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)

Localization of t-PA, u-PA, PAI-1, PI and TGF-beta within tumors was examined immunohistologically in 31 patients with squamous cell carcinoma (SCC) of the head and neck, and correlations between the localization of these factors and local cancer infiltration, tumor size or cervical lymph node metastasis were investigated. The results revealed that u-PA, PAI-1 and PI tend to stain more intensely in infiltrating tumors than in peripheral connective tissue or normal epithelium, whereas neither t-PA nor TGF-beta showed any such tendency. Not all of these fibrinolytic factors participated in lymph node metastases or influenced tumor size in head and neck SCCs. These results suggest a disorder of fibrinolytic systems in carcinoma cells and that u-PA plays a part in the infiltration of head and neck SCCs by degenerating connective tissue.
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PMID:Relationship between head and neck squamous cell carcinomas and fibrinolytic factors. Immunohistological study. 890 83

The aim of this study was to investigate whether breast cancer growth in vivo could be due to a failure in the activation of TGF-beta 1, a growth factor which has been shown to affect the development of normal breast tissue. Tissue samples of 40 breast carcinomas and the normal adjacent tissue from 37 (henceforth referred to as 'adjacent tissue'), as well as 13 specimens of benign lesions, were included in this study. The specimens were used in vitro to produce conditioned medium (CM), and this was examined for TGF-beta 1 activity by measuring growth inhibition of the mink lung epithelial cell line CCL-64. Immunoblotting and electrophoresis were used to detect the presence of TGF-beta 1 in CM and homogenised tissue samples. We demonstrated that the majority of TGF-beta 1 in breast cancer conditioned medium was biologically active, in direct contrast to CM prepared from benign disease specimens. Furthermore, active TGF-beta 1 was also identified in CM prepared from adjacent tissue, suggesting an important early role for this growth factor in the spread of this disease. Three distinct breast cancer related (BCR) molecular weight species of TGF-beta 1 (12.5/25 kDa, 50 kDa and 95 kDa) were identified. Both the 50 kDa and 95 kDa bands immunoprecipitated by an anti-TGF-beta 1 antibody were also immunoreactive with anti-TGF-beta 1 binding protein antibodies suggesting that the 50 kDa band may comprise at least part of the previously described small latent complex of TGF-beta 1. However, using the CCL-64 cell assay, we were able to demonstrate that the 50 kDa TGF-beta 1 BCR protein was biologically active whereas the large (95 kDa) TGF-beta 1 BCR latent complex protein was not. Adjacent tissue was more likely to contain the 50 kDa form than the tumour tissues (P < 0.05). Similarly, the 50 kDa molecule was also more common in patients who had oestrogen receptor (ER) negative tumours (compared with ER positive patients; P < 0.05) and in those who had received tamoxifen treatment prior to surgery (P < 0.01). In all of these cases, the increase in the incidence of the small active complex form was accompanied by a decrease in the incidence of the high molecular weight complex (95 kDa). We confirmed that, in vitro, the 95 kDa TGF-beta 1 BCR can be proteolytically cleaved to yield a 50 kDa TGF-beta 1 BCR. Finally, we observed a correlation between the presence of the 50 kDa complex protein and reduced levels of plasminogen activator (PA), which was significant in ER negative patients (P < 0.05) and tamoxifen-pretreated patients (P < 0.01). This suggests that the secretion of this active TGF-beta 1 protein may provide breast tumours with a mechanism whereby they can escape oestrogen dependence, and may provide an explanation for the common problem of tamoxifen resistance.
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PMID:Multiple forms of TGF-beta 1 in breast tissues: a biologically active form of the small latent complex of TGF-beta 1. 891 Nov 19

The cellular events causing pathological extracellular matrix (ECM) accumulation in vivo are not well understood. Prolonged serial passage of several cell types in culture leads to increased production of extracellular matrix (ECM) proteins, but the mechanism for these putative fibrotic changes is not known. Here, human fetal glomerular mesangial cells were subjected to serial passage (P) in culture and the expression of ECM proteins, proteases and protease inhibitors was comprehensively evaluated. From P11 through P14, a series of phenotypic changes occurred. Steady-state expression of mRNA for alpha 1 chains of type III and type IV (but not type I) collagen, and for laminin beta 1 and gamma 1, increased 2- to 8-fold, while expression of mRNA for interstitial collagenase (MMP-1) and gelatinase A (MMP-2) virtually ceased. Expression of tissue-type plasminogen activator (tPA) mRNA also decreased markedly. Expression of mRNA for the tissue inhibitor of metalloproteinases (TIMP)-1, and of the smaller of two mRNA species for the PA inhibitor PAI-1, ceased by P14. There was a switch in expression of the two species of TIMP-2 mRNA: whereas the ratio of signal intensity comparing the 3.5 kb mRNA species to the 1.0 kb species was 5:1 up to P11, it was reversed (1:5) at P14 and later. Serial passage also led to changes in protein expression, with increased type IV collagen and laminin, but decreased interstitial collagenase and gelatinase A. The cells showed a progressive increase in staining for type IV collagen. These findings define the appearance of a matrix-accumulating phenotype in later-passage mesangial cells. Matrix expansion in vivo has been associated with increased transforming growth factor (TGF)-beta synthesis; the cells were found to show at least 5-fold increased expression of TGF-beta 1 mRNA from P8 to P16. However, treatment of P9 or P10 cells with graded doses of TGF-beta 1 increased expression of both collagen IV and gelatinase A mRNA and did not alter the ratio of signal intensity for TIMP-2 mRNA species. Thus, assumption of a matrix-accumulating phenotype by these cultured fetal glomerular mesangial cells is not accelerated by exogenous TGF-beta. These data describe an in vitro model of mesangial cell matrix turnover in which matrix accumulation could result from a concerted increase in ECM synthesis and decrease in ECM degradation.
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PMID:Increased expression of extracellular matrix proteins and decreased expression of matrix proteases after serial passage of glomerular mesangial cells. 892 13

We studied the mechanism by which 9,13-di-cis-retinoic acid (9,13dcRA), a novel and endogenous stereoisomer of all-trans-RA, induces TGF-beta formation in a human liver stellate cell line, LI90. 9,13dcRA induced the expression of RAR alpha and RARbeta, enhanced the production of tissue-type plasminogen activator (tPA), thereby, surface plasmin levels, and induced the activation of latent TGF-beta. Similar effects were obtained with RAR alpha-selective retinoid, but not with RARbeta- or RARgamma-selective retinoid, and the induction was inhibited by RAR alpha-selective antagonist. These results suggest that 9,13dcRA up-regulates tPA expression, resulting in the formation of TGF-beta by LI90 cells, at least in part, via induction and activation of RAR alpha.
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PMID:9,13-di-cis-Retinoic acid induces the production of tPA and activation of latent TGF-beta via RAR alpha in a human liver stellate cell line, LI90. 924 51

In addition to autoregulating its own expression, transforming growth factor-beta 1 (TGF-beta1) also regulates the production of proteases, protease inhibitors and extracellular matrix proteins. To investigate the relationship between plasminogen activator (PA), plasminogen activator inhibitor-1 (PAI-1) and the extracellular matrix in malignant and normal lung epithelial cells and to determine whether malignant lung epithelial cells may be more invasive than normal lung epithelial cells because of differences in expression of these proteins in response to TGF-beta, the regulation of PA, PAI-1, fibronectin, laminin and thrombospondin by TGF-beta1 in human non-small cell lung cancer (NSCLC) cells was examined and compared with normal human bronchial epithelial (NHBE) cells. TGF-beta1 caused a persistent increase in expression of the mRNAs for both PA and PAI-1 in NSCLC cells, with the increase in PAI-1 mRNA beginning several hours before that of PA mRNA. By immunoprecipitation analysis, it was shown that TGF-beta1 also induced a corresponding increase in the amount of PAI-1 protein in these NSCLC cells as well. In contrast, while TGF-beta1 also increased expression of PAI-1 mRNA in NHBE cells, expression of PA mRNA decreased simultaneously. Treatment of NSCLC cells with TGF-beta1 resulted in a persistent increase in expression of the mRNAs for fibronectin, laminin and thrombospondin; expression of fibronectin protein also increased after treatment with TGF-beta1 in these cells. When NHBE cells were similarly cultured in the presence of TGF-beta1, expression of fibronectin mRNA also increased in a persistent manner; however, only an early transient increase in the level of the mRNAs for laminin and thrombospondin was detected in these cells. These data show that there is differential regulation of the genes for PA and PAI-1 and the extracellular matrix protein fibronectin in response to TGF-beta1 not only when NSCLC and NHBE cells are compared, but also when different NSCLC cells are compared with each other.
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PMID:Differential regulation of protease and extracellular matrix protein expression by transforming growth factor-beta 1 in non-small cell lung cancer cells and normal human bronchial epithelial cells. 929 10

Previous studies suggest a role for the plasminogen or fibrinolytic system in the activation of latent-transforming growth beta (L-TGFbeta) into active TGFbeta. In the present study, the anti-apoptotic activity of TGFbeta on cultured vascular smooth muscle cells (SMC) isolated from the aorta of transgenic mice with single inactivation of genes encoding the tissue-type plasminogen activator (t-PA(-/-)), urokinase-type plasminogen activator (u-PA(-/-)), urokinase receptor (u-PAR(-/-)) or plasminogen (Plg(-/-)) genes was examined. Latent-TGFbeta inhibited serum deprivation-induced apoptosis of SMC isolated from wild-type and t-PA(-/-) mice but failed to reduce apoptosis of SMC isolated from u-PA(-/-), u-PAR(-/-) or Plg(-/-) mice. Active TGFbeta, however, was able to inhibit serum deprivation-induced apoptosis of these 5 cell types, indicating that u-PA and/or plasmin were involved in the activation of L-TGFbeta. The anti-apoptotic effect of L-TGFbeta could not be evoked by addition of exogenous t-PA to u-PA(-/-) cells, but was revealed by addition of exogenous u-PA or plasmin. This effect was dependent on the catalytic activity of plasmin as revealed by the dose-dependent inhibition of aprotinin or epsilon aminocaproic acid (EACA). These results therefore indicate that, at least in vitro, u-PA-mediated plasmin, through the generation of active TGFbeta from L-TGFbeta, is required for the anti-apoptotic activity of TGFbeta on SMC.
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PMID:Involvement of u-PA in the anti-apoptotic activity of TGFbeta for vascular smooth muscle cells. 930 44

Cultured fibroblasts from patients with systemic sclerosis (SSc) and normal individuals were examined for gene expression of types I and III collagen, decorin, matrix metalloproteinases (MMP) MMP-1, MMP-2, and MMP-3, tissue inhibitors of metalloproteinases (TIMP) TIMP-1 and TIMP-2, urokinase- and tissue-type plasminogen activators (u-PA and t-PA). Fibroblasts from patients with early stage SSC (less than 1 year duration of disease) exhibited higher levels of types I and III procollagen, decorin, MMP-1, MMP-3, TIMP-1, and PAs than those from normal individuals. The gene expression of procollagen alpha 1(I) and TIMP-1 mRNAs were increased, but those of decorin, MMP-1, MMP-2, and MMP-3 were decreased, in fibroblasts from SSc patients with mid-stage SSc (2 to 4 years duration) as compared with those from normal individuals. In contrast, no significant difference in gene expression was found between fibroblasts from normal individuals and from patients with late-stage SSc (more than 6 years duration). These results suggest that gene expression of collagen, decorin, and degrading factors is dynamically modulated during fibrillogenesis. The responses of procollagen alpha 1(I) mRNA to IL-1 and TGF-beta were lower in fibroblasts from SSc patients with early and mid-stage disease, but not in those from patients with-late stage disease, than in control fibroblasts, which indicates that these cytokines may be involved in the earlier phases of fibrosis in SSc.
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PMID:Gene expression of types I and III collagen, decorin, matrix metalloproteinases and tissue inhibitors of metalloproteinases in skin fibroblasts from patients with systemic sclerosis. 937 15

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

Accumulation of the glomerular extracellular matrix (ECM) is a pivotal event in the progression from acute glomerular injury to end-stage renal disease. Although enhanced ECM synthesis has been demonstrated to contribute to ECM accumulation, the role of decreased ECM degradation is largely unknown. It was previously shown that glomerular ECM degradation is mediated by a plasminogen activator (PA)/plasmin/matrix metalloproteinase 2 (MMP-2) cascade. However, little information is available regarding the factors that regulate the activity of this degradative cascade in normal or pathologic states. Transforming growth factor-beta1 (TGF-beta1) is shown here to be a potent inhibitor of ECM degradation by cultured human mesangial cells. Using human mesangial cells grown on thin films of 125I-labeled Matrigel, dose-dependent inhibition of ECM degradation in the presence of TGF-beta1 was observed, reaching >90% inhibition with 0.4 ng/ml TGF-beta1. Addition of anti-TGF-beta antibodies (4 microg/ml) in the absence of exogenous TGF-beta increased ECM degradation (1.8+/-0.2-fold versus controls, P<0.05). In contrast, platelet-derived growth factor, at concentrations up to 10 ng/ml, had no effect on ECM degradation. TGF-beta completely blocked the conversion of plasminogen to plasmin and markedly reduced the conversion of latent MMP-2 to active MMP-2. TGF-beta did not significantly alter the levels of tissue PA, total MMP-2, or tissue inhibitor of metalloproteinase-1, but did increase the levels of PA inhibitor- (1.8-fold, P<0.05), the major physiologic inhibitor of PA. These data document that TGF-beta is a potent inhibitor of ECM degradation by cultured human mesangial cells, and they suggest that decreased mesangial matrix degradation, caused by TGF-beta-mediated decreases in the activity of the PA/plasmin/MMP-2 cascade, may contribute to the glomerular matrix accumulation that occurs in progressive renal disease.
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PMID:Transforming growth factor-beta is a potent inhibitor of extracellular matrix degradation by cultured human mesangial cells. 1020 63

The tissue type plasminogen activator (t-PA) is a serine protease that is involved in neuronal plasticity and cell death induced by excitotoxins and ischemia in the brain. t-PA activity in the central nervous system is regulated through the activation of serine protease inhibitors (serpins) such as the plasminogen activator inhibitor (PAI-1), the protease nexin-1 (PN-1), and neuroserpin (NSP). Recently we demonstrated in vitro that PAI-1 produced by astrocytes mediates the neuroprotective effect of the transforming growth factor-beta1 (TGF-beta1) in NMDA-induced neuronal cell death. To investigate whether serpins may be involved in neuronal cell death after cerebral ischemia, we determined, by using semiquantitative RT-PCR and in situ hybridization, that focal cerebral ischemia in mice induced a dramatic overexpression of PAI-1 without any effect on PN-1, NSP, or t-PA. Then we showed that although the expression of PAI-1 is restricted to astrocytes, PN-1, NSP, and t-PA are expressed in both neurons and astrocytes. Moreover, by using semiquantitative RT-PCR and Western blotting, we observed that only the expression of PAI-1 was modulated by TGF-beta1 treatment via a TGF-beta-inducible element contained in the PAI-1 promoter (CAGA box). Finally, we compared the specificity of TGF-beta1 action with other members of the TGF-beta family by using luciferase reporter genes. These data show that TGF-beta and activin were able to induce the overexpression of PAI-1 in astrocytes, but that bone morphogenetic proteins, glial cell line-derived neutrophic factor, and neurturin did not. These results provide new insights into the regulation of the serpins/t-PA axis and the mechanism by which TGF-beta may be neuroprotective.
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PMID:Transforming growth factor-beta1 as a regulator of the serpins/t-PA axis in cerebral ischemia. 1042 56

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