UNIPROT:P00750 - FACTA Search

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Query: UNIPROT:P00750 (PLA)
16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cell-associated plasmin is a putative physiological activator of latent transforming growth factor-beta (LTGF-beta). Since retinoids enhance the production of plasminogen activator (PA) and thereby increase cell-associated plasmin activity, we tested the possibility that retinoids might induce the activation of LTGF-beta using bovine endothelial cells (ECs) as a model system. ECs treated with physiological concentrations of retinol or retinoic acid formed active TGF-beta in the culture media in a dose- and time-dependent fashion. Cells were treated with 2 microM retinol for 24 h, and the amount of TGF-beta produced during a subsequent 12-h incubation period was measured. Out of a total of 14 pM LTGF-beta secreted, 0.7 pM was converted to active TGF-beta. Northern blot analyses showed that mRNA levels for TGF-beta 2 but not for TGF-beta 1 increased in cells treated with retinol. Inclusion of either inhibitors of PA or of plasmin or antibody against PA in the culture medium as well as depletion of plasminogen from the serum blocked the formation of TGF-beta, suggesting that PA, plasminogen, and the resulting plasmin are essential for activation of LTGF-beta in retinoid-stimulated cells. Antibody against the LTGF-beta binding protein blocked activation implying that localization of LTGF-beta through its binding protein may be important. However, inhibition of binding of LTGF-beta to the cell surface mannose 6-phosphate receptor did not prevent activation. These data indicate that retinoids up-regulate the production of LTGF-beta in ECs and induce activation of LTGF-beta, perhaps, by increasing PA and plasmin levels. Thus, TGF-beta might be a local mediator of some of the biological activities of retinoids both in vivo and in vitro.
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PMID:Mechanism of retinoid-induced activation of latent transforming growth factor-beta in bovine endothelial cells. 848 24

The effect of transforming growth factor-beta (TGF-beta) was analyzed on the synthesis of fibronectin, collagen type IV, and urokinase plasminogen activator in human glomerular epithelial cells in culture. An increase in the abundance of specific mRNA was found for collagen type IV and fibronectin. Fibronectin protein synthesis was also increased in TGF-beta treated cells; most of the de novo synthesized fibronectin was found as an unsoluble protein associated with extracellular matrix. In the same cells the amount of plasminogen activator mRNA was found leading also to a decreased surface expression of urokinase plasminogen activator. The data support the concept that by upregulating matrix protein synthesis and downregulating the plasminogen activator system, TGF-beta favors the development of sclerosis.
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PMID:Interaction of transforming growth factor beta 1 with human glomerular epithelial cells in culture: opposite effects on synthesis of matrix proteins and on urokinase plasminogen activator. 884 65

Confluent cultures of two renal collecting duct cell lines (M-1 and mIMCD-K2 cells derived from cortical and inner medullary collecting ducts, respectively) express endothelin1 (ET1), transforming growth factor-beta (TGF beta; both TGF beta 1 and TGF beta 2), and both types of the TGF beta receptor. Experiments were performed to test whether endogenous TGF beta may be a paracrine modulator of ET1 expression in these cells. Treatment of M-1 and mIMCD-K2 cells with TGF beta 2 antisense oligodeoxynucleotides (ODN) significantly reduced ET1 messenger RNA (mRNA) and ET secretion (as well as TGF beta 2 mRNA) in a concentration-dependent manner, whereas control ODN were without significant effects. To produce ET inhibition, antisense ODN had to be present in the basolateral medium, whereas its sole presence in the apical medium was without effect. In addition, a pan-specific TGF beta antibody caused a significant reduction of ET1 mRNA expression and ET1 secretion. M-1 cells were found to express high levels of the mRNA for plasminogen activator of both tissue and urokinase types. Addition of the nonspecific serine protease inhibitor aprotinin (50 micrograms/ml) to the medium for 24 h significantly reduced the secretion of ET1. These results suggest that secretion of endogenous TGF beta, at least in part activated by the plasminogen/plasmin system, participates in the regulation of ET1 synthesis and secretion by collecting duct cell lines.
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PMID:Regulation of endothelin production and secretion in cultured collecting duct cells by endogenous transforming growth factor-beta. 889 74

The multifunctional cytokine, transforming growth factor-beta (TGF beta), is found in many tissues in a latent or inactive form. The nature and composition of the latent complex can vary depending on tissue type. The release of active TGF beta from its latent complex is a potentially important mechanism for regulation of TGF beta activity. We have shown previously that osteoclasts activate latent TGF beta produced by bone and that bone cells produce a 100-kDa latent complex that lacks the latent TGF beta-binding protein. Here we investigated the effects of retinol on osteoclast activation of various forms of latent TGF beta. Two sources of osteoclasts were used that provide either mature avian osteoclasts or avian osteoclast precursors. Whereas both cell populations activate latent TGF beta, only mature osteoclasts respond to retinol with an increase in activation of latent TGF beta over basal levels. Activation could not be ascribed to pH changes in conditioned medium. Nonacid-dissociable 100-kDa latent complex, which is also produced by bone cells, was added to mature osteoclasts and to osteoclast precursors, but no activation was observed. Platelet latent TGF beta, which contains the 130-kDa latent TGF beta-binding protein, was activated by both osteoclast populations. Conditioned medium from the precursor population activated latent complex, whereas conditioned medium from mature cells did not. Activation of latent TGF beta by retinol-treated mature cells was not blocked by inhibitors of plasmin, nor was activation by conditioned medium from precursor cells. These data suggest that retinol-induced activation of latent TGF beta by osteoclasts is dependent on the stage of differentiation of these cells and the presence of other cell types, and that unlike other cell systems, the plasmin-plasminogen activator mechanism is not involved.
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PMID:Effects of retinol on activation of latent transforming growth factor-beta by isolated osteoclasts. 900

When cultured in type I collagen gels, two kidney-derived cell lines, Madin-Darby canine kidney (MDCK) cells and murine inner medullary collecting duct (mIMCD3) cells, from branching tubular structures in the presence of Swiss 3T3 conditioned medium, in which hepatocyte growth factor (HGF) is the major branching tubule inducing factor. However, upon incubation with transforming growth factor-beta (TGF-beta) in the presence of 3T3 conditioned medium, MDCK tubulogenesis and branching was markedly inhibited. In contrast, mIMCD3 cells, which are much less susceptible to growth and tubulogenesis inhibition by TGF-beta, formed long straight tubulelike structures in presence of TGF-beta, suggesting a dissociation between tubulogenesis and branching morphogenesis. Interestingly, those long tubules that did branch often superficially resembled the early branching ureteric bud in embryonic kidneys. Quantitation of branching events revealed a selective branch-inhibiting effect of TGF-beta on mIMCD3 cells at concentrations between 0.02 and 2 ng/ml. There was no qualitative or quantitative difference among TGF-beta 1, -beta 2, and -beta 3 on inhibition of branching events, suggesting existence of potentially redundant mechanisms for modulating branching morphogenesis. Concentrations of TGF-beta that resulted in long nonbranching tubules also altered the profile of extracellular matrix-degrading proteases and their inhibitors expressed by developing tubules. Ratios of urokinase type plasminogen activator (u-PA) to plasminogen activator inhibitor (PAI-l) and matrix metalloprotease (MMP)-1 to tissue inhibitor of metalloprotease (TIMP)-1 were both markedly decreased. In addition, apart from a direct effect on epithelial cell branching morphogenesis, TGF-beta downregulated the expression of HGF mRNA in Swiss 3T3 cells. Thus TGF-beta exerts at least three distinct effects relevant to tubulogenesis and branching morphogenesis inhibition of branching morphogenesis alone (mIMCD3 cells), inhibition of both tubulogenesis and branching morphogenesis (MDCK cells), and inhibition of the expression of growth factor which induce tubulogenesis and branching morphogenesis (3T3 cells). In the context of epithelial tissue development, which requires tightly regulated branching tubulogenesis of epithelial cells, the data suggest a model where branching patterns are regulated by a precise temporal and spatial balance between branching morphogens such as HGF and inhibitory morphogens such as members of the TGF-beta superfamily [e.g., TGF-beta isoforms, certain bone morphogenetic proteins].
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PMID:Transforming growth factor-beta selectively inhibits branching morphogenesis but not tubulogenesis. 903 60

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

Vitamin D3 and its analogs are potent regulators of growth and differentiation of various cell types. A mechanism of action of vitamin D3 and other steroid hormones is to enhance the secretion of transforming growth factor-beta (TGF-beta) in target cells. In epidermal keratinocytes, vitamin D3 induced the expression of both TGF-beta 1 and TGF-beta 2 with minor changes in mRNA levels, while in BT-20 breast carcinoma cells the increase in TGF-beta activity was preceded by an induction of mRNA. In both cell systems, the absolute amounts of active TGF-beta increased, and in keratinocytes the proportion of active TGF-beta was also enhanced. A concomitant enhancement of secretion of the latent TGF-beta-binding protein by vitamin D3 was observed in BT-20 cells. Retinoic acid, which is known to interfere with vitamin D3 signaling, slightly decreased the levels of secreted TGF-beta 1 protein in BT-20 cells, but did not significantly affect the vitamin D3-induced increase. In addition to regulation of the TGF-beta system, vitamin D3 decreases pericellular plasminogen activator activity in keratinocytes. Plasmin-mediated proteolytic events are involved in the release from pericellular space and activation of TGF-beta. We analyzed vitamin D3 regulation of fibroblast growth and the secretion of PA activity. Vitamin D3 inhibited fibroblast growth in a concentration-dependent manner and downregulated plasminogen activator activity as in keratinocytes. In fibroblasts, vitamin D3 did not induce notable alterations in TGF-beta 1 or latent TGF-beta-binding protein secretion, suggesting divergent growth inhibitory mechanisms. Our results indicate that vitamin D3 and its analogs are potent regulators of the TGF-beta and plasminogen activator systems in cells of epithelial and mesenchymal origin.
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PMID:Vitamin D3 regulation of transforming growth factor-beta system in epithelial and fibroblastic cells--relationships to plasminogen activation. 962 89

Glomerular fibrin deposition is thought to be one of the factors causing progressive glomerular injury and may be related to defective intraglomerular fibrinolysis. Recently, it was shown that tissue plasminogen activator (t-PA) is produced by mesangial cells and is associated with degradation of the extracellular matrix. This study was designed to clarify the factors regulating t-PA production in human mesangial cells. The levels of t-PA activity, t-PA antigen and t-PA inhibitor-1 (PAI-1) antigen were estimated in the supernatants of cultured human fetal mesangial cells incubated for 72 h with thrombin, IL-Ibeta, IL-6, IL-10, and transforming growth factor-beta (TGF-beta). The t-PA activity was measured by an amidolytic assay, and the levels of t-PA antigen and PAI-1 antigen were also measured by enzyme-linked immunosorbent assay. Thrombin increased t-PA activity and TGF-beta decreased it in parallel with t-PA antigen level, although these agents did not affect the synthesis of PAI-1. Incubation with IL-1beta, IL-6 and IL-10 did not change the t-PA activity. It was concluded that the release of t-PA from human fetal mesangial cells was stimulated by thrombin and inhibited by TGF-beta in parallel with that of t-PA antigen. These factors may participate in the glomerular fibrin deposition and the accumulation of extracellular matrix.
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PMID:Regulation of tissue plasminogen activator production in cultured human fetal mesangial cells. 980 22

Mesangial cells are one of the main targets of angiotensin II (AngII) in the renal cortex. AngII receptors on mesangial cells are of high affinity (nanomolar range). They belong to the AT1 subtype as shown by the inhibitory effect of AT1 antagonists on [125I]-Sar1, Ala8 AngII binding and on all of the biologic effects mediated by AngII, such as cytosolic calcium stimulation, inositol phosphate formation, prostaglandin production, and cell contraction. AngII also exerts long-term effects on mesangial cells, including stimulation of cell growth and synthesis of a variety of proteins, essentially the components of the extracellular matrix (collagen, fibronectin) and the type 1 inhibitor of plasminogen activator. These effects are mediated, at least in part, by autocrine products, in particular endothelin, platelet-derived growth factor, and transforming growth factor-beta, whose synthesis is enhanced by AngII. Treatment by an AT1 receptor blocker of mice with experimental nephritis inhibits activation of type I collagen alpha2 chain promoter and prevents the development of glomerulosclerosis. AngII receptors in rat mesangial cells are equally distributed between the AT1A and AT1B isoforms. Treatment of these cells by AngII or losartan, an AT1 receptor blocker, has no effect on AT1A and AT1B receptor mRNA expression, whereas candesartan, another AT1 receptor blocker, increases and dexamethasone decreases this expression.
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PMID:Mesangial AT1 receptors: expression, signaling, and regulation. 989 39

The clinical benefit of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) may derive from a qualitative, functional change in atherosclerotic lesions in addition to their lipid-lowering properties. We examined whether statins altered expression of the major determinants of fibrinolytic balance, plasminogen activator inhibitor-1 (PAI-1), and tissue-type plasminogen activator (tPA) in human vascular smooth muscle (SMC) and endothelial (EC) cells. Simvastatin reduced levels of PAI-1 antigen released from SMCs and ECs stimulated with platelet-derived growth factor or transforming growth factor-beta (IC(50) approximately 1 micromol/L). Levels of EC-derived tPA increased 2-fold over the same concentrations of simvastatin that inhibited release of PAI-1. Simvastatin's inhibitory effect was mimicked by C3 exoenzyme and prevented by geranylgeranyl pyrophosphate, but not by farnesyl pyrophosphate, suggesting the involvement of geranylgeranyl-modified intermediates. Decreased PAI-1 antigen was correlated with reduced mRNA transcription and activity of the PAI-1 promoter. By inhibiting expression of PAI-1 from SMCs and ECs while increasing expression of tPA from ECs, simvastatin may alter the local fibrinolytic balance within the vessel wall toward increased fibrinolytic capacity that, in turn, would reduce thrombotic risk after plaque rupture.
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PMID:HMG CoA reductase inhibitors reduce plasminogen activator inhibitor-1 expression by human vascular smooth muscle and endothelial cells. 1066 56

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