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)

Malignant tumors are generally characterized by extensive local tissue invasion and destruction of ECM which may be due to increased constitutive expression and activity of secreted proteases. Moreover, a large number of diverse protease activities may be constitutively over-expressed in a simultaneous or co-ordinated fashion, thereby significantly increasing cellular invasive potential of the cells. To explore this relationship, we have measured steady-state levels of mRNA coding for urokinase plasminogen activator (uPA), tissue plasminogen activator (tPA), transin and tissue-specific inhibitor of metalloproteinases (TIMP); as well as gelatinolytic, caseinolytic and plasminogen activator activities secreted by SPI, a non-metastatic mouse mammary carcinoma cell line and 4 metastatic sublines derived from it. mRNA encoding metalloproteinase transin was increased 15- to 20-fold, while TIMP transcripts were decreased 3-fold in the metastatic sublines compared to parental SPI tumor cells. Metastatic sublines secreted higher levels of gelatinase (i.e., 92 kDa and 64 kDa) as well as proteases with caseinolytic activity (i.e., 115 kDa and 57 kDa) when compared with SPI cells. Moreover, these enzymes were identified as neutral metalloproteinases. Although the amount of uPA mRNA appeared to be the same in SPI and the metastatic sublines, the latter secreted 1.5-3 times more uPA activity into the culture supernatants. Metastatic competence in the SPI tumor model is therefore associated with increased secretion of several metalloproteinase activities and uPA, as well as decreased TIMP expression, consistent with a more invasive phenotype.
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PMID:Constitutive expression and secretion of proteases in non-metastatic SP1 mammary carcinoma cells and its metastatic sublines. 204

In the course of studies on the regulation of plasminogen activator-mediated extracellular matrix degradation in muscle we found the presence of a factor, a cellular inhibitor of serine proteases having features similar to the serpin protease nexin I (PNI). This factor was present in the medium and at maximum concentration following fusion of skeletal muscle cells in culture. The ability of the PNI homologue in mouse muscle to inhibit ECM degradation by urokinase in myoblast medium was compared to that of human PNI purified from human fibroblasts. Stable (to SDS) 1:1 molar ratio complex formation between PNI and proteases, the proposed means by which these enzymes are regulated and removed, was also detected. Cell surface receptors for protease:PNI complexes, the specific binding sites for inactive complex internalization, were found on multinucleated myotubes, while little or no receptor activity was detected on myoblasts. These data suggest that developmental regulation of a) increased PNI proteolytic inhibitory activity expression and b) the appearance of protease:inhibitor complex receptors on muscle cell surfaces during myogenesis may constitute important regulatory features of muscle surface proteolytic activity. They complement previous studies of proteoglycan metabolism in muscle, which itself contains molecules capable of regulating the activity of myotube surface proteases.
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PMID:Plasminogen activators and their inhibitors in the neuromuscular system: II. Serpins and serpin: protease complex receptors increase during in vitro myogenesis. 216 58

The adult mammalian central nervous system (CNS) lacks the capacity to support axonal regeneration. There is increasing evidence to suggest that astrocytes, the major glial population in the CNS, may possess both axon-growth promoting and axon-growth inhibitory properties and the latter may contribute to the poor regenerative capacity of the CNS. In order to examine the molecular differences between axon-growth permissive and axon-growth inhibitory astrocytes, a panel of astrocyte cell lines exhibiting a range of axon-growth promoting properties was generated and analysed. No clear correlation was found between the axon-growth promoting properties of these astrocyte cell lines with: (i) the expression of known neurite-outgrowth promoting molecules such as laminin, fibronectin and N-cadherin; (ii) the expression of known inhibitory molecules such tenascin and chondroitin sulphate proteoglycan; (iii) plasminogen activator and plasminogen activator inhibitor activity; and (iv) growth cone collapsing activity. EM studies on aggregates formed from astrocyte cell lines, however, revealed the presence of an abundance of extracellular matrix material associated with the more inhibitory astrocyte cell lines. When matrix deposited by astrocyte cell lines was assessed for axon-growth promoting activity, matrix from permissive lines was found to be a good substrate, whereas matrix from the inhibitory astrocyte lines was a poor substrate for neuritic growth. Our findings, taken together, suggest that the functional differences between the permissive and the inhibitory astrocyte cell lines reside largely with the ECM.
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PMID:An analysis of astrocytic cell lines with different abilities to promote axon growth. 758 24

This study aims to investigate the mechanism by which prolactin and GH interact to maintain mammary epithelial cell function in the rat. IGF-I is an important survival factor for the mammary gland and we have demonstrated that the effects of GH and prolactin involve IGF-I. GH acts by increasing IGF-I whilst prolactin acts by inhibiting the expression of IGFBP-5 from the mammary epithelium. During mammary involution, when serum prolactin levels decline, IGFBP-5 expression is dramatically upregulated and it binds with high affinity to IGF-I preventing IGF-I interaction with the IGF-receptor and thus leading to epithelial cell apoptosis. We have identified a specific interaction of IGFBP-5 with alpha s2-casein. This milk protein has also been shown to bind plasminogen and its activator tissue-type plasminogen activator (tPA) leading to enhanced conversion of plasminogen to plasmin. Plasmin is an important initiator of re-modelling of the extracellular matrix during mammary involution. A potential interaction between the cell death and extracellular matrix remodelling is evident from the observation that IGFBP-5 binds to plasminogen activator inhibitor-I (PAI-1). We thus hypothesized that IGFBP-5 could activate cell death by sequestration of IGF-I and activate plasminogen cleavage by sequestering PAI-1. In support of this hypothesis we have shown that both prolactin and GH inhibit tPA activity and plasminogen activation in the involuting mammary gland. Our results suggest that GH and prolactin inhibit cell death and ECM remodelling via the IGF-axis and also indicate a novel role for the milk protein alpha s2-casein in this process. We have now established lines of transgenic mice expressing IGFBP-5 on the beta-lactoglobulin promoter to explore its function in greater detail.
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PMID:Insulin-like growth factor binding protein-5 (IGFBP-5) potentially regulates programmed cell death and plasminogen activation in the mammary gland. 1095 8

The aim of this study was to determine the effects of ECM protein coatings and surface modification of PTFE on the ability of seeded human endothelial cells (EC) to secrete prostacyclin (PGI2), plasminogen inhibitor-1 (PAI-1) and tissue plasminogen activator (t-PA). PTFE surfaces were modified by a novel surface modification technique based on ammonia plasma. Fibronectin, collagen type-1 and gelatin-coated ammonia plasma modified PTFE and unmodified PTFE surfaces were employed and compared in this study. All ammonia plasma modified surfaces showed similar secretions of PGI2 compared to non-modified PTFE surfaces. With the exception of gelatin-coated modified PTFE, seeded EC seeded on all modified PTFE showed lower levels of PAI-1 secretion compared to those seeded on unmodified PTFE. The specific activity of t-PA secreted by EC seeded on ammonia plasma modified and fibronectin coated modified PTFE showed increases of 100 and 30%, respectively, when compared to their unmodified counterparts. Our studies show that EC seeded on modified PTFE have ability to secrete PGI2 that modulates the early phase of thrombus formation. Furthermore, superior t-PA profile, along with lower levels of PAl-1 suggest that ammonia plasma modification and use of appropriate ECM proteins can modulate antithrombotic and fibrinolytic properties of in vitro endothelialized vascular prostheses. Accordingly, these surfaces may be suitable to further develop protocols and other strategies for arterial and venous reconstruction.
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PMID:Antithrombotic and fibrinolytic system of human endothelial cells seeded on PTFE: the effects of surface modification of PTFE by ammonia plasma treatment and ECM protein coatings. 1133 19

Plasminogen activator inhibitor-1 (PAI-1) is the primary inhibitor of both tissue- and urokinase-type plasminogen activators (t-PA, u-PA). PAI-1 also regulates the attachment of cells to the adhesive glycoprotein vitronectin (VN). PAI-1 gene expression has been observed in various cell types, and many regulatory factors have been identified to play a role in PAI-1 gene transcription. The complete picture of how the PAI-1 gene is expressed when cells adhere to a culture plate has not been fully elucidated. We found that in anchorage-dependent cells, PAI-1 gene was up-regulated when cells were beginning to attach to a culture dish and was down-regulated when cells had attached completely. The PAI-1 gene expression was induced only in adhered cells but not in non-adhered cells. The regulation of PAI-1 protein was also found in both culture medium and cell lysate when cells were attached to a culture dish. Our experiment indicates that vitronectin and fibronectin, as components of ECM, may be the factors involved in the regulation of PAI-1 gene expression. PAI-1, as an inhibitor of the interaction between vitronectin and integrin alphavbeta3, may also be a regulator of its own expression.
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PMID:Cell adhesion regulates the plasminogen activator inhibitor-1 gene expression in anchorage-dependent cells. 1182 81

Age-related macular degeneration (ARMD), proliferative vitreoretinopathy (PVR) and uveitis are characterized by RPE motility through the ECM of retinal lesions. The purpose of this study was to test the hypothesis that multiple proteolytic systems are functionally intact at the HRPE surface and peri-cellular region and that these activities are differentially modulated by IL-1beta. HRPE cells were evaluated: (1). as individual cells or cell extracts, (2). during migration across three-dimensional ECM-like layers and (3). in tissue sections. The urokirase plasminogen activator receptor (uPAR; CD87) was detected on HRPE cells as well as its functional activity. Although uPAR was associated with CD11b (CR3) on live resting cells, polarized migratory HRPE cells were found to dissociate uPAR from CR3; uPAR then translocated to anterior pole of the cell, where it enhanced PAI-1-inhibitable local proteolytic activity. The relative contribution of uPAR and collagenase in HRPE migration was evaluated using three-dimensional gelatin matrices. Interestingly, uPAR/uPA was found to play a key role in migration across these layers. IL-1 upregulated uPAR, collagenase, and elastase activities, suggesting that cytokines may affect the invasive program of HRPE cells in vivo. Immunohistochemistry for uPAR was performed in sections of human retina. Immunoreactive uPAR was present along the HRPE basolateral membrane in retinal sections and in sections of diseased retinal tissue at an enhanced level. Our results suggest that multiple proteolytic systems are present in association with HRPE and that the uPAR/uPA system may be particularly important.
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PMID:Human RPE cell lysis of extracellular matrix: functional urokinase plasminogen activator receptor (uPAR), collagenase and elastase. 1269 22

Dual ligand treatment of streptavidin(SA)-biotin and fibronectin (Fn) enhances the adhesion of endothelial cells (EC) onto synthetic surfaces and promotes the quiescent phenotype of adherent EC. The current study investigates the effect of the dual ligand on the expression of endothelial genes in static culture and under shear stress (4 h at 10 dynes/cm2). Expression of 23 genes in the classes of signaling, cytoskeleton/ECM, vasoregulation, and shear-responsive were examined. Eight genes (argininosuccinate synthetase, K+ channel, TGFbeta, Mn-SOD, alpha-tubulin, t-PA, COX2, and eNOS) were significantly upregulated by shear stress. Two genes (caveolin-1 and ET-1) were downregulated by shear stress. Three genes (RhoA, elastin, alpha-actinin) were upregulated by the dual ligand treatment in static culture, and four genes (FAK, elastin, COX2, and eNOS) were upregulated when the dual ligand and shear stress were applied simultaneously. Northern blot analyses on FAK, RhoA, elastin, and alpha-actinin revealed similar results. The results suggest (1) the use of SA-biotin to supplement EC adhesion enhances the integrity of the EC cytoskeleton by upregulating the expression of cytoskeleton/ECM genes, and (2) a likely relationship between the expression of cytoskeleton/ECM genes and the downstream events, such as the shear-induced expression of eNOS and COX2 genes. Analyses presented in this study provide insights into the mechanism by which SA-biotin-supplemented EC mediate gene expression.
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PMID:Synergistic effect of shear stress and streptavidin-biotin on the expression of endothelial vasodilator and cytoskeleton genes. 1553 41

Cancer progression depends on an accumulation of metastasis supporting cell signaling molecules that target signal transduction pathways and ultimately gene expression. Osteopontin (OPN) is one such chemokine like metastasis gene which plays a key signaling event in regulating the oncogenic potential of various cancers by controlling cell motility, invasiveness and tumor growth. We have reported that OPN stimulates tumor growth and nuclear factor kappaB (NFkappaB)-mediated promatrix metalloproteinase-2 (pro-MMP-2) activation through IkappaBalpha/IKK (IkappaBalpha kinase) signaling pathway in melanoma cells. Urokinase type plasminogen activator (uPA), a widely acting serine protease degrades the ECM components and plays a pivotal role in cancer progression. However, the molecular mechanism by which upstream kinases regulate the OPN-induced NFkappaB activation and uPA secretion in human breast cancer cells is not well defined. Here we report that OPN induces the phosphatidylinositol 3'-kinase (PI 3'-kinase) activity and phosphorylation of Akt/PKB (protein kinase B) in highly invasive (MDA-MB-231) and low invasive (MCF-7) breast cancer cells. The OPN-induced Akt phosphorylation was inhibited when cells were transfected with dominant negative mutant of p85 domain of PI 3'-kinase (Deltap85) indicating that PI 3'-kinase is involved in Akt phosphorylation. OPN enhances the interaction between IkappaBalpha kinase (IKK) and phosphorylated Akt. OPN also induces NFkappaB activation through phosphorylation and degradation of IkappaBalpha by inducing the IKK activity. OPN also enhances uPA secretion, cell motility and ECM-invasion. Furthermore, cells transfected with Deltap85 or super-repressor form of IkappaBalpha suppressed the OPN-induced uPA secretion and cell motility. Pretreatment of cells with PI 3'-kinase inhibitors or NFkappaB inhibitory peptide (SN50) reduced the OPN-induced uPA secretion, cell motility and ECM-invasion. Taken together, OPN induces NFkappaB activity and uPA secretion by activating PI 3'-kinase/Akt/IKK-mediated signaling pathways and further demonstrates a functional molecular link between OPN induced PI 3'-kinase dependent Akt phosphorylation and NFkappaB-mediated uPA secretion, and all of these ultimately control the motility and invasiveness of breast cancer cells.
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PMID:Osteopontin: it's role in regulation of cell motility and nuclear factor kappa B-mediated urokinase type plasminogen activator expression. 1601 53

Human kallikrein 8 (KLK8) is a member of the human kallikrein gene family of serine proteases, and its protein, hK8, has recently been suggested to serve as a new ovarian cancer marker. To gain insights into the physiological role of hK8, the active recombinant enzyme was obtained in a pure state for biochemical and enzymatic characterizations. hK8 had trypsin-like activity with a strong preference for Arg over Lys in the P1 position, and its activity was inhibited by typical serine protease inhibitors. The protease degraded casein, fibronectin, gelatin, collagen type IV, fibrinogen, and high-molecular-weight kininogen. hK8 also converted human single-chain tissue-type plasminogen activator (65 kDa) to its two-chain form (32 and 33 kDa) by specifically cleaving the peptide bond Arg275-Ile276. This conversion resulted in a drastic increase in the activity of the activator toward the fluorogenic substrate Pyr-Gly-Arg-MCA and plasminogen in the absence of fibrin. Our findings suggest that hK8 may be implicated in ECM protein degradation in the area surrounding hK8-producing cells.
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PMID:Biochemical characterization of human kallikrein 8 and its possible involvement in the degradation of extracellular matrix proteins. 1633


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