Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.69 (APC)
 16,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We recently described a subset of peripheral CD14+CD34+ cells able to migrate across endothelial cell monolayers and differentiate into immunostimulatory dendritic cells (DC). In this paper we show that immature DC derived from CD14+CD34+ precursors are also capable of reverse transendothelial migration and extracellular matrix (ECM) invasion using the urokinase plasminogen activator receptor (uPAR). We found that these cells respond to macrophage-inflammatory protein (MIP)-1alpha, enhancing their ability to invade ECM and supporting the idea that immature DC are selectively recruited at the site of inflammation to expand the pool of APCs. Interestingly, MIP-1alpha was also capable of preventing the decreased matrix invasion observed by blocking uPAR, suggesting that the uPA/uPAR system and MIP-1alpha cooperate in driving immature DC migration through the subendothelial matrix. Upon exposure to maturating stimuli, such as TNF-alpha, CD14+CD34+-derived DC enhance their APC function and decrease the capacity of invading ECM; these changes are accompanied by altered expression and function of uPAR. Moreover, mature DC shift their sensitivity from MIP-1alpha to MIP-3beta, enhancing their transendothelial migration capability in response to the latter chemokine. Our data support the hypothesis that bloodborne DC can move through ECM toward the site of pathogen entry where they differentiate into fully mature APCs with their motility and function regulated by microenvironmental stimuli, including MIP-1alpha, MIP-3beta, and TNF-alpha.
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PMID:uPA/uPAR system is active in immature dendritic cells derived from CD14+CD34+ precursors and is down-regulated upon maturation. 1062 14

Protein C inhibitor (PCI) is a nonspecific, heparin-binding serpin (serine protease inhibitor) that inactivates many plasmatic and extravascular serine proteases by forming stable 1:1 complexes. Proteases inhibited by PCI include the anticoagulant activated protein C, the plasminogen activator urokinase, and the sperm protease acrosin. In humans PCI circulates as a plasma protein but is also present at high concentrations in organs of the male reproductive tract. The biological role of PCI has not been defined so far. However, the colocalization of high concentrations of PCI together with several of its target proteases in the male reproductive tract suggests a role of PCI in reproduction. We generated mice lacking PCI by homologous recombination. Here we show that PCI(-/-) mice are apparently healthy but that males of this genotype are infertile. Infertility was apparently caused by abnormal spermatogenesis due to destruction of the Sertoli cell barrier, perhaps due to unopposed proteolytic activity. The resulting sperm are malformed and are morphologically similar to abnormal sperm seen in some cases of human male infertility. This animal model might therefore be useful for analyzing the molecular bases of these human conditions.
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PMID:Disruption of the protein C inhibitor gene results in impaired spermatogenesis and male infertility. 1112 Jul 60

Single-chain urokinase-type plasminogen activator (scu-PA) can be cleaved by thrombin into a virtually inactive form called thrombin-cleaved two-chain urokinase-type plasminogen activator (tcu-PA/T), a process accelerated by thrombomodulin, which contains six epidermal growth factor (EGF)-like domains. In this study, we identified the EGF-like domains of thrombomodulin required for the acceleration of the inactivation of scu-PA by thrombin using various forms of thrombomodulin (TM). scu-PA was treated with thrombin in the absence and presence of full-length rabbit TM (containing EGF1-6), recombinant TM comprising all of the extracellular domains including EGF1-6 (TMLEO) and recombinant TM comprising EGF4-6 plus the interconnecting region between EGF3 and EGF4 (TMEi4-6), and the tcu-PA/T generated was quantitated in each case. Rabbit TM accelerated the inactivation of scu-PA approximately 35-fold, while both recombinant forms accelerated it only threefold due to the absence of a critical chondroitin sulfate moiety. Subsequently, TME5-6 was prepared by cyanogen bromide digestion of TMEi4-6. TME5-6 bound to thrombin but did not accelerate the activation of protein C. In contrast, the inactivation of scu-PA by thrombin was accelerated to the same extent as that induced by TMLEO and TMEi4-6. This study demonstrates that, in addition to the chondroitin sulfate moiety, only EGF-like domains 5 and 6 are essential for the acceleration of the inactivation of scu-PA by thrombin. This differs from the domains that are critical for activation of protein C (EGF-like domains i4-6) and thrombin activatable fibrinolysis inhibitor (EGF-like domains 3-6).
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PMID:Identification of the epidermal growth factor-like domains of thrombomodulin essential for the acceleration of thrombin-mediated inactivation of single-chain urokinase-type plasminogen activator. 1168 79

Invasion and dissemination of well-differentiated carcinomas are often associated with loss of epithelial differentiation and gain of mesenchymal-like capabilities of dedifferentiated tumor cells at the invasive front. However when analysing central areas of metastases of colorectal carcinomas one finds a regain of the differentiated epithelial growth patterns like in the primary tumor. More than 80% of these tumor have loss of function mutations in the APC tumor suppressor gene, leading to an overexpression of beta-catenine. In its nuclear pool beta-catenine acts as a transcription factor and is now considered as one of the main oncogenic proteins in colorectal carcinogenesis. We could define several molecules important for the processes of invasion and dissemination, like MMP-7, uPA, laminin-5, as target genes activated by nuclear beta-catenine. Moreover the characteristic phenotypic changes during tumor progression were associated with distinct expression patterns of beta-catenine and E-cadherin. Nuclear beta-catenine was found in dedifferentiated mesenchyme-like tumor cells at the invasive front, but strikingly, like in central areas of the primary tumors, was localized to the membrane and cytoplasm in polarized epithelial tumor cells in the metastases. This was accompanied by changes in the proliferative activity. Based on these data, we postulate that an important driving force for progression of well-differentiated colorectal carcinomas is the specific environment, initiating two transient phenotypic transition processes by modulating intracellular beta-catenine distribution in the tumor cells.
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PMID:[The Rudolf Virchow Prize 2001. The role of the oncoprotein beta-catenin ni the progression of colorectal cancers]. 1189 5

Pigs are often used as animal models in research on blood coagulation and fibrinolysis. The usefulness of the assays applied within this field, and the knowledge of reference intervals are therefore essential and of utmost importance. In the study reported here, we investigated the applicability of commercial human coagulation and fibrinolysis assays for use with porcine plasma. In total, 22 functional and immunologic assays were applied to plasma obtained from domestic pigs, and the following blood coagulation and fibrinolysis variables were measured: prothrombin time, activated partial thromboplastin time, tissue factor, tissue factor pathway inhibitor, factor VII, protein C, protein S, prothrombin fragment 1+2, antithrombin, thrombin-antithrombin complexes, fibrinogen, soluble fibrin, urokinase-type plasminogen activator, plasmin inhibitor, plasminogen activator inhibitor 1, and D-dimer. We found that 11 of 12 functional assays, but only 3 of 10 immunoassays, were applicable to porcine plasma, and we determined the normal range of these variables. We conclude that human functional assays are useful in porcine plasma, whereas only a few immunologic assays can be used. However, precautions must be taken in interpretation of the results and in extrapolation toward human results because possible differences between porcine and human values can be due to species variations and/or methodologic errors.
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PMID:Usefulness of human coagulation and fibrinolysis assays in domestic pigs. 1190 Apr 11

Protein C inhibitor (PCI), also known as plasminogen activator inhibitor-3, is a serine proteinase inhibitor that can inhibit enzymes in blood coagulation, fibrinolysis and fertility. The role of PCI in regulating the blood coagulation mechanism is not known, as it can inhibit both procoagulant (thrombin, factor Xa, factor XIa) and anticoagulant (activated protein C, thrombin-thrombomodulin, urokinase) enzymes. To determine the relevance of this inhibitor in thrombosis, PCI levels were assessed in the Leiden Thrombophilia Study, a case-control study of venous thrombosis in 473 patients with a first deep-vein thrombosis and 474 age- and sex-matched control subjects. PCI levels above the 95th percentile of the controls (136.1%) increased the risk 1.6-fold compared with PCI levels below the 95th percentile (95% confidence interval 0.9-2.8). There was a gradual increase in risk of thrombosis with further increasing levels of PCI. Adjustment for a number of possible confounders led to a reduction of the risk estimates associated with PCI. However, it is unclear whether adjustment for such factors in the risk models is justified. These results indicate that high levels of PCI may constitute a mild risk factor for venous thrombosis.
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PMID:Protein C inhibitor (plasminogen activator inhibitor-3) and the risk of venous thrombosis. 1213 54

DPC423, 1-[3-(aminomethyl)phenyl]-N-[3-fluoro-2'-(methylsulfonyl)[1,1'-biphenyl]-4-yl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide, is a synthetic, orally bioavailable, competitive, and selective inhibitor of human coagulation factor Xa (K(i) [nM]: factor Xa, 0.15; trypsin, 60; thrombin, 6000; plasma kallikrein, 61; activated protein C, 1800; factor IXa, 2200; factor VIIa, >15,000; chymotrypsin, >17,000; urokinase, >19,000; plasmin, >35,000; tissue plasminogen activator, >45,000; complement factor I, 44,000 [IC(50)]). In vitro, DPC423 produced anticoagulant effects in human plasma in which it doubled prothrombin time, activated partial thromboplastin time, and Heptest clotting time at 3.1 +/- 0.4, 3.1 +/- 0.4, and 1.1 +/- 0.5 microM, respectively. In dogs, DPC423 had a good pharmacokinetic profile with an oral bioavailability of 57%, a plasma clearance of 0.24 L/kg/h, and a plasma half-life of 7.5 h. In rabbit and rat models of arteriovenous shunt thrombosis, DPC423 was an effective antithrombotic agent with an IC(50) of 150 and 470 nM, respectively. The antithrombotic effect of DPC423 is likely to be related to the inhibition of factor Xa but not to the inhibition of thrombin or due to direct inhibition of platelet aggregation. Therefore, based on potency, selectivity, efficacy, and oral bioavailability, DPC423 was selected for clinical development as an oral anticoagulant for the potential treatment of thrombotic disorders. Preliminary human data suggest that DPC423 is orally bioavailable in humans and has a long plasma half-life.
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PMID:Nonpeptide factor Xa inhibitors: DPC423, a highly potent and orally bioavailable pyrazole antithrombotic agent. 1217 91

SSR182289A competitively inhibits human thrombin (K(i) = 0.031 +/- 0.002 microM) and shows good selectivity with respect to other human proteases, e.g., trypsin (K(i) = 54 +/- 2 microM), factor Xa (K(i) = 167 +/- 9 microM), and factor VIIa, factor IXa, plasmin, urokinase, tPA, kallikrein, and activated protein C (all K(i) values >250 microM). In human plasma, SSR182289A demonstrated anticoagulant activity in vitro as measured by standard clotting parameters (EC100 thrombin time 96 +/- 7 nM) and inhibited tissue factor-induced thrombin generation (IC50 of 0.15 +/- 0.02 microM). SSR182289A inhibited thrombin-induced aggregation of human platelets with an IC50 value of 32 +/- 9 nM, but had no effect on aggregation induced by other platelet agonists. The anticoagulant effects of SSR182289A were studied by measuring changes in coagulation markers ex vivo after i.v. or oral administration in several species. In dogs, SSR182289A (0.1-1 mg/kg i.v. and 1-5 mg/kg p.o.) produced dose-related increases in clotting times. After oral dosing, maximum anticoagulant effects were observed 2 h after administration with increases in thrombin time, 2496 +/- 356%; ecarin clotting time (ECT), 1134 +/- 204%; and activated partial thromboplastin time (aPTT), 91 +/- 20% for the dose of 3 mg/kg p.o., and thrombin time, 3194 +/- 425%; ECT, 2017 +/- 341%; and aPTT, 113 +/- 9% after 5 mg/kg p.o. Eight hours after administration of 3 or 5 mg/kg SSR182289A, clotting times were still elevated. SSR182289A also showed oral anticoagulant activity in rat, rabbit, and macaque. Hence, SSR182289A is a potent, selective, and orally active thrombin inhibitor.
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PMID:SSR182289A, a novel, orally active thrombin inhibitor: in vitro profile and ex vivo anticoagulant activity. 1243 43

Many serine proteases play important regulatory roles in complex biological systems, but only a few have been linked directly with capillary morphogenesis and angiogenesis. Here we provide evidence that serine protease activities, independent of the plasminogen activation cascade, are required for microvascular endothelial cell reorganization and capillary morphogenesis in vitro. A homology cloning approach targeting conserved motifs present in all serine proteases, was used to identify candidate serine proteases involved in these processes, and revealed 5 genes (acrosin, testisin, neurosin, PSP and neurotrypsin), none of which had been associated previously with expression in endothelial cells. A subsequent gene-specific RT-PCR screen for 22 serine proteases confirmed expression of these 5 genes and identified 7 additional serine protease genes expressed by human endothelial cells, urokinase-type plasminogen activator, protein C, TMPRSS2, hepsin, matriptase/MT-SP1, dipeptidylpeptidase IV, and seprase. Differences in serine protease gene expression between microvascular and human umbilical vein endothelial cells (HUVECs) were identified and several serine protease genes were found to be regulated by the nature of the substratum, ie. artificial basement membrane or fibrillar type I collagen. mRNA transcripts of several serine protease genes were associated with blood vessels in vivo by in situ hybridization of human tissue specimens. These data suggest a potential role for serine proteases, not previously associated with endothelium, in vascular function and angiogenesis.
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PMID:Endothelial cell serine proteases expressed during vascular morphogenesis and angiogenesis. 1262 42

During normal pregnancy the hemostatic balance changes in the direction of hypercoagulability, thus decreasing bleeding complications in connection with delivery. The most important initial factor for acute hemostasis at delivery is, however, uterine muscle contractions, which interrupt blood flow. Global tests such as Sonoclot signature, the Thromboelastogram, and a new method analyzing overall plasma hemostasis, all show changes representative of hypercoagulability during pregnancy. Increased endogenous thrombin generation, acquired activated protein C resistance, slightly decreased activated partial thromboplastin time (aPTT) and increased prothrombin complex level (PT) measured as international normalized ratio (INR) of less than 0.9 have been reported as well. In normal pregnancy, the platelet count is within normal range except during the third trimester when benign gestational thrombocytopenia, 80 to 150 x 10 9/L, can be observed. Platelet turnover is usually normal. Activation of platelets and release of beta-thromboglobulin and platelet factor 4 are reported. The bleeding time is unchanged during normal pregnancy. Most blood coagulation factors and fibrinogen increase during pregnancy. Factor (F) XI is the only blood coagulation factor that decreases. Blood coagulation inhibitors are mainly unchanged but the level of free protein S decreases markedly and the level of tissue factor pathway inhibitor increases. Thrombomodulin levels increase during pregnancy. Fibrinolytic capacity is diminished during pregnancy, mainly because of markedly increased levels of plasminogen activator inhibitor-1 (PAI-1) from endothelial cells and plasminogen activator inhibitor-2 (PAI-2) from the placenta. Thrombin-activated fibrinolysis inhibitor is reported to be unaffected. The total hemostatic balance has been studied by analyses of prothrombin fragment 1+2, thrombin-antithrombin complex, fibrinopeptide A, soluble fibrin, D-dimer, and plasmin-antiplasmin complex. There is activation of blood coagulation and a simultaneous increase in fibrinolysis without signs of organ dysfunction during normal pregnancy. These changes increase as pregnancy progresses. During delivery, there is consumption of platelets and blood coagulation factors, including fibrinogen. Fibrinolysis improves and increases fast following childbirth and expulsion of the placenta, resulting in increased D-dimer levels. These changes are self-limiting at normal delivery. The hemostatic changes, noted during pregnancy, normalize after delivery within 4 to 6 weeks. Platelet count and free protein S, however, can be abnormal longer. Hemostasis should not be tested earlier than 3 months following delivery and after terminating lactation to rule out influences of pregnancy. PAI-1 and PAI-2 levels decrease fast postpartum, but PAI 2 has been detected up to 8 weeks postpartum. alpha 2 -antiplasmin, urokinase, and kallikrein inhibitor levels have been reported to be increased 6 weeks postpartum.
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PMID:Hemostasis during normal pregnancy and puerperium. 1270 15


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