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 regeneration following 70% partial hepatectomy leads to rapid activation of genes in the remnant liver. Interleukin-6 deficient (IL-6 -/-) mice have impaired liver regeneration and abnormalities in immediate early gene expression. In this study, the gene expression program in the IL-6 +/+ and -/- livers at 2 hours posthepatectomy was examined with a cDNA array representing 588 highly regulated mouse genes. Thirty-six percent of the 103 immediate early genes were induced differently in IL-6 +/+ compared with IL-6 -/- livers, implying regulation by IL-6. IL-6 treatment of the IL-6 -/- mice in the absence of hepatectomy induced a much smaller set of genes in the liver, suggesting that IL-6 cooperates with other hepatectomy-induced factors to activate the large number of genes. Northern blot analyses were used to verify gene expression data obtained from the arrays. The expression of urokinase type plasminogen activator receptor (uPAR) and plasminogen activator inhibitor-1 (PAI-1), critical components of the urokinase plasminogen activator (uPA) system, was lower and delayed in IL-6 -/- livers. Despite the fact that active uPAR/uPA complex is critical for hepatocyte growth factor (HGF) activation, no differences were detected between the IL-6 +/+ and -/- livers in HGF activation as measured by receptor phosphorylation. On the contrary, the mitogen-activated protein kinase (MAPK) pathway was activated in IL-6 +/+ livers early during regeneration but remarkably delayed in IL-6 -/- livers. Defective liver regeneration may be explained by the large number of gene activation pathways altered in IL-6 -/- livers and further supports the finding that IL-6 is necessary for normal liver regeneration.
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PMID:Global changes in interleukin-6-dependent gene expression patterns in mouse livers after partial hepatectomy. 1139 26

Endostatin, a M(r) 20,000 fragment of collagen XVIII, is able to inhibit angiogenesis and induce apoptosis in endothelial cells in vivo. We analyzed the effectsof recombinant endostatin on human microvascular endothelial cells, focusing on pericellular plasminogen activation and its targeting by the focal adhesion-associated cytoskeletal structures. Analysis of the proteolytic plasminogen activator system revealed that endostatin modulates the distribution of soluble and cell surface-associated urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor, type 1 (PAI-1). Casein zymographic and immunoprecipitation analyses indicated that endostatin exerts its effects by decreasing the levels of soluble uPA and PAI-1 and their complexes in a dose-dependent manner. Immunofluorescence analysis of cell surface-associated uPA indicated that endostatin treatment caused the redistribution of receptor-bound uPA from focal contacts, resulting in diffuse cell surface staining. In accordance with this observation, immunofluorescence staining of the urokinase receptor revealed that endostatin treatment removed uPAR from focal adhesions. Accordingly, endostatin caused a rapid disassembly of focal adhesions as observed by immunofluorescence analysis of the focal adhesion proteins vinculin and paxillin. A prominent change in the cytoskeletal architecture was observed as the actin stress fiber network was dissociated in response to endostatin treatment. The effect of focal adhesion disassembly was reversible, persisting from 1 h up to 6 h. Our results suggest that the antiangiogenic activity of endostatin involves the modulation of focal adhesions and actin stress fibers and the down-regulation of the urokinase plasminogen activator system.
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PMID:Endostatin-induced modulation of plasminogen activation with concomitant loss of focal adhesions and actin stress fibers in cultured human endothelial cells. 1152 48

One of the potential therapeutic interventions to hormone-independent breast cancer would be to reactivate the expression of estrogen receptor or progesterone receptor (PR) in the tumor cells so as to render the tumor responsive to the hormones. We have reported previously that progesterone markedly inhibited cell growth and induced remarkable focal adhesions in PR-transfected MDA-MB-231 cells. The aim of this study was to determine the effects of progesterone on the invasive properties and in vivo tumor growth of PR-transfected MDA-MB-231 cells. It was found that progesterone has increased cell resistance to trypsin digestion and increased cell attachment to extracellular matrix proteins, especially laminin and fibronectin. In vitro invasion assays using modified Boyden chambers showed that progesterone increased cell migration through matrix protein-coated membranes. However, Northern blotting analysis demonstrated that progesterone strongly down-regulated (up to 60-fold) the gene expression of urokinase plasminogen activator and increased (up to 5-fold) the expression of tissue-type plasminogen activator in these cells. This pattern of gene regulation suggested an inhibition of cell invasiveness because numerous clinical studies have indicated that low levels of urokinase plasminogen activator and high levels of tissue-type plasminogen activator in breast cancer are associated with favorable prognosis. Furthermore, animal studies showed that progesterone strongly inhibited the tumor formation and growth in Scid mice. After 12 weeks of inoculation, the median weight of tumors in the progesterone-treated group was 25 mg compared with 203 mg in the placebo group (P < 0.001). These results suggest that progesterone may provide effective treatment for estrogen receptor- and PR-negative breast cancer if the PR expression were reactivated. Alternatively, activation of progesterone-mediated molecular pathways in hormone-independent breast cancer may achieve similar therapeutic effects.
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PMID:Effect of progesterone on the invasive properties and tumor growth of progesterone receptor-transfected breast cancer cells MDA-MB-231. 1155 6

Pericellular proteolysis plays a crucial role in tumor cell invasion. The controlled degradation of the extracellular matrix by tumor cell-associated proteases allows tumor cells to invade surrounding tissues and gain access to the circulation. One of the main protease systems involved in tumor cell invasion and metastasis is the plasminogen/plasmin system (PPS). The components of the PPS include the urokinase plasminogen activator (uPA), its cell surface receptor urokinase plasminogen activator receptor (uPAR), and its naturally occurring inhibitors, plasminogen activator inhibitors 1 and 2 (PAI-1 and PAI-2). Increases in tumor and serum levels of uPA, uPAR, and PAI-1 are associated with a worse prognosis in patients with colon cancer. Use of these proteins as either tumor or serum markers may allow more accurate determination of the prognosis in colon cancer patients. Furthermore, these proteins appear to be attractive as targets for the biologic therapy of colon cancer.
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PMID:Plasmin/plasminogen system in colorectal cancer. 1196 42

This study examined the effect of the preovulatory gonadotropin surge on the temporal and spatial regulation of tissue plasminogen activator (tPA), urokinase plasminogen activator (uPA), and uPA receptor (uPAR) mRNA expression and tPA, uPA, and plasmin activity in bovine preovulatory follicles and new corpora lutea collected at approximately 0, 6, 12, 18, 24, and 48 h after a GnRH-induced gonadotropin surge. Messenger RNAs for tPA, uPA, and uPAR were increased in a temporally specific fashion within 24 h of the gonadotropin surge. Localization of tPA mRNA was primarily to the granulosal layer, whereas both uPA and uPAR mRNAs were detected in both the granulosal and thecal layers and adjacent ovarian stroma. Activity for tPA was increased in follicular fluid and the preovulatory follicle apex and base within 12 h after the gonadotropin surge. The increase in tPA activity in the follicle base was transient, whereas the increased activity in the apex was maintained through the 24 h time point. Activity for uPA increased in the follicle apex and base within 12 h of the gonadotropin surge and remained elevated. Plasmin activity in follicular fluid also increased within 12 h after the preovulatory gonadotropin surge and was greatest at 24 h. Our results indicate that mRNA expression and enzyme activity for both tPA and uPA are increased in a temporally and spatially specific manner in bovine preovulatory follicles after exposure to a gonadotropin surge. Increased plasminogen activator and plasmin activity may be a contributing factor in the mechanisms of follicular rupture in cattle.
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PMID:Gonadotropin surge-induced up-regulation of the plasminogen activators (tissue plasminogen activator and urokinase plasminogen activator) and the urokinase plasminogen activator receptor within bovine periovulatory follicular and luteal tissue. 1196 5

In the present study we trained tissue-plasminogen activator (tPA)-knockout (tPA -/-) and wild-type (tPA +/+) male mice in step-down inhibitory avoidance learning, a hippocampus-dependent task. tPA -/- displayed significantly shorter latencies to step down at 90 min, one, two and seven days after training indicating the learning deficit in these animals (P < 0.05 vs tPA +/+). The locomotor activity, the level of anxiety in an elevated-plus maze, as well as the pain threshold did not differ between the two strains of mice. The learning disability of tPA -/- was overcome by more intense training. The learning deficit was also partially restored by limited intrahippocampal delivery of tPA (infused for 2 h before training; P < 0.05 vs control), but not by the delivery of urokinase plasminogen activator, indicating the acute need for tPA in learning. The beneficial effect of tPA was abolished by co-infusion of its inhibitor tPA-STOP, indicating that the facilitatory effect of tPA on learning requires a proteolytic step. However, tPA activity in the hippocampus was not indispensable for effective memory retrieval in tPA-infused tPA -/- mice. Thus, rapid, specific and proteolytic action of tPA facilitates hippocampus-dependent learning, but not retrieval of previously acquired information.
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PMID:Rapid, specific and active site-catalyzed effect of tissue-plasminogen activator on hippocampus-dependent learning in mice. 1218 3

Melanoma cells produce tissue plasminogen activator (t-PA) that plays an important role in tumor invasion and metastasis. The production of t-PA by normal human uveal melanocytes has not been reported previously. In order to explore this possibility, we studied the production of t-PA by cultured human uveal melanocytes and compared that with the production by cultured human uveal melanoma cells and epidermal melanocytes. Human adult uveal melanocytes were isolated and cultured from donor eyes. The cells were cultured in serum-free medium for 48 h and the conditioned medium then collected for the plasminogen activator (PA) activity assay. Free PA activity was tested in an amidolytic assay using a t-PA standard curve. PA type was identified by fibrinography and antihuman t-PA and urokinase plasminogen activator (u-PA) blocking antibodies. Free PA activity was found in the conditioned medium of normal melanocytes and melanoma cells. The predominant PA activity was t-PA. Normal uveal melanocytes produced more t-PA (3.23 +/- 0.73 IU/105 cells/24 h) than that of epidermal melanocytes (1.25 IU/105 cells/24 h) but much less than uveal melanoma cells (11.0 +/- 3.39 IU/105 cells/24 h). Western blot analysis revealed that most t-PA in conditioned media were one-chain t-PA with molecular weight of 69 kDa. Our study indicates that uveal melanocytes may contribute to the free t-PA activity previously found in aqueous humor and choroidal eye cup superfusions. Therefore, this function of uveal melanocytes may play a role in intraocular matrix remodeling, fibrinolysis and aqueous humor outflow.
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PMID:Tissue plasminogen activator is released into cultured medium by cultured human uveal melanocytes. 1221 94

Matrix metalloproteinase (MMP)-3 inhibited human MDA-MB-231 breast cancer cell invasion through reconstituted basement membrane in vitro. Inhibition of invasion was dependent upon plasminogen and MMP-3 activation, was impaired by the peptide MMP-3 inhibitor Ac-Arg-Cys-Gly-Val-Pro-Asp-NH2 and was associated with: rapid MMP-3-mediated plasminogen degradation to microplasminogen and angiostatin-like fragments; the removal of single-chain urokinase plasminogen activator from MDA-MB-231 cell membranes; impaired membrane plasminogen association; reduced rate of tissue plasminogen activator (t-PA) and membrane-mediated plasminogen activation; and reduced laminin-degrading capacity. Purified human plasminogen lysine binding site-1 (kringles 1-3) exhibited a similar capacity to inhibit MDA-MB-231 invasion, impair t-PA and cell membrane-mediated plasminogen activation and impair laminin degradation by plasmin. Our data provide evidence that MMP-3 can inhibit breast tumour cell invasion in vitro by a mechanism involving plasminogen degradation to fragments that limit plasminogen activation and the degradation of laminin. This supports the hypothesis that MMP-3, under certain conditions, may protect against tumour invasion, which would help to explain why MMP-3 expression, associated with benign and early stage breast tumours, is frequently lost in advanced stage, aggressive, breast disease.
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PMID:Inhibition of human MDA-MB-231 breast cancer cell invasion by matrix metalloproteinase 3 involves degradation of plasminogen. 1223 May 59

Intrapleural loculation can increase morbidity in hemothoraces or parapneumonic effusions. Intrapleural fibrin precedes visceral-parietal pleural adhesions. We speculated that single-chain urokinase plasminogen activator alone or bound to its receptor could prevent these adhesions by their relative resistance to local inhibition by plasminogen activator inhibitors. We found that recombinant human single-chain urokinase-bound rabbit pleural mesothelial cells or lung fibroblasts with kinetics similar to that reported for human cells (kD of approximately 5 nM). The receptor-bound fibrinolysin maintained in vitro fibrinolytic activity in the presence of pleural fluids from rabbits with tetracycline-induced pleural injury over 24 hours. In rabbits given intrapleural single-chain urokinase 24 and 48 hours after intrapleural tetracycline (n = 10 animals), adhesions were prevented, whereas the receptor-complexed form (n = 12) attenuated adhesions versus vehicle/tetracycline-treated rabbits (n = 22, p <or= 0.005 in both cases). There were more adhesions in the complex than the single-chain urokinase group (p = 0.02). Residual antigenic but not functional evidence of the interventional agents remained in pleural fluids at 72 hours after tetracycline. No local or systemic bleeding occurred because of either interventional agent. The data demonstrate that single-chain urokinase inhibits, whereas lysin-receptor complexes attenuate, adhesion formation in tetracycline-induced pleural injury in rabbits.
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PMID:Single-chain urokinase alone or complexed to its receptor in tetracycline-induced pleuritis in rabbits. 1235 44

Overexpression of plasminogen activator inhibitor 1 (PAI-1) reduces tumor cell migration in vitro and metastasis in mice in vivo by mechanisms involving either inhibition of urokinase plasminogen activator (u-PA) activity or competition for an integrin binding site on vitronectin. To analyze the effects of PAI-1 on tumor cell migration in vitro and metastasis in vivo, recombinant adenoviral vectors expressing wild-type or mutant PAI-1 proteins were constructed. The mutant PAI-1 proteins were defective in either vitronectin binding (PAI-1(VN-)), plasminogen activator inhibition (PAI-1(INH-)) or both (PAI-1(VN-,INH-)). In vitro, migration of HT1080 human fibrosarcoma cells through a reconstituted extracellular matrix (ECM) was reduced 73% by overexpression of wild-type PAI-1 and 65% by PAI-1(VN-) compared with control virus-infected cells. Migration of cells infected by virus expressing either PAI-1(INH-) or PAI-1(VN-,INH-) was unaffected, indicating a requirement for plasminogen activator inhibitory activity. In vivo, however, only overexpression of wild-type PAI-1 reduced the burden of metastasis by 68% compared with the control group. This indicates that both u-PA inhibition and PAI-1 ECM interactions contribute to the mechanism of PAI-1-mediated regulation of cell migration.
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PMID:Both u-PA inhibition and vitronectin binding by plasminogen activator inhibitor 1 regulate HT1080 fibrosarcoma cell metastasis. 1244 99


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