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)

Liver fibrosis is a dynamic process caused by changes in not only the synthesis of matrix proteins but also their degradation. Current evidence indicates that Ito cells, when activated to a myofibroblastic phenotype, play a very active role in regulating matrix degradation in liver. This is mediated via their ability to synthesize and release several members of the matrix metalloproteinase family, a class of enzymes which are responsible for degradation of matrix proteins in the extracellular space. Activated Ito cells have been demonstrated to release prostromelysin, progelatinase A and the pro-enzyme form of interstitial collagenase. In addition, these cells can express appropriate systems for cleaving pro-metalloproteinases to active forms (e.g. the plasminogen activator system, urokinase) as well as specific tissue inhibitors of the activated metalloproteinases (TIMP). In the early phases of liver injury, enzymes with the ability to degrade components of normal liver matrix are expressed (stromelysin and gelatinase A). In contrast, in the fibrotic phase of liver injury, during which fibrillar collagens accumulate, there is little (if any) expression of interstitial collagenase but marked expression of TIMP. These findings suggest that metalloproteinase and their inhibitors play a significant role in liver injury and fibrosis.
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PMID:Role of Ito cells in the degradation of matrix in liver. 858 45

Proteolytic remodeling of the extracellular matrix occurs normally during development and pathologically in arthritis, tumor metastasis, wound healing, and angiogenesis. The major extracellular matrix-degrading proteinases belong to the matrix metalloproteinase (MMP) and plasminogen activator gene families. Intracerebral injection of 72-kDa type IV collagenase (gelatinase A) opens the blood-brain barrier. During hemorrhagic brain injury or intracerebral injection of proinflammatory cytokines, endogenous production of 92-kDa type IV collagenase (gelatinase B) occurs. The gelatinase B gene contains a phorbol ester responsive region (TRE) that binds AP-1 proteins, including c-Fos/c-Jun dimer, the early immediate response gene products. Maximum production of gelatinase B in injury occurs between 16 and 24 h, making this a late effector gene. The serine proteinase, urokinase-type plasminogen activator (uPA), is also produced at that time. Gelatinases and plasminogen activators work in concert to disrupt basement membranes proteolytically. A similar process opens the blood-brain barrier after ischemic and hemorrhagic brain injury, leading to secondary vasogenic brain edema. Delayed damage by proteolytic cascade enzymes provides opportunities for treatment much later than had been thought possible. Potential treatments possible in this second therapeutic window include interfering with the genes that produce the MMPs or inhibiting the action of the gene products.
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PMID:Matrix metalloproteinases in brain injury. 859 11

Endothelial-cell-stimulating angiogenesis factor (ESAF) has been shown to activate procollagenase and reactivate complexes of collagenase and gelatinase A with tissue inhibitor of metallo-proteinase (TIMP)-1. In the present paper we show a purification protocol for bovine pineal ESAF and that purified ESAF activates progelatinase A and prostromelysin-1. Unlike the activation of procollagenase by plasmin/plasminogen activator, which requires the presence of stromelysin for full activation, ESAF is able to activate fully all three proenzymes. Purified ESAF is also shown to reactivate the complexes of gelatinase A, collagenase and stromelysin-1 with TIMP-2. Once separated, both enzyme and inhibitor are active; however, ESAF binds to the enzyme in a manner preventing it from further inhibition by TIMP. ESAF is the only physiological molecule able to reactivate the TIMP/enzyme complex.
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PMID:Endothelial-cell-stimulating angiogenesis factor (ESAF) activates progelatinase A (72 kDa type IV collagenase), prostromelysin 1 and procollagenase and reactivates their complexes with tissue inhibitors of metalloproteinases: a role for ESAF in non-inflammatory angiogenesis. 876 Mar 57

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

The purpose of this study was to examine whether changes in growth, ductal histology, and expression of plasminogen activator (PA) and matrix metalloproteases are associated with the increased prostatic weight and DNA content seen in adult rats that were treated neonatally with the goitrogen 6-propyl-2-thiouracil (PTU). Ventral prostatic weights were initially reduced in PTU-treated rats but were increased 40% over those of controls by Day 180; this increase in prostatic weight was also accompanied by increases in the number of prostatic ductal tips. In controls, prostatic PA and gelatinase A activities decreased after completion of morphogenesis at 21-28 days of age. In contrast to controls, PA and gelatinase A activities were maintained through puberty (42 days) in PTU-treated rats but declined by 90 days. The elevated PA activity in both prostatic lobes at 42 days of age in PTU-treated rats was inhibited by amiloride, indicating that it is the urokinase form of PA. These data show that the increased prostatic weight and DNA content in adult rats following neonatal PTU treatment results from a delayed but extended period of growth and the formation of new ductal elements. There is a temporal overexpression of urokinase and gelatinase A associated with the increased ductal branching, indicating as well an extended period of morphogenesis that results in their eventual increased adult size. The prostatic enlargement in PTU-treated rats may serve as a useful model to study regulation of both normal and abnormal prostatic growth and morphogenesis.
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PMID:Neonatal hypothyroidism alters the pattern of prostatic growth and differentiation, as well as plasminogen activator and metalloprotease expression, in the rat. 911 49

Fucoidan is a sulfated poly(L-fucopyranose) present in brown marine algae. In this study, we examined the effect of native and chemically oversulfated fucoidans (NF and OSF) on the tube structure formation by human umbilical vein endothelial cells (HUVEC) on the basement membrane preparation, Matrigel. Unlike NF, OSF significantly decreased the tube formation: maximal inhibition (50% of control) was obtained with 25 micrograms/ml. The OSF effect was mediated, at least in part, through the inhibition of HUVEC migration, as determined by the ability to block chemotaxis in a Transwell chamber assay. Quantitative immunoreactive assays for tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) in the culture media indicated that OSF (25 micrograms/ml) increased the accumulation of PAI-1 antigen, but not of t-PA antigen, 2.7-fold compared with control. The release of both antigens by HUVEC was slightly affected by the addition of NF. Determination of the media levels of type IV collagenase activity and tissue inhibitor of metalloproteinase-1 (TIMP-1) antigen showed that OSF (25 micrograms/ml) decreased the collagenolytic activity by 50% compared to the control, without alteration of the TIMP antigen level. However, the collagenase inhibition by OSF was not observed in an assay system using purified enzyme. NF had no effect on collagenase activity or TIMP-1 antigen levels. These results indicate that the introduction of sulfate groups into NF enables it to effectively inhibit the formation of capillary-like structures by HUVEC on Matrigel by reducing the basement membrane destruction and cell migration. It is involved as at least one of the mechanisms by which the OSF-induced increase in HUVEC PAI-1 decreases plasmin formation and suppresses the following pro-collagenase activation.
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PMID:Inhibitory effect of oversulfated fucoidan on tube formation by human vascular endothelial cells. 940 18

To investigate a potential physiological role of the plasminogen/plasmin system in activation of the matrix metalloproteinase (MMP) system, the distribution of latent and active MMP-2 (gelatinase A) or MMP-9 (gelatinase B) was monitored in aorta extracts and in serum-free conditioned cell culture medium obtained from wild-type (WT) mice and from mice with deficiency of tissue-type plasminogen activator (t-PA(-/-)), urokinase-type plasminogen activator (u-PA(-/-)), plasminogen activator inhibitor-1 (PAI-1(-/-)) or plasminogen (Plg(-/-)). In aorta extracts, the contribution of active MMP-2 to the total MMP-2 level ranged between 7 and 16% for the different genotypes, whereas active MMP-9 was not detected. The contribution of active 58 kDa MMP-2 to the total MMP-2 level (active plus latent) ranged between 14 and 29% (mean of 3 experiments) for fibroblasts of the different genotypes, and between 18 and 32% for smooth muscle cells, and was relatively constant in time (7-72 h). The contribution of active 83 kDa MMP-9 to the total MMP-9 level ranged between 15 and 29% for fibroblasts of the different genotypes and was relatively constant in time (24-72 h); corresponding values were 17 to 57% for smooth muscle cells, with the exception of Plg(-/-) smooth muscle cells which had undetectable levels of active MMP-9. Addition of plasmin(ogen) to the cell culture medium of fibroblasts did not significantly affect the distribution of active and latent MMP-2, but resulted in an approximately two-fold enhancement of the contribution of active MMP-9. In macrophages of Plg(-/-) mice, active MMP-9 was detected only when the cells were cultured in the presence of plasminogen. These data indicate that activation of proMMP-2 occurs independently of the physiological plasminogen activators and of plasmin(ogen) in all the cell types evaluated. Activation of proMMP-9 was enhanced in the presence of plasmin(ogen), but active MMP-9 was also detected in fibroblasts of Plg(-/-) mice, indicating that in vivo activation may occur via plasmin(ogen)-independent mechanisms.
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PMID:Regulation of gelatinase activity in mice with targeted inactivation of components of the plasminogen/plasmin system. 965 44

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

To investigate developmental differences in the wound repair process between fetal and adult skin fibroblasts, we studied the expression of plasminogen activator, plasminogen activator inhibitor, matrix metalloproteinase, and tissue inhibitor of metalloproteinase in E-15, E-17, newborn and adult mouse skin fibroblasts cultured within three dimensional matrices of either collagen or fibrin. Fibrin overlay and reverse overlay analyses revealed that mouse skin fibroblasts secreted tissue plasminogen activator and type1 plasminogen activator inhibitor. However, only E-15 and E-17 fibroblasts secreted the active form of tissue plasminogen activator, while in newborn and adult fibroblasts tissue plasminogen activator was conjugated to type1 plasminogen activator inhibitor. Only adult fibroblasts expressed a high level of active type1 plasminogen activator inhibitor. Gelatin zymography revealed that the predominant matrix metalloproteinase secreted by all the mouse fibroblasts was gelatinase A (matrix metalloproteinase -2). Matrix metalloproteinase -2 was partially activated in the adult fibroblasts cultured within a collagen matrix. The tissue inhibitor of metalloproteinase-2 was expressed by all fibroblasts, but levels were highest in the newborn and adult fibroblasts. When E-15 fibroblasts were cultured within a fibrin matrix, tissue plasminogen activator was downregulated. Transforming growth factor-betadownregulated tissue plasminogen activator while upregulating type1 plasminogen activator inhibitor, and platelet-derived growth factor enhanced tissue plasminogen activator expression in E-15 fibroblasts. Therefore, plasminogen activator and its inhibitor, and matrix metalloproteinase and its associated tissue inhibitor are differentially expressed in fetal and adult fibroblasts, and their expression is controlled by extracellular matrix components and growth factors present in wounds.
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PMID:Developmental differences in the expression and modulation of extracellular matrix proteases and inhibitors in mouse skin fibroblasts. 1063 6

We have previously reported a constitutively activated form of the Flt-1 kinase (BCR-FLTm) molecularly engineered based on the structural backbone of the activated tyrosine kinase BCR-ABL. Here we show that it can induce not only growth stimulation but also tubulogenic differentiation of non-tubulogenic NP31 (non parenchymal) sinusoidal endothelial cells of rat liver in basement membrane matrix. Tubules formed in vitro were accompanied by fenestration structures and allowed circulation when transplanted into syngeneic animals. This biological response was not observed in other activated forms of kinases constructed in a similar fashion, which include Trk (BCR-TRK), KDR (BCR-KDR), and the parental BCR-ABL. Interestingly, formation of fine tubules was accomplished with lower but not higher expression levels of BCR-FLTm. Compared to NP cells in primary culture NP31 is deficient in expression of alpha1 integrin subunit, which was restored by expression of BCR-FLTm that had tubulogenic ability. Matrix-induced tyrosine phosphorylation of an adaptor protein Shc with recruitment of Grb-2 was observed even when tubulogenesis was nearly completed at G1 stage of the cell cycle in 2-3 weeks. Activation of matrix metalloproteinase 2 (MMP-2) and expression of urokinase type plasminogen activator (uPA) was observed with cellular invasion into matrix at the depth of 200-300 microm. Inhibitors for MAP kinase activator MEK1 and for serine proteases showed deleterious effects on the tubulogenesis. We suppose that matrix ligand-induced integrin signals cooperate with a low level of Flt-1 kinase activity to promote tubulogenic behaviors of endothelial cells in this system.
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PMID:An oncogenic form of the Flt-1 kinase has a tubulogenic potential in a sinusoidal endothelial cell line. 1072 21


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