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 accumulation of excessive extracellular matrix (ECM) following tubular injury likely represents an imbalance between ECM production and degradation. We assessed the temporal relationship between the accumulation of ECM, cell adhesion molecules, matrix degrading proteinases, and their inhibitors in a rat model of anti-tubular basement membrane (TBM) antibody-associated tubulointerstitial nephritis (TIN) by the RNase protection assay and immunohistochemistry. There was an increase in the steady state expression of fibronectin (FN) and alpha 2(IV) collagen mRNAs beginning on day 7 with the onset of neutrophil infiltration. An increase in alpha 1(III) collagen and alpha 1-integrin did not occur until days 9 and 10, respectively, at which time mononuclear leukocytes were the predominant infiltrating cell. Increased levels of FN, alpha 1(III), alpha 2(IV) and alpha 1-integrin mRNAs occurred through day 14. By immunohistochemistry, increased accumulation of collagen IV, heparan sulfate proteoglycan, and laminin were detected along the thicken TBM; collagens I and III were immunolocalized within the tubulo-interstitium, while FN was present in both the TBM and interstitium in rats with TIN on day 14. The increase in matrix accumulation was associated with little or no increase in proteinases. u-PA transcripts fell beginning on day 8, with recovery to control values by day 12. Transin mRNA was found at low levels only on days 8 and 9, and the protein could not be detected by Western blotting. In contrast, these changes were associated with an increase in proteinase inhibitors, so that TIMP and PAI-1 mRNAs increased beginning on day 7 and persisted through day 14.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Extracellular matrix accumulation in immune-mediated tubulointerstitial injury. 800 77

Three major components of the plasminogen activators (PA)/plasmin system are synthesized physiologically in glomeruli, and can be involved in glomerular proteolysis and extracellular matrix metabolism: tissue-type PA (tPA), urokinase (uPA) and PA inhibitor type 1 (PAI-1). To explore the possible role of a dysregulation of the plasmin protease system in the development and progression of lupus-like glomerulonephritis, we studied the expression of the renal plasmin protease components during the course of the disease, either acute, induced by IgG3 monoclonal cryoglobulins, or chronic, occurring spontaneously in three different lupus-prone mice: (NZBxNZW)F1, BXSB and MRL-lpr/lpr. RNase protection assays and in situ hybridizations revealed a marked glomerular induction of PAI-1 mRNA abundance without any significant changes in renal tPA and uPA mRNA levels in the two different types of lupus-like glomerulonephritis. The overexpression of PAI-1 mRNA occurred in parallel with a significant decrease in glomerular tPA-catalyzed enzymatic activity as determined by zymographic analysis. In addition, a concomitant increase in glomerular expression of transforming growth factor beta 1 (TGF-beta 1) mRNA was observed. The demonstration of a close correlation between the PAI-1 and TGF-beta 1 mRNA levels and the severity of lupus-like glomerular lesions suggests that a pertubation of the glomerular PA/PAI balance, resulting from a marked TGF-beta 1-mediated induction of PAI-1 gene expression, plays an important role in the progression of lupus-like glomerular lesions, leading to glomerulosclerosis.
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PMID:Induction of plasminogen activator inhibitor type 1 in murine lupus-like glomerulonephritis. 854 2

The B10/B10.A congenic mouse pair serves as a model for identifying specific genes related to morphogenesis and dysmorphogenesis of the embryonic palate and other organs. The present report describes our initial investigation of the Fraser-Juriloff paradigm, which proposes that susceptibility to malformation results from genetically determined differences in normal developmental patterns. Specifically, we evaluated the relationship between Igf2r gene expression, transforming growth factor-beta (TGF-beta) activation, and cdk4 gene expression. By using in situ hybridization, RNase protection assays, indirect immunofluorescence, Western blots, and bioassays, we show 1) the presence of insulin-like growth factor II (IGF-II), IGF-II receptor (IGF-IIR), IGF-IR, TGF-beta, plasminogen, plasminogen activators [urokinase plasminogen activator (uPA) and tissue plasminogen activator (tPA)], and Cdk4 in developing palates; 2) on embryonic day 14 (E14), which is a critical day for palatal growth, B10.A embryos have 82% greater IGF-IIR mRNA than B10; 3) on E14, B10.A embryonic palates have a 57% greater level of active TGF-beta2 than B10, although the total TGF-beta2 is nearly identical; and 4) on E14, B10 embryonic palates have a 52% greater level of Cdk4 mRNA than B10.A palates, a measure of cell cycle progression. Because cellular activation of latent TGF-beta appears to require binding to the mannose-6-phosphate (M6P) binding site of the IGF-IIR and is plasmin and plasminogen activator dependent, the positive correlation of IGF-IIR levels and active TGF-beta2 levels seems to be key. Thus, the strain variation of TGF-beta2/IGF-IIR-mediated growth inhibition in late G1 phase would appear to account for the slower growth and development of B10.A palates relative to B10. Elevated corticosteroid (CORT) exposure in E14 B10.A embryos significantly increases TGF-beta levels, 87% of which is TGF-beta2, as well as the levels of active TGF-beta, 64% of which is TGF-beta2. Without exogenous CORT, B10.A embryos do not have clefts; hence, we present an outline of pathogenesis: slower growing B10.A embryos have an up-regulation of IGF-IIR, which serves to sequester IGF-II from the growth-promoting IGF-IR and to bind more CORT-up-regulated, latent TGF-beta2 for subsequent plasmin-dependent activation; higher levels of TGF-beta2 signaling down-regulate Cdk4 and result in greater palatal growth inhibition at a critical stage of palatogenesis and, thus, cleft palate. We present an epigenetic model of information processing related to cell proliferation. The model is a dynamical network that uses continuous logic to learn its rules from changing conditions.
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PMID:Insulin-like growth factor II receptor, transforming growth factor-beta, and Cdk4 expression and the developmental epigenetics of mouse palate morphogenesis and dysmorphogenesis. 943 20

The urokinase receptor (uPAR) influences several biological functions relevant to lung injury and repair, including proteolysis, cell migration, and adhesion. In malignant mesothelioma cells, we recently found that a posttranscriptional mechanism involving a cis-trans interaction between a uPAR mRNA sequence and a cytoplasmic uPAR mRNA binding protein (mRNABP) regulates uPAR gene expression (S. Shetty, A. Kumar, and S. Idell. Mol. Cell Biol. 17: 1075-1083, 1997). In this study, we sought to determine if uPAR expression in lung and pleural cells involves a similar posttranscriptional pathway. We first identified and characterized the uPAR mRNABP in rabbit tissues using gel mobility shift, ultraviolet (UV) cross-linking, and RNase protection assays and detected it in liver, heart, brain, spleen, colon, and lung. Phorbol 12-myristate 13-acetate, lipopolysaccharide, transforming growth factor-beta, tumor necrosis factor-alpha, or cycloheximide induced uPAR and uPAR mRNA expression in cultured rabbit pleural mesothelial cells and lung fibroblasts and concurrently reduced the uPAR mRNA-uPAR mRNABP interaction. Using conventional and affinity chromatography, we purified a 50-kDa uPAR mRNABP that selectively binds to a 51-nucleotide fragment of the uPAR coding region. This protein migrates as a monomer when analyzed by SDS-PAGE and UV cross-linking and does not possess intrinsic RNase activity in vitro. A uPAR mRNABP physicochemically and functionally similar to that of human malignant mesothelioma is constitutively expressed in the rabbit lung and other nonneoplastic tissues. In rabbit lung fibroblasts and mesothelial cells, expression of uPAR involves posttranscriptional regulation whereby the uPAR mRNABP appears to interact with a specific coding region cis-element to decrease the stability of uPAR mRNA.
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PMID:A urokinase receptor mRNA binding protein from rabbit lung fibroblasts and mesothelial cells. 960 25

During liver fibrogenesis, hepatic stellate cells (HSC) proliferate and migrate under the influence of growth factors, including platelet-derived growth factor (PDGF) and basic-fibroblast growth factor (b-FGF). The plasminogen activation system regulates extracellular matrix (ECM) catabolism and cell movement. We evaluated the expression and biological functions of the plasminogen activation system in human HSC and its interaction with PDGF and b-FGF. Urokinase-plasminogen activator receptors (u-PAR) were measured by radioligand binding, cell cross-linking, immunoassay, and RNAse protection assay. u-PA and plasminogen activator inhibitors (PAIs) expression and activities were analyzed by zymography, immunoassay, and RNase protection assay. Cell migration and proliferation, studied in Boyden chambers and by microscopic counting, were evaluated after the addition of PDGF, b-FGF, and blockade with anti-u-PA, anti-u-PAR antibodies, and antisense oligodeoxynucleotides (aODN) against u-PAR mRNA. We have shown that HSC produce u-PAR, u-PA, and PAI-1. PDGF and b-FGF up-regulate u-PA and u-PAR, but not PAI-1, and exogenous addition of u-PA stimulates HSC proliferation, chemotaxis, and chemoinvasion. Inhibition of u-PA/u-PAR with antibodies against u-PA or u-PAR and with u-PAR aODN inhibit the proliferative, chemotactic, and chemoinvasive activity of PDGF and b-FGF. These findings indicate that u-PA and u-PAR are required for the mitogenic and chemoinvasive activity of PDGF and b-FGF on HSC.
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PMID:Functions of the fibrinolytic system in human Ito cells and its control by basic fibroblast and platelet-derived growth factor. 1005 91

The urokinase-type plasminogen activator (uPA) interacts with its receptor (uPAR) to promote proteolysis as well as cell proliferation and migration. These functions contribute to the pathogenesis of neoplastic growth and invasiveness. Expression of uPAR in tumor extracts also inversely correlates with prognosis in many forms of cancer. In this study, we sought to determine if differences in uPAR expression were distinguishable between cultured human lung carcinoma and malignant mesothelioma subtypes. We also sought to determine if, as in malignant mesothelioma cells, uPAR expression is regulated at the posttranscriptional level in cultured malignant lung carcinoma cells. Using 125I-uPA binding and ligand blotting techniques, uPAR was expressed by phenotypically diverse lung carcinoma cell lines, including the H460, H157 and H1395 non-small cell lines and the H146 small cell lung carcinoma line. Increased uPAR expression was also detected in spindle-shaped (M33K) and epithelioid (M9K and MS-1) malignant mesothelioma cells. Selected mediators, including TGF-beta, TNF-alpha, LPS and PMA, uniformly enhanced uPAR expression in each of the tumor cell lines. Steady state uPAR mRNA expression was determined by RNase protection assay and correlated directly with the changes in cell surface uPAR expression. By gel mobility shift and UV-cross linking assays, a uPAR mRNA binding protein (uPAR mRNABp) implicated in the posttranscriptional control of message stability, was identified in each of the cell lines. Expression of uPAR and its message in cultured lung carcinoma and malignant mesothelioma cells is similarly influenced by effectors present in the tumor microenvironment. Regulation of the uPAR message occurs at the posttranscriptional level in cultured small and non-small cell lung carcinoma cells as well as spindle-shaped and fibrous malignant mesothelioma cell lines. Posttranscriptional regulation of uPAR in all these cells involves the interaction of the uPAR mRNABp with uPAR mRNA, which promotes uPAR mRNA destabilization.
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PMID:Posttranscriptional regulation of urokinase receptor gene expression in human lung carcinoma and mesothelioma cells in vitro. 1054 67

Thickening of the glomerular basement membrane (GBM) results from excessive accumulation of extracellular matrix (ECM) proteins following glomerular injury. We studied the temporal relationship between the expression of growth factors, ECM accumulation, ECM degrading proteinases, and their inhibitors in a rat model of anti-GBM antibody (Ab) glomerulonephritis (GN) by the RNase protection assay and immunohistochemistry. There were two- or fourfold increases in the expression of transforming growth factor-beta(1) (TGF-beta(1)) and platelet-derived growth factor (PDGF) A and B chain mRNAs 4 days after anti-GBM Ab administration. These changes were temporally associated with increased accumulation of alpha1(III) and alpha2(IV) collagens, fibronectin, and heparan sulfate proteoglycan along the GBM. The increase in matrix accumulation was associated with little or no increases in the proteinases, urokinase plasminogen activator (u-PA) and transin, respectively. There was a 1.6x increase in the u-PA/28s mRNA ratio on day 4 in rats with anti-GBM Ab GN, but this was not associated with an increase in u-PA biologic activity. By comparison, the mRNAs of the proteinase inhibitors, plasminogen activator inhibitor-1 (PAI-1) and tissue inhibitor of metalloproteinase (TIMP) were 5x greater than that of control rats on day 4. PAI-1 mRNA correlate with increased biologic activity. These data demonstrate a temporal association between TGF-beta(1) and PDGF expression and matrix accumulation within the GBM in anti-GBM Ab GN. In addition, it suggest that this matrix accumulation results from an imbalance between matrix synthesis and degradation.
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PMID:Glomerular extracellular matrix accumulation in experimental anti-GBM Ab glomerulonephritis. 1064 7

The activation of hepatic stellate cells (HSC) during liver fibrogenesis has been shown to be mediated by paracrine and autocrine loops involving transforming growth factor-beta1 (TGF-beta1) as the main fibrogenic mediator secreted by activated macrophages, endothelial cells and liberated by disintegrated platelets. The cell-associated plasminogen activation system regulates extracellular matrix (ECM) catabolism and cell movement. We have studied whether TGF-beta1 could modulate the plasminogen activation system in human HSC and the role of such protease system in the activity of TGF-beta1 on HSC. Urokinase plasminogen activator receptors (u-PAR), u-PA and plasminogen activator inhibitor type 1 (PAI-1) were determined by immunoassay and RNase protection assay. Cell migration, evaluated either as chemotaxis or as chemoinvasion, was studied in Boyden chambers after addition of TGF-beta1, and inhibition with anti-u-PA and anti-u-PAR antagonists [antibodies against u-PA and u-PAR and antisense oligonucleotides (aODN) against u-PAR mRNA]. We have shown that TGF-beta1 is not mitogenic for HSC, while it is a powerful motogen either in chemotaxis or chemoinvasion assays. TGF-beta1 up-regulates the synthesis and expression of PAI-1, as well as u-PAR expression and exposure at the cell membrane, while it does not affect u-PA levels. TGF-beta1-dependent chemoinvasion of reconstituted basement membrane exploits the cell-associated plasminogen activation system, since it is blocked by monoclonal antibodies against u-PA and against various u-PAR domains, as well as by anti-u-PAR aODN. We have also observed a cumulative effect of TGF-beta1, b-FGF and PDGF in the invasion assay of HSC: in the presence of low amounts of TGF-beta1 the chemoinvasive activity of PDGF and bFGF is dramatically increased. Also this cooperation requires u-PAR and is inhibited by monoclonal antibodies against u-PAR domains I, II and III.
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PMID:Transforming growth factor beta-1 stimulates invasivity of hepatic stellate cells by engagement of the cell-associated fibrinolytic system. 1176 74

The accumulation of fibrillar amyloid-beta protein (A beta) in cerebral blood vessels, a condition known as cerebral amyloid angiopathy (CAA), is a key pathological feature of Alzheimer's disease and certain related disorders and is intimately associated with cerebrovascular cell death both in vivo and in vitro. Moreover, severe CAA leads to loss of vessel wall integrity and cerebral hemorrhage. Although the basis for these latter pathological consequences in CAA remains unresolved alterations in local proteolytic mechanisms may be involved. Here we show that pathogenic forms of A beta stimulate the expression of plasminogen activator activity in cultured human cerebrovascular smooth muscle (HCSM) cells, an in vitro model of CAA. RNase protection assays and plasminogen zymography showed that urokinase-type plasminogen activator (uPA) was responsible for this activity. There was preferential accumulation of uPA on the HCSM cell surface that was mediated through a concomitant increase in expression of the uPA receptor. In the presence of plasminogen there was robust degradation of A beta that was added to the HCSM cells resulting in restoration of cell viability. This suggests that increased expression of uPA may initially serve as a protective mechanism leading to localized degradation and clearance of the pathogenic stimulus A beta. On the other hand, chronic expression of uPA and plasminogen activation led to a profound loss of HCSM cell attachment. This suggests that a similar prolonged effect in vivo in the cerebral vessel wall may contribute to loss of integrity and cerebral hemorrhage in CAA.
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PMID:Amyloid beta-protein stimulates the expression of urokinase-type plasminogen activator (uPA) and its receptor (uPAR) in human cerebrovascular smooth muscle cells. 1275 71