator were not expressed in normal-appearing skin of patients with dermatitis herpetiformis. Our results suggest that in lesions of dermatitis herpetiformis, collagenase and stromelysin-1 may be induced in basal keratinocytes by neutrophil cytokines or by altered cell-matrix interactions through contact of keratinocytes with the matrix due to damaged basement membrane. Stromelysin-1, in particular, may contribute to formation of blisters by degrading basement membrane components.
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PMID:Enhanced expression of interstitial collagenase, stromelysin-1, and urokinase plasminogen activator in lesions of dermatitis herpetiformis. 763 99

The purpose of this study was to characterize stromal-epithelial interactions that result in induction of protease gene expression in squamous cell carcinoma of the skin. Coculture of the human squamous cell carcinoma cell line II4 with primary human foreskin fibroblasts was observed to induce mRNA expression of urokinase-type plasminogen activator (uPa), matrilysin, 92-kDa type IV collagenase, and c-ets, a transcriptional activator of several genes within the serine and matrix metalloprotease families. uPA and c-ets induction were localized to the fibroblast cell population. uPa induction was found to be dependent upon cell-cell contact with the tumor cell population, whereas c-ets induction was due to a combination of cell-cell contact and a tumor cell-derived soluble factor. In contrast, matrilysin induction localized to the tumor cells and was shown by Northern and Western analyses to occur in response to a fibroblast-derived soluble factor. These data demonstrate that both paracrine factors and cell-cell contact between stromal fibroblasts and epithelial tumor cells can influence protease gene expression.
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PMID:Paracrine factor and cell-cell contact-mediated induction of protease and c-ets gene expression in malignant keratinocyte/dermal fibroblast cocultures. 802 May 84

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

Matrilysin (MAT) is a member of the matrix metalloproteinase (MMP) family which is believed to degrade components of the extracellular matrix (ECM) during processes of tissue remodeling. Although MAT is similar to the stromelysins in its substrate specificity, and to interstitial collagenase in the crystal structure of its catalytic domain, this enzyme is unique in that it lacks the carboxy-terminal segments encoded by other MMP genes. Characterization of the human MAT gene has revealed that the promoter region contains typical MMP promoter elements such as AP-1 and PEA3, which mediate responsiveness to growth factors, oncogenes, and phorbol esters. Activated recombinant forms of human MAT cleave ECM and basement membrane proteins such as fibronectin, collagen type IV, laminin, and particularly elastin, entactin, and cartilage proteoglycan aggregates. Furthermore, MAT appears to mediate the proteolytic processing of other molecules (e.g. tumor necrosis factor alpha precursor, urokinase plasminogen activator). MAT is expressed in a variety of tumors ranging from adenomas to carcinomas and adenocarcinomas of the breast, colon, prostate, stomach, upper aerodigestive tract, lung, and skin, where it may be involved in tumor formation as well as the tissue degradation which accompanies tumor cell extravasation. Localization of MAT mRNA and protein to the tumor cells is unusual in that the majority of MMPs are produced in the stroma. This distinctive tissue-restricted pattern of MAT expression is a recapitulation of the expression pattern in normal human tissue, where MAT protein localizes to secretory and ductal epithelium in the endometrium and in various exocrine glands. In the mouse, high constitutive levels of MAT mRNA are found in epithelial cells in the uterus, small intestine, and extra-testicular ducts. Taken together, these findings suggest that MAT may have a specific role in normal gland and organ function, a possibility which can be explored further by the genetic manipulation of MAT levels in vivo.
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PMID:Matrilysin: an epithelial matrix metalloproteinase with potentially novel functions. 872

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

Matrilysin (PUMP-1) is a member of the matrix metalloproteinase (MMP) family of extracellular matrix degrading enzymes that has been found to be overexpressed in human prostate cancer. The rat ventral prostate (RVP) following castration has been used as a model for both tissue involution and apoptosis. Northern analysis and in situ hybridization were used to determine the time course and localization of matrilysin during 8 days of RVP involution. Northern analysis revealed that the 1.2 kb matrilysin mRNA was undetectable in normal RVP. An increase in the steady-state levels of matrilysin mRNA was observed 5 days after castration, and the levels began to decline by 8 days after castration. The mRNAs for tissue inhibitor of metalloproteinase-1 and urokinase-type plasminogen activator also showed a time-dependent induction during the course of involution. Localization of matrilysin by in situ hybridization indicated that the mRNA was produced by epithelial cells of the involuting RVP. The matrilysin message was observed in a small number of glands within the whole RVP. Matrilysin protein was present in the RVP and peaked 3 days after castration. The combination of proteinase genes expressed in the RVP following castration indicate that the MMP and serine protease families of enzymes may interact during tissue remodeling of the RVP following castration.
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PMID:Matrilysin expression in the involuting rat ventral prostate. 882 84

The expression of extracellular-matrix (ECM)-degrading proteases has been shown to be necessary for invasion of tumor cells into surrounding tissue. For several tumor types, overexpression of these proteases is dependent upon interactions with adjacent fibroblast cell populations. We previously demonstrated activation of matrix metalloprotease (MMP) and urokinase-type plasminogen activator (uPa) expression in a coculture model consisting of squamous cell carcinoma cells (SCC) with dermal fibroblasts. In the present study we have examined whether melanocytes, which are known to interact closely with keratinocytes of the basal epidermal layer, might influence ECM-degrading protease expression in SCC cells as well. Upon coculture of the human SCC cell line II-4 with the nontumorigenic mouse melanocyte cell line Melan-a or treatment of II-4 cells with Melan-a conditioned media, induction of expression of the MMP matrilysin and uPa was observed. In contrast, no induction was observed for stromelysin-1 or 92-kDa type IV collagenase. Matrilysin/uPa-inducing activity was found to act at the level of gene transcription for both matrilysin and uPa and was ubiquitously expressed among six different human melanocytic cell strains/lines, ranging from primary normal melanocytes to cell lines established from metastatic melanoma lesions. These data demonstrate that melanocytic cells can exert a paracrine influence in SCC cells on the expression of specific proteases involved in ECM turnover and tumor invasiveness.
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PMID:Melanocyte mediated paracrine induction of extracellular matrix degrading proteases in squamous cell carcinoma cells. 905 12

We have previously shown that the extracellular-matrix-degrading enzymes, urokinase-type plasminogen activator (u-PA), stromelysin 1, stromelysin 3, and matrilysin, may play an important role in the transition from lung preneoplasia to invasive carcinoma. Using in situ hybridization and immunohistochemistry, we analyzed serial frozen sections for the expression of these enzymes in 89 lung carcinomas including 25 neuroendocrine (NE) carcinomas (10 small-cell lung carcinomas, 7 large-cell NE carcinomas, 1 atypical, and 7 typical carcinoids) and 64 non-small-cell, non-NE carcinomas (29 squamous and 7 basaloid carcinomas, 23 adenocarcinomas, and 5 large-cell carcinomas). Proteases, except matrilysin, were more often expressed in stromal than cancer cells. In non-small-cell, non-NE carcinomas, stromal co-expression of u-PA and stromelysin 3 was seen in 80 to 90% of the tumors and was highly correlated (P < 0.0001). Stromal u-PA and stromelysin 3 expression was linked to tumor size (P = 0.01 and 0.03, respectively) and lymph node involvement (P = 0.001 and 0.02, respectively). Epithelial expression of u-PA was correlated to tumor size (P = 0.04). Epithelial expression of stromelysin 3 predominated in squamous and basaloid carcinomas (P = 0.0005) and was inversely correlated to squamous differentiation (P = 0.018). Epithelial expression of matrilysin predominated in adenocarcinomas and large-cell carcinomas (P = 0.07). In NE carcinomas including small-cell lung carcinomas, stromal expression of u-PA was correlated to lymph node metastasis (P = 0.017). Epithelial expression of all enzymes were significantly less frequent in NE than in non-NE tumors. We conclude that 1) epithelial expression of matrix proteases in lung cancer is linked to cell phenotype (NE versus non-NE, squamous versus glandular) and 2) their stromal, rather than epithelial, expression influences local metastasis.
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PMID:Expression of urokinase-type plasminogen activator, stromelysin 1, stromelysin 3, and matrilysin genes in lung carcinomas. 913 88

Matrix metalloproteinases have been implicated to play a vital role in glioma invasion as they degrade extracellular matrix to facilitate the subsequent migration of tumor cells into the surrounding brain tissue. The cytokine Interleukin-10 (IL-10) was detected recently in glial tumors in vivo. Expression of specific IL-10 mRNA as well as blood serum levels of IL-10 in glioma patients increased with malignancy suggesting a functional role of IL-10 in glioma progression. Moreover, glioma cell migration in vitro was enhanced in the presence of IL-10. We therefore investigated the expression of the matrix metalloproteinases (MMPs) stromelysin-1 (MMP-3), 72-kDa collagenase (MMP-2), 92-kDa collagenase (MMP-9), matrilysin (MMP-7) and the human macrophage metalloelastase (MMP-12). In addition, a possible relation between exposure of glioma cells to IL-10 and invasiveness of these cells due to MMP expression was analyzed. Experiments with Matrigel coated Boyden chambers revealed a pronounced dose dependent effect of IL-10 on glioma invasiveness. The synthetic MMP-inhibitor Marimastat markedly reduced cell invasion in the Boyden chambers confirming the significance of MMPs in the process of invasion. Subsequently, the expression level of MMPs and the serine protease uPA was investigated in 7 glioma cell lines (U373, GaMG, U251, GHE, SNB19, U138 and D54) by RT-PCR. In all but one cell line no enhancement of MMP expression by IL-10 was detected. Matrilysin in U373 cells was the only protease found to be upregulated in the presence of IL-10 dependent on cell density. The present data suggest that IL-10 related effects on the invasive properties of the cell lines are not directly mediated by an upregulation of matrix metalloproteinase expression.
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PMID:Expression of matrix metalloproteinases in human glioma cell lines in the presence of IL-10. 989 93


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