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)

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

Al-trans retinoic acid (RA) enhanced human, S-type, SK-N-SH neuroblastoma cell invasion of reconstituted basement membrane in vitro but did not induce terminal differentiation of this cell line. In contrast to basal invasion, which was urokinase (uPA)- and plasmin-dependent, RA-enhanced invasion was dependent on tissue-type plasminogen activator (t-PA) and plasmin activity. Neither basal nor RA-enhanced invasion involved TIMP-2 inhibitable metalloproteinases. Enhanced invasion was associated with the induction of t-PA expression, increased expression of the putative t-PA receptor amphoterin, increased association of t-PA with cell membranes and increased net membrane-associated PA activity. Enhanced invasion was not associated with significant changes in the expression of uPA or its membrane receptor UPAR; plasminogen activator inhibitors PAI-1 and PAI-2; metalloproteinases MMP-1, MMP-2, MMP-3, MMP-9 and membrane type MMP1; or tissue inhibitors of metalloproteinases TIMP-1 and TIMP-2. RA stimulated the association of t-PA with the external cell membrane surface, which could be inhibited by heparin sulphate but not by mannose sugars or chelators of divalent cations, consistent with a role for amphoterin. Our data indicate that RA can promote the malignant behavior of S-type neuroblastoma cells refractory to RA-mediated terminal differentiation by enhancing their basement membrane invasive capacity. We suggest that this results from the action of a novel, RA-regulated mechanism involving stimulation of t-PA expression and its association with the cell membrane leading to increased PA-dependent matrix degradation.
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PMID:Retinoic acid-enhanced invasion through reconstituted basement membrane by human SK-N-SH neuroblastoma cells involves membrane-associated tissue-type plasminogen activator. 939 56

Transforming growth factor-beta (TGFbeta1) enhances human MDA-MB-231 breast tumour cell invasion of reconstituted basement membrane in vitro but does not inhibit proliferation of this cell line. In contrast to basal invasion, which is plasmin-, urokinase (uPA)-, tissue-type plasminogen activator (t-PA)-, matrix metalloproteinase (MMP)-9- and TIMP-1-inhibitable MMP-dependent, TGFbeta1 enhanced-invasion is dependent upon plasmin and uPA activity but does not appear to involve t-PA-, MMP9- or TIMP-1-inhibitable MMPs, as judged by inhibitor studies. Enhanced invasion is associated with increased u-PA, UPAR, PAI-1, MT-MMP-1, MMP-9 and TIMP-1 expression; with reduced t-PA, MMP-1 and MMP-3 expression; and with the induction of membrane MMP-9 association. The net result of these changes includes increased secreted, but not membrane-associated, uPA levels and activity and reduced secreted levels of plasmin and APMA-activatable gelatinolytic, collagenolytic and caseinolytic MMP activity but no change in membrane-associated gelatinolytic activity, despite increased MT-MMP-1 expression and MMP-9 membrane association. TGFbeta1 does not induce MMP-2 expression. Our data indicate that TGFbeta1 can promote the malignant behaviour of MDA-MB-231 cells refractory to TGFbeta1-mediated proliferation control by enhancing their invasive capacity. We suggest that this results from the action of a uPA/plasmin-dependent mechanism resulting from stimulation of uPA expression, secretion and subsequent activity, despite elevated PAI-1 inhibitor levels.
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PMID:Transforming growth factor-beta1 enhances the invasiveness of human MDA-MB-231 breast cancer cells by up-regulating urokinase activity. 949 40

Osteoarthritis is the most common joint disease in humans. It is characterized by a gradual loss of extracellular matrix components of articular cartilage such as collagen and proteoglycan. Presently, however, emphasis is placed on enzymes exerting a strong influence on cartilage degradation. These enzymes include matrix metalloproteinases (MMP), their specific inhibitors (TIMP) and the plasminogen activator/inhibitor system. We applied monoclonal antibodies against MMP-1, -2, -3, -9 and their inhibitors TIMP-1/-2, as well as against urokinase-plasminogen activator u-PA and its inhibitor PAI to investigate their influence on articular cartilage degradation in patients with varusgonarthritis. We examined the cartilage of the lateral and medial compartments of 20 tibia plateaus, which can present with slight and severe cartilage degradations at the same time. In doing so, we tried to show whether or not immunohistological detection of enzymes could serve as a parameter for chondral degradation. The strongest immunoreaction for all enzymes was noted in the superficial layer of articular cartilage both medially and laterally. Between medial and lateral compartments, however, there were striking differences in the immunoreaction intensity of chondrocytes for MMP-1 and -3 as well as for TIMP-1 and u-PA. We noted that in cartilage with more advanced degradation, the immunoreaction for these enzymes was significantly higher in medial than in lateral compartments (p < 0.05). At the immunohistological level, a direct correlation between the grade of cartilage degradation and immunoreaction intensity was found. Our results corroborate the assumption that the expression of certain matrix-degradating enzymes serves as a parameter for the grade of cartilage degradation.
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PMID:Immunohistochemical analysis of several proteolytic enzymes as parameters of cartilage degradation. 958 19

Normal as well as neoplastic cells traverse extracellular matrix barriers by mobilizing proteolytic enzymes in response to epidermal growth factor (EGF)-EGF receptor (EGFR) or hepatocyte growth factor/scatter factor (SF)-c-Met interactions. The plasminogen activator-plasminogen axis has been proposed to play a key role during cell invasion, but the normal development of plasminogen activator- as well as that of plasminogen-deficient mice supports the existence of alternate proteolytic systems that permit cells to traverse extracellular matrix barriers. To characterize the role that matrix-degrading proteinases play in EGF- or SF-stimulated invasion, a human squamous carcinoma cell line (UM-SCC-1) was triggered atop the matrices of type I collagen or human dermal explants in a three-dimensional culture system. During EGF- or SF-induced invasion, UM-SCC-1 cells expressed urokinase-type plasminogen activator (uPA) and uPA receptor as well as the matrix metalloproteinases (MMPs), membrane-type MMP-1, collagenase 1, stromelysin 1, and gelatinase B. Despite the presence of a positive correlation between uPA receptor-uPA expression and growth factor-stimulated invasion, UM-SCC-1 invasion was not affected by inhibitors directed against the plasminogen activator-plasminogen axis. In contrast, both recombinant and synthetic MMP inhibitors completely suppressed invasion by either EGF- or SF-stimulated cells without affecting either proteinase expression or cell motility across collagen-coated surfaces. These data demonstrate that MMPs, but not the plasminogen activator-plasmin system, can directly regulate the ability of either EGF- or SF-stimulated tumor cells to invade interstitial matrix barriers.
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PMID:Role of the plasminogen activator and matrix metalloproteinase systems in epidermal growth factor- and scatter factor-stimulated invasion of carcinoma cells. 982 36

Clinical trials with monoclonal antibodies directed against TNF alpha (anti-TNF mAbs) and soluble TNF receptor fusion proteins (sTNFR-IgGs) have demonstrated that systemic and synovial trapping of TNF alpha results in long lasting anti-inflammatory and anti-nociceptive effects in patients with rheumatoid arthritis. Clinical indices of inflammatory synovitis and laboratory parameters (CRP and ESR) respond to single and repeated administrations of anit-TNF alpha therapies in a dose-dependent fashion. Studies on the immuno-pharmacological profile in patients suggest evidence that TNF alpha trapping down-regulates the effector mechanisms involved in the immuno-inflammatory response in rheumatoid arthritis. Inhibition of PLA 2- and COX-2-derived pathways of mediators of inflammation (prostanoids and leukotrienes) decreases signs and symptoms of inflammatory synovitis such as joint swelling, tenderness and pain. Down-regulating of the cytokine-inducible adhesion molecules ICAM-1, VCAM-1 and ELAM-1 in endothelial cells and synoviocytes results in a marked inhibition of transendothelial migration of inflammatory and immune cells. A decrease of cytokine-regulated metalloproteinase expression results in normalization of circulating MMP-1 and MMP-3 levels. The effect of TNF alpha neutralization on mechanisms of rheumatoid joint destruction has the long-term potential for preventing or decreasing the rate of erosive changes of cartilage and bone.
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PMID:[Immunopharmacologic profile and therapeutic prospects of anti-TNF-alpha therapy]. 986 33

Proteolytic enzymes, postulated to create an avenue for cell migration by digestion of host extracellular matrix molecules, have been implicated in neoplastic glial cell migration. A similar process is likely to occur in the developing brain. Fetal rabbit brain fragments transplanted into the striatum of the neonatal Shiverer mouse give rise to cells which migrate from the graft site and differentiate into astrocytes and oligodendrocytes. Proteinase expression by transplanted brain cells was studied using immunohistochemistry and in situ hybridization. Immature donor cells expressed the mRNAs for matrix metalloproteinases (MMP) 1 (collagenase) and 3 (stromelysin). Northern blot analysis of rabbit brain showed that MMP-1 in particular is expressed in the immature rabbit cerebrum and down-regulated during maturation. Immature donor cells exhibited immunoreactivity for urokinase plasminogen activator. However, immunoreactivity was also present in maturing neurons. Donor and host astroglia in the vicinity of grafts were immunoreactive for MMP-2 and tissue-type plasminogen activator. This expression may represent a reactive phenomenon, not specifically related to cell migration, by mature astrocytes. Based upon our findings, MMP-1 appears to be a candidate for involvement in migration of immature brain cells in the cerebrum.
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PMID:Expression of extracellular matrix degrading enzymes during migration of xenografted brain cells. 1019 76

We investigated the inhibitory action of a synthetic peptidyl hydroxamate inhibitor of matrix metalloproteinase (MMP), Galardin (GM6001), on collagen degradation by rabbit corneal stromal fibroblasts (keratocytes) cultured three-dimensionally in the type I collagen gel with medium containing interleukin 1alpha (IL-1alpha) and/or plasminogen. Degradation of collagen fibrils during culture was measured by the release of hydroxyproline, and activation of MMPs was also analyzed by gelatin zymography and Western blotting. Plasmin activity was measured using a synthetic substrate. In the absence of plasminogen, treatment of the cells with IL-1alpha in collagen gel greatly enhanced the production of proMMP-1, -3 and -9, but no significant degradation of collagen was detected. In the presence of plasminogen, IL-1alpha stimulated collagen degradation by keratocytes in a dose-dependent manner. This resulted from the plasminogen activator-plasmin system-dependent activation of proMMP-1, -3 and -9. Galardin inhibited the collagen degradation in a dose-dependent fashion in the presence of plasminogen, whether IL-1alpha was present or not. Galardin inhibited the activation of proMMP-3, and also prevented the activation of proMMP-9 and the conversion of MMP-1 intermediates to the fully active MMP-1. Galardin did not affect plasmin activity. The present results suggest that Galardin inhibits IL-1alpha-stimulated collagen degradation in the presence of plasminogen, resulting from not only inhibiting active MMPs but also preventing the conversion of proMMPs to active MMPs.
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PMID:Galardin inhibits collagen degradation by rabbit keratocytes by inhibiting the activation of pro-matrix metalloproteinases. 1032 70

Fibroblast growth factor 7 (FGF7/KGF) is synthesized exclusively by fibroblasts in normal tissues; it acts as a potent mitogen on epithelial cells, through interaction with the FGF7-specific receptor FGFR2/IIIb. To examine the importance of this growth factor both to prostate physiology and to prostate-cancer progression, we have tested the exogenous effect of FGF7. Thus, by mimicking the paracrine pathway (on proliferation, growth in soft agar and invasion) on the human prostatic epithelial cell line PNT1A positively checked for FGFR2/IIIb expression, FGF7 significantly enhanced cell proliferation at an optimal concentration of 7.5 x 10(-11) M, but no significant invasion or growth in soft agar were observed. To confirm FGF7 properties on human prostatic epithelial cells, we constitutively expressed FGF7 by transfecting PNT1A cells with FGF7-cDNA. The FGF7-transfected clones, PNT1A/ FGF7-T5 and PNT1A/FGF7-T6, were stable and expressed FGF7. Analysis of the FGF7-autocrine loop on the non-tumorigenic epithelial cells PNT1A showed acquired invasive potential in in vitro extracellular-matrix migration assays, specifically inhibited by an FGF7-neutralizing antibody, and over-expressed factors implicated in the migration process: the metalloproteinase MMP-1 and the plasminogen activator uPA. Taken together, these results demonstrate a role for FGF7 in triggering invasion of human prostatic epithelial cells. Furthermore, these FGF7-transfected clones exhibited functional and physiological differences from the original PNT1A cell line: anchorage-independent growth, growth in serum-free media and increased proliferation. These data confirm the oncogenic function of FGF7 in prostate progression potentially acting through paracrine and/or autocrine regulatory pathways.
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PMID:FGF7/KGF triggers cell transformation and invasion on immortalised human prostatic epithelial PNT1A cells. 1038 58

Local invasiveness is an important prognostic factor in endometrial carcinoma. To study the role of two groups of secreted proteinases (serine proteinases and matrix metalloproteinases) in this process, we examined three endometrial cancer cell lines (Ishikawa HEC 1A, AN3CA) for their invasiveness in vitro. Additionally, we considered the secretion of urokinase type plasminogen activator (uPA), plasminogen activator inhibitor 1 and 2 (PAI-1 and PAI-2), as well as matrix metalloproteinases (MMP) 1, 2, 3, and 9, and their inhibitors TIMP-1 and TIMP-2. Compared to the highly invasive fibrosarcoma cell line HT 1080, Ishikawa displayed low and AN3CA moderate invasiveness, while HEC 1A cells were almost as invasive as HT 1080 cells. Ishikawa cells secreted the highest amounts of proteinases. Cytokine and steroid treatments upregulated MMP-1 in all cell lines while the effects were heterogeneous regarding other proteinases and inhibitors. No effect of these treatments on invasiveness could be detected. Both basal secretion and regulation of the proteinases tested in this set of experiments seem to be markers of differentiation rather than of invasiveness.
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PMID:Invasiveness corresponds to differentiation rather than to proteinase secretion in endometrial cancer cell lines. 1060 96


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