Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

During the process of tumor cell invasion and metastasis, tumor cells are known to interact with extracellular matrix proteins, endothelial cells, platelets and other organ-specific structures. Integrins are cell surface molecules which mediate cell-matrix and cell-cell interactions and are likely to be important for tumor cell survival and dissemination. The purpose of this study was to characterize the integrin and proteolytic enzyme repertoire from low (A375P), medium (A375M) and high metastatic (A375SM) human melanoma cell lines. These cell lines are also invasive through human amniotic membranes in vitro and their invasiveness parallels the reported metastatic phenotype. The types and levels of expression of the various integrin receptors were analysed by quantitative immunoprecipitation using a panel of monoclonal antibodies directed to known integrin subunits. In addition, cDNA probes to the integrin subunits were used in quantitative northern blot analysis. These data show that the integrin alpha v beta 3 increases 50- to 100-fold as these cells progress to a more metastatic phenotype. alpha 4 beta 1 levels also appeared to increase several fold, while other beta 1 integrins did not differ in their expression levels. The increased alpha v beta 3 expression in the more metastatic cells resulted in an increased adhesion to vitronectin and fibrinogen substrates in cell attachment assays. However, alpha v- and beta 3-specific antibodies did not inhibit A375 cell invasion through the amnion. Each cell line was found to release similar quantities of a 72-kDa gelatinase/type IV collagenase and tissue type plasminogen activator. These results suggest that during the progression of these tumor cells from a low to high metastatic phenotype, marked changes in integrin expression occurred which may facilitate interactions with platelets, endothelial cells and specific extracellular matrix proteins to promote metastasis.
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PMID:Integrin expression in human melanoma cells with differing invasive and metastatic properties. 131 Dec 25

The immunocharacterization of a metalloproteinase isolated from rat glioma cell conditioned medium is described and confirms that the enzyme is identical to type IV collagenase. Free, active plasminogen activator (PA) and PA-PAI complexes were identified as being secreted by the same cells. Using affinity-purified metalloproteinase we demonstrate that the enzyme can be partially activated by u-PA but not by plasmin in vitro. On the basis of these findings and previous published work we propose a scheme for the proteolytic degradation of normal brain tissue during tumour invasion.
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PMID:Invasion of brain tissue by primary glioma: evidence for the involvement of urokinase-type plasminogen activator as an activator of type IV collagenase. 132 8

Cell clones derived from a human melanoma metastasis selected for different integrin profiles were examined in vitro for invasive potential and biological and biochemical features potentially related to this process. Clones which expressed high levels of integrins showed high invasive potential, extracellular matrix degradation, and adhesion to gelatin-coated substrates. A correlation was also found between invasiveness and intracellular and extracellular plasminogen activator activity. Heparanase and collagenase type IV activities were apparently unrelated to invasiveness. gamma-Glutamyl transferase (GGT) activity was high in highly invasive clones, whereas melanin content was high in slightly invasive clones. Heterogeneity was also observed in cellular parameters such as cell dimensions, growth features and DNA index. The intrinsic biological and biochemical heterogeneity of a cell population derived from a single metastasis may be responsible for the different behaviour of clones, regardless of their invasive potential. Since slightly invasive cells are more differentiated than highly invasive cells, malignancy and differentiation are inversely correlated in such human melanoma clones.
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PMID:Biological and enzymatic features of human melanoma clones with different invasive potential. 136 80

Regulation of the activity of proteolytic enzymes is of major importance in the turnover of connective tissues. The search for physiologically relevant activation mechanisms of principal tissue-degrading enzymes, e.g., metalloproteinases, has therefore been of wide interest. We have now studied whether the initiating factor of the fibrinolytic system, urokinase plasminogen activator (u-PA), may also function in the early steps of activation of one of the metalloproteinases, the M(r) 72,000 gelatinase/type IV collagenase produced by cultured fibroblasts. Treatment of the secreted M(r) 72,000 proteinase by u-PA yielded a cleavage product of M(r) 62,000 as revealed by fluorography of radioactively labeled proteins as well as by gelatin zymography SDS-PAGE gels. The u-PA-catalyzed cleavage of the M(r) 72,000 proteinase was blocked by anti-u-PA antibodies, but was unaffected by the plasmin inhibitor aprotinin, thus indicating a specific action for the activator. On the contrary, the tissue activator of plasminogen, t-PA, did not cleave the type IV collagenase in similar assays. u-PA-catalyzed cleavage of recombinant type IV collagenase, produced in a baculovirus expression system, yielded a similar M(r) 62,000 activity in gelatinolysis assay. Zymograms of the isolated pericellular matrices of cultured fibroblasts also revealed M(r) 72,000 gelatinolytic polypeptide that was converted to an M(r) 62,000 form by u-PA. Both polypeptides were recognized in immunoblotting by antibodies against the gelatinase/type IV collagenase, suggesting immunological identity with the secreted enzyme. Thus the M(r) 72,000 gelatinase/type IV collagenase is not only secreted, but also deposited into the pericellular fibroblast matrix, and both forms are substrates for u-PA. The results suggest a new potential role for u-PA as a direct regulator of metalloproteinase-mediated extracellular proteolysis via the cleavage of the M(r) 72,000 gelatinase/type IV collagenase to an M(r) 62,000 form.
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PMID:Proteolytic processing of the 72,000-Da type IV collagenase by urokinase plasminogen activator. 139 99

The preovulatory surge of gonadotropins activates a cascade of proteolytic enzymes resulting in the rupture of the follicular wall and the release of a fertilizable ovum during ovulation. In the rat the process is initiated by a rise in follicular tissue-type plasminogen activator, produced predominantly in granulosa cells. Recent studies revealed a preovulatory increase in ovarian collagenolytic activity in vivo and an increase in activatable collagenase in vitro. In view of the complicated control of mammalian collagenase synthesis and activity by local inhibitors and activators, we examined the expression of ovarian interstitial and type IV collagenases and tissue inhibitor of metalloproteinase (TIMP) mRNA after an ovulatory stimulus. Ovarian mRNA was isolated from immature PMSG-treated rats 3, 6, and 9 h after hCG stimulation. Northern blot analyses revealed a mRNA of 1.7 kilobases (kb) hybridizing with the human interstitial collagenase cDNA probe. The levels of this mRNA showed a 25-fold increase between 3-6 h after hCG stimulation. The human cDNA probe of collagenase IV hybridized with a mRNA of 3.1 kb, which showed only a 4-fold increase 9 h after hCG treatment. The interstitial collagenase mRNA was expressed in both granulosa cells of preovulatory follicles and the residual ovarian tissue, whereas the expression of collagenase IV mRNA was limited to the residual tissue. Inhibitors of eicosanoid synthesis, previously shown to block ovulation and the LH/hCG-induced rise in ovarian collagenolysis, suppressed the gonadotropic stimulation of interstitial collagenase mRNA, but slightly stimulated that of collagenase IV. The mouse cDNA probe of TIMP hybridized with a 0.9-kb mRNA, which was stimulated by hCG to reach a maximum (7- to 8-fold increase) between 6-9 h after stimulation. TIMP was expressed and stimulated in both the granulosa cells and the residual tissue. Inhibitors of eicosanoid synthesis did not affect the gonadotropic stimulation of TIMP mRNA. These data support the suggested role of interstitial collagenase in follicle rupture and the essential role of eicosanoids in the mediation of gonadotropic stimulation of interstitial collagenase production and action. The observed stimulation of TIMP mRNA expression by the gonadotropin and the lack of any effect of eicosanoid synthesis inhibitors on this action of LH/hCG offer an additional mechanism by which these inhibitors may block ovulation. Thus, the suppression of ovulation by inhibitors of eicosanoid synthesis may result from selective inhibition of interstitial collagenase expression and undisturbed gonadotropin-stimulated TIMP expression.
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PMID:Preovulatory changes in ovarian expression of collagenases and tissue metalloproteinase inhibitor messenger ribonucleic acid: role of eicosanoids. 165 86

To identify agents and mechanisms responsible for the thickened basement membranes characteristic of diabetic angiopathy we examined the effects of high glucose (30 mM) on the expression of genes related to extracellular matrix composition and turnover and investigated whether the changes induced by high glucose were mimicked and sustained by activation of protein kinase C or A. In human umbilical vein endothelial cells high glucose increased fibronectin, collagen IV, tissue plasminogen activator (tPA), and plasminogen activator-inhibitor 1 (PAI-1) mRNA levels 2-fold but did not affect type IV and interstitial collagenase expression. Acute treatment with phorbol esters resulted in increased collagen IV, tPA, PAI-1, and interstitial collagenase mRNAs; the type IV collagenase mRNA levels were instead suppressed to 50% of control. Upon longer exposure to phorbol esters (48 h) suppression of fibronectin and PAI-1 mRNAs also occurred. Intracellular elevation of cAMP led to over-expression of fibronectin and type IV collagenase and potentiated the effects of phorbol esters on collagen IV, tPA, and interstitial collagenase expression. The mRNA changes induced by high glucose occurred in the absence of protein kinase C activation or cAMP elevation. These studies indicate that events other than activation of protein kinase C or A bridge high ambient glucose to changes in endothelial cell gene expression that may contribute to diabetic angiopathy.
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PMID:Expression of genes related to the extracellular matrix in human endothelial cells. Differential modulation by elevated glucose concentrations, phorbol esters, and cAMP. 171 80

Laminin is a large multidomain glycoprotein with diverse biological activities which include stimulation of neurite outgrowth, enhancement of tumor metastasis, and promotion of cell growth, adhesion, and differentiation. A 19 amino acid synthetic peptide derived from the E8 fragment of the laminin A chain (Cys-Ser-Arg-Ala-Arg-Lys-Gln-Ala-Ala-Ser-Ile-Lys-Val-Ala-Val-Ser-Ala-Asp -Arg- NH2) was identified which promotes metastasis and stimulates collagenase IV activity in the culture medium of B16 melanoma cells (Kanemoto et al., 1990). We report that this peptide, here designated LamA2091-2108, is also a potent stimulator of tissue plasminogen activator (t-PA)-catalyzed plasminogen activation, resulting in a 22-fold increase in the kcat/Km of the activation reaction. The activity of purified type I and type IV collagenase was inhibited by LamA2091-2108 with IC50 values of 3 and 43 microM, respectively. These data support an alternative mechanism for the appearance of collagenase activity in the culture media of melanoma cells, namely, that the peptide stimulates plasminogen activation, subsequently generating collagenase activity.
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PMID:Modulation of plasminogen activation and type IV collagenase activity by a synthetic peptide derived from the laminin A chain. 184 24

The specialized interaction between embryonic and maternal tissues is unique to mammalian development. This interaction begins with invasion of the uterus by the first differentiated embryonic cells, the trophoblasts, and culminates in formation of the placenta. The transient tumor-like behavior of cytotrophoblasts, which peaks early in pregnancy, is developmentally regulated. Likewise, in culture only early-gestation human cytotrophoblasts invade a basement membrane-like substrate. These invasive cells synthesize both metalloproteinases and urokinase-type plasminogen activator. Metalloproteinase inhibitors and a function-perturbing antibody specific for the 92-kD type IV collagen-degrading metalloproteinase completely inhibited cytotrophoblast invasion, whereas inhibitors of the plasminogen activator system had only a partial (20-40%) inhibitory effect. We conclude that the 92-kD type IV collagenase is critical for cytotrophoblast invasion.
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PMID:92-kD type IV collagenase mediates invasion of human cytotrophoblasts. 184 41

In the testis, interactions between peritubular cells (mesenchyme) and Sertoli cells (epithelium), together with proteolytic remodeling of the extracellular matrix, may play a central role in testicular development, morphogenesis, and spermatogenesis. In this study we demonstrate that a metalloproteinase of 72 kDa present in rat Sertoli cell and Sertoli-peritubular cell coculture medium is activated by p-aminophenylmercuric acetate (p-APMA) to a lower molecular mass form, indicating that it is likely to be a latent collagenase. Immunoblots using antibodies to three different domains of type IV collagenase show that the 72-kDa protease and a 76-kDa protease are type IV pro-collagenases. Sertoli cells cultured alone produce basal levels of type IV collagenase that can be immunolocalized in the cytoplasm of cultured cells. Peritubular cells cultured alone produce much less type IV collagenase. However, Sertoli and peritubular cells in coculture do produce type IV pro-collagenase, and in cultures consisting predominantly of peritubular cells, the activated form of type IV collagenase was detected by both zymography and immunoblotting. Cells growing during the transitional phase (from cell attachment to confluence) secrete more metalloproteinases than during the confluent phase. In contrast, plasminogen activator levels are unaffected by time in culture. These results show that rat testicular cells in culture produce and secrete type IV collagenase, and that the secretion and activation of this enzyme and other metalloproteases is regulated by the ratio of mesenchymal cells to epithelial cells and time in culture.
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PMID:Identification of type IV collagenase in rat testicular cell culture: influence of peritubular-Sertoli cell interactions. 196 27

The capacity of solid tumours to invade the surrounding tissue and to metastasize, is correlated with the formation and degradation of structural elements in the vicinity of the tumour cells. Substances with both procoagulant activity and fibrinolytic activity are important factors in the formation or degradation of a "fibrin-fibronectin-gel matrix". This gel is subsequently transformed into the extracellular matrix, which, together with cells, will form the tumour stroma. When analyzing tumour stroma degradation products, it is obvious that the protease plasmin catalyses the disintegration of fibrin and fibronectin. Additional compounds of the tumour stroma and of the basal membrane are also, at least in part, broken down by plasmin or other proteases, such as collagenase IV and cathepsin D. The plasminogen activator urokinase (uPA) seems to play a central role as it was shown that elevated content of uPA is correlated with a high risk of early relapse and shorter overall survival, at least in breast cancer. It has been shown, that by means of quantifying uPA, patients with a relative high or low risk can even be selected within the classical risk groups, which so far are defined by the locoregional extension of the tumour and the hormone receptor status only. Evidently, as uPA content in human breast cancer tissue is an independent prognostic factor, one may speculate, that those experimental or in vitro data, which correlated increase in uPA-synthesis with malignancy, may be of direct relevance for human tumour biology. Moreover, due to these recent observations on the prognostic significance of tumour-associated proteases, new aspects for the selection of risk collectives within the node-negative breast cancer patients for adjuvant therapy have to be considered. It may well be possible, that one may affect tumour invasion and metastasis by inhibiting protease action of solid tumours by disturbing the binding of proteases to tumour cell surface receptors. As it is only a quantitative aspect, which separates benign physiological processes from tumour cell pathophysiology, experimental evidence suggests, that less drastic forms of palliative therapy can be proposed.
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PMID:[Clinical and prognostic significance of tumor-associated proteases in gynecologic oncology]. 204 Apr 18


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