Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.21.73 (urokinase-type plasminogen activator)
10,685 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a ligand-inducible nuclear receptor that functions as a transcription factor involved in lipid metabolism, inflammatory response and angiogenesis. The most potent endogenous PPARgamma activator is 15-deoxy-Delta(12,14)prostaglandin-J(2) (15d-PGJ(2)), whereas synthetic ligands include the oral antidiabetic drugs thiazolidinediones (TZDs). Activation of PPARgamma was reported to decrease the synthesis of matrix metalloproteinases (MMPs) in vascular smooth muscle cells and macrophages. We aimed to investigate the effect of PPARgamma ligands on expression of MMP-1 and urokinase plasminogen activator (uPA) in human microvascular endothelial cells (HMEC-1). We found that treatment of HMEC-1 with 15d-PGJ(2) increased the synthesis of MMP-1 protein up to 168% comparing to untreated cells. TZDs (ciglitazone and troglitazone), more potent activators of PPARgamma in HMEC-1, did not influence MMP-1 production, arguing against the involvement of PPARgamma in this process. Importantly, the stimulatory effect of 15d-PGJ(2) was reversed by the antioxidant N-acetyl-cysteine (NAC), suggesting a contribution of oxidative stress. We demonstrated also that 15d-PGJ(2) did not change the activity of MMP-1 promoter, but increased the stability of MMP-1 mRNA. In contrast, 15d-PGJ(2) very potently inhibited the synthesis of uPA. This effect was in part mimicked by ciglitazone and troglitazone implying an involvement of PPARgamma. Accordingly, NAC did not modify the inhibitory effect of 15d-PGJ(2) on uPA expression. In conclusion, we postulate that 15d-PGJ(2) may differently regulate the synthesis of proteases involved in angiogenesis: it upregulates MMP-1 expression in HMEC-1 through induction of oxidative stress, and inhibits uPA synthesis partly by activation of PPARgamma.
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PMID:Prostaglandin-J(2) upregulates expression of matrix metalloproteinase-1 independently of activation of peroxisome proliferator-activated receptor-gamma. 1451 49

The N-terminal cysteine-rich somatomedin B (SMB) domain (residues 1-44) of the human glycoprotein vitronectin contains the high-affinity binding sites for plasminogen activator inhibitor-1 (PAI-1) and the urokinase receptor (uPAR). We previously showed that the eight cysteine residues of recombinant SMB (rSMB) are organized into four disulfide bonds in a linear uncrossed pattern (Cys(5)-Cys(9), Cys(19)-Cys(21), Cys(25)-Cys(31), and Cys(32)-Cys(39)). In the present study, we use an alternative method to show that this disulfide bond arrangement remains a major preferred one in solution, and we determine the solution structure of the domain using NMR analysis. The solution structure shows that the four disulfide bonds are tightly packed in the center of the domain, replacing the traditional hydrophobic core expected for a globular protein. The few noncysteine hydrophobic side chains form a cluster on the outside of the domain, providing a distinctive binding surface for the physiological partners PAI-1 and uPAR. The hydrophobic surface consists mainly of side chains from the loop formed by the Cys(25)-Cys(31) disulfide bond, and is surrounded by conserved acidic and basic side chains, which are likely to contribute to the specificity of the intermolecular interactions of this domain. Interestingly, the overall fold of the molecule is compatible with several arrangements of the disulfide bonds. A number of different disulfide bond arrangements were able to satisfy the NMR restraints, and an extensive series of conformational energy calculations performed in explicit solvent confirmed that several disulfide bond arrangements have comparable stabilization energies. An experimental demonstration of the presence of alternative disulfide conformations in active rSMB is provided by the behavior of a mutant in which Asn(14) is replaced by Met. This mutant has the same PAI-1 binding activity as rVN1-51, but its fragmentation pattern following cyanogen bromide treatment is incompatible with the linear uncrossed disulfide arrangement. These results suggest that active forms of the SMB domain may have a number of allowed disulfide bond arrangements as long as the Cys(25)-Cys(31) disulfide bond is preserved.
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PMID:Disulfide bonding arrangements in active forms of the somatomedin B domain of human vitronectin. 1515 85

Effect of three epsilon-aminocaproylaminoacids with a significant antifibrinolytic activity on amidolytic activity of tissue plasminogen activator (t-PA), urokinase and kallikrein was examined. epsilon-Aminocaproyl-S-benzyl)-L-cysteine and epsilon-aminocaproyl-L-norleucine were weak inhibitors of kallikrein. Weak activation of t-PA activity was observed at high concentration of the tested compounds. Only one of the examined dipeptides was a weak inhibitor of amidolytic activity of urokinase.
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PMID:Effects of epsilon-aminocaproiloaminoacids on the amidolytic activity of tissue plasminogen activator, urokinase and kallikrein. 1525 61

Three decades of research have revealed that cancer is easier to prevent than to treat and that consumption of certain fruits and vegetables can reduce the risk of cancer. Whereas chemotherapy is designed to destroy cancer after it appears, chemoprevention involves the abrogation or delay in the onset of cancer. Regardless of whether a chemopreventive or chemotherapeutic approach is taken, cancer is a multifactorial disease that requires modulation of multiple pathways and multiple targets. Various molecular targets of chemoprevention are also relevant to the therapy of cancer. These targets include the activation of apoptosis; suppression of growth factor expression or signalling; downregulation of antiapoptotic proteins; suppression of phosphatidylinositol-3'-kinase/Akt, NF-kappaB, Janus kinase-signal transducer and activator of transcription and activator protein-1 signalling pathways; and downregulation of angiogenesis through inhibition of vascular endothelial growth factor expression, cyclooxygenase-2, matrix metalloproteinase-9, urokinase-type plasminogen activator, adhesion molecules and cyclin D1. Pharmacologically safe phytochemicals that have been identified from plants or their variant forms can modulate these molecular targets. These phytochemicals include genistein, resveratrol, dially sulfide, S-ally cysteine, allicin, lycopene, capsaicin, curcumin, 6-gingerol, ellagic acid, ursolic acid, betulinic acid, flavopiridol, silymarin, anethol, catechins and eugenol. Recent work has shown that these phytochemicals also can reverse chemoresistance and radioresistance. Because of their pharmacological safety, these agents can be used alone to prevent cancer and in combination with chemotherapy to treat cancer.
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PMID:From chemoprevention to chemotherapy: common targets and common goals. 1546 61

Plasminogen activator inhibitor type-1 (PAI-1) is considered one of the key regulators of tumor invasion, metastasis, as well as cancer-related angiogenesis. The literature suggests that PAI-1 plays a dual role in these processes because it inhibits plasmin-originated proteolysis and binds to vitronectin or integrins. Stimulation or inhibition of angiogenesis largely depends on which of these elements PAI-1 interacts. Wild PAI-1 converts quickly into its latent, inactive form and loses its anti-proteolytic activity, but still binds to vitronectin and integrins. Thus we constructed PAI-1s with extended half-life to prolong their anti-proteolytic activity. We have analyzed the effects of sprout formation inhibition by PAI-1s on two functionally different endothelial cell (EC) systems, human umbilical vein endothelial cells (HUVEC), expressing moderate amounts of urokinase (uPA), and human lung microvascular endothelial cells (HLMVEC), expressing high amounts of this enzyme. We have used wild-type PAI-1 (wPAI-1) (t(1/2) = 1.6 h) and PAI-1 cysteine mutants (CysPAI-1) characterized by their prolonged half-life time (hDbetaT) (t(1/2) = 63.6 h and t(1/2) = 7,000 h). We have observed a significant inhibitory dose-dependent effect exerted by the CysPAI-1s on sprout formation by HUVEC and HLMVEC cells. The inhibition rate was considerably stronger in lung capillary cell cultures and significantly more pronounced for CysPAI-1 mutants with longer anti-uPA activity (betaT). wPAI-1 with a short anti-proteolytic half-life has induced sprout formation in HUVEC, but not in HLMVEC cultures. This difference in behavior was most likely related to the presence of excessive amounts of uPA in HLMVEC cells and the known mechanism of clearing PAI-1/uPA/uPAR complexes from the cell surface. A less efficient system of HUVEC cells might give wPAI-1 the chance to interact with non-proteolytic pathways of angiogenesis stimulation. We conclude that while the anti-proteolytic properties of PAI-1 constructs are preserved, these proteins inhibit angiogenesis and inhibitory activity dominates over any stimulatory effects of PAI-1.
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PMID:Plasminogen activator inhibitor type-1 mutants regulate angiogenesis of human umbilical and lung vascular endothelial cells. 1554 31

Adenosylmethionine decarboxylase (AdoMetDC), a key enzyme in the biosynthesis of polyamines, is often up-regulated in cancers. We have demonstrated previously that overexpression of AdoMetDC alone is sufficient to transform NIH 3T3 cells and induce highly invasive tumors in nude mice. Here, we studied the transformation-specific alterations in gene expression induced by AdoMetDC by using cDNA microarray and two-dimensional electrophoresis technologies. We specifically tried to identify the secreted proteins contributing to the high invasive activity of the AdoMetDC-transformed cells. We found a significant increase in the expression and secretion of procathepsin L, which was cleaved and activated in the presence of glycosaminoglycans (heparin), and a smaller increase in cathepsin B. Inhibition of the cathepsin L and B activity by specific peptide inhibitors abrogated the invasive capacity of the AdoMetDC transformants in Matrigel. The transformed cells also showed a small increase in the activity of gelatin-degrading matrix metalloproteinases (MMPs) and urokinase-type plasminogen activator activities, neither of which was sensitive to the inhibitors of cathepsin L and B. Furthermore, the invasive potency of the transformed cells remained unaffected by specific inhibitors of MMPs. The results suggest that cysteine cathepsins are the main proteases contributing to the high invasiveness of the AdoMetDC-transformed cells and that the invasion potential is largely independent of activation of the MMPs.
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PMID:Cysteine cathepsins are central contributors of invasion by cultured adenosylmethionine decarboxylase-transformed rodent fibroblasts. 1560 41

Plasminogen activator inhibitor type-1 (PAI-1), the primary regulator of plasminogen activator - urokinase (uPA) plays a crucial role in the cell adhesion and migration and in angiogenesis. We had previously demonstrated that PAI-1 - endothelial cell interplay is critical for the formation of new blood vessels and the process is mostly conducted via uPA- anti-proteinase interaction. In the present study we wished to further examine the role of PAI-1 in the sprout formation, representing the first step of new capillary vessels development by evaluating the effect of PAI-1 on the sprout area. We addressed the issue by assessing the influence of cysteine-mutated PAI-1 proteins characterized by a prolonged half-life time (hD beta T - T(1/2)= 63.59 h and beta T-T(1/2)= 6931.47 h), and therefore more stable anti-uPA activity, on the appearance of newly formed sprouts. We found that both CysPAI-1 proteins significantly diminished the mean sprout area in a concentration-dependent fashion. The inhibitory effect present in the two examined endothelial cells systems of different origin and functional characteristics - human umbilical vein endothelial cells (HUVEC) and human lung microvascular endothelial cells (HLMVEC) cultures - was noticeably greater for HLMVEC -high urokinase-producers. Moreover, the inhibition rate was significantly greater for the beta T mutant than that for the hD beta T PAI-1 mutant in all examined doses (P<0.002), proving a key role of anti-proteinase activity for this effect. We concluded that, apart from the total sprout length, as it had repeatedly been demonstrated before, also affects the sprout area in the in vitro sprout formation angiogenesis assay. This effect was achieved mainly via PAI-1's antiproteinase activity.
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PMID:Plasminogen activator inhibitor type-1 controls the process of the in vitro sprout formation. 1561 93

To evaluate the possible role of cysteine proteases and serine proteases, as well as their respective inhibitors and receptors, as new prognostic factors in NSCLC, we examined, for the first time, 10 biological parameters related to three proteolytic systems within a homogeneous collective of 147 cases of NSCLC. Activities (cath B(AT), cath B(A7.5)) and protein levels of cath B(C), cath L(C), uPA, PAI-1, uPAR [measured by three different assays uPAR (ADI), uPAR (HD13), uPAR (IIIF10)] and TF were measured in homogenates of lung tumour tissue and corresponding non-malignant lung parenchyma. Total cath B activity (cath B(AT)) and enzymatic activity of the fraction of cath B, which is stable and active at pH 7.5 (cath B(A7.5)), were determined by a fluorogenic assay using synthetic substrate Z-Arg-Arg-AMC. The concentrations of cath B(C), cath L(C), uPA, PAI-1, uPAR and TF were determined by ELISAs. uPAR was determined using three different ELISA formats. The median levels of cath B(AT) (5.1-fold), cath B(A7.5) (2.5-fold), cath B(C), (8.5-fold), cath L(C) (6.6-fold), uPA (6.5-fold), PAI-1 (4.2-fold), uPAR (ADI) (2.2-fold), uPAR (HD13) (4.0-fold) and uPAR (IIIF10) (2.6-fold) were higher in tumour tissue compared to the lung parenchyma. Cath B(AT), cath B(A7.5) and cath B(C) in primary tumours correlated with lymph node metastases. Regarding histologies, the concentration of PAI-1 seems to be associated with the histological cell types of NSCLC. We found the highest values of PAI-1 in large cell carcinoma > SCC, AC > carcinoid and lowest values in metastases of primary tumours of other organs. Only PAI-1 was significantly increased in poorly-differentiated cells (G3) compared to well- and moderately- differentiated cells (G1/G2). PAI-1 significantly correlated with cath B(AT) and cath B(A7.5) with uPAR (ADI), uPAR (HD13), uPAR (IIIF10) with uPA, and only weakly with TF, but not with cath B(C) and cath L(C). Significant correlations with overall survival in the total population of NSCLC patients were observed in univariate analysis for cath B(AT), cath B(C), PAI-1, uPAR (ADI), uPAR (HD13), and uPAR (IIIF10). Cath L(C) was not significantly associated with poor prognosis. Regarding the histological tumour type, only in patients with squamous cell carcinomas did cath B(A7.5) and PAI-1 remain significant prognostic factors. In multivariate survival analysis only two proteolytic factors, PAI-1 and uPAR (III101F), stayed significant. In conclusion, among 10 biological parameters evaluated within the same cohort of patients, only PAI-1, uPAR (ADI), uPAR (HD13), uPAR (IIIF10), cath B(AT) and cath B(C) are prognostic factors for overall survival of NSCLC patients. Moreover, PAI-1 and uPAR (IIIF10) add independent prognostic information with regard to established clinical and histomorphological factors in NSCLC.
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PMID:Cathepsin B, plasminogenactivator-inhibitor (PAI-1) and plasminogenactivator-receptor (uPAR) are prognostic factors for patients with non-small cell lung cancer. 1573 66

Cancer development is essentially a tissue remodeling process in which normal tissue is substituted with cancer tissue. A crucial role in this process is attributed to proteolytic degradation of the extracellular matrix (ECM). Degradation of ECM is initiated by proteases, secreted by different cell types, participating in tumor cell invasion and increased expression or activity of every known class of proteases (metallo-, serine-, aspartyl-, and cysteine) has been linked to malignancy and invasion of tumor cells. Proteolytic enzymes can act directly by degrading ECM or indirectly by activating other proteases, which then degrade the ECM. They act in a determined order, resulting from the order of their activation. When proteases exert their action on other proteases, the end result is a cascade leading to proteolysis. Presumable order of events in this complicated cascade is that aspartyl protease (cathepsin D) activates cysteine proteases (e.g. cathepsin B) that can activate pro-uPA. Then active uPA can convert plasminogen into plasmin. Cathepsin B as well as plasmin are capable of degrading several components of tumor stroma and may activate zymogens of matrix metalloproteinases, the main family of ECM degrading proteases. The activities of these proteases are regulated by a complex array of activators, inhibitors and cellular receptors. In physiological conditions the balance exists between proteases and their inhibitors. Proteolytic-antiproteolytic balance may be of major significance in the cancer development. One of the reasons for such a situation is enhanced generation of free radicals observed in many pathological states. Free radicals react with main cellular components like proteins and lipids and in this way modify proteolytic-antiproteolytic balance and enable penetration damaging cellular membrane. All these lead to enhancement of proteolysis and destruction of ECM proteins and in consequence to invasion and metastasis.
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PMID:Proteolytic-antiproteolytic balance and its regulation in carcinogenesis. 1576 61

Extracellular proteolysis plays a key role in many pathophysiologic processes including cancer, inflammatory diseases, and cardiovascular conditions such as atherosclerosis and restenosis. Whereas matrix metalloproteinases are their best known member, many others are becoming better known. The extracellular proteases are a complex and heterogeneous superfamily of enzymes. They include metalloproteinases (matrix metalloproteinases, adamalysins, or pappalysins), serine proteases (elastase, coagulation factors, plasmin, tissue plasminogen activator, urokinase plasminogen activator), and the cysteine proteases (such cathepsins). In addition to their matrix degradation capabilities, they have other less well known biologic functions that include angiogenesis, growth factor bioavailability, cytokine modulation, receptor shedding, enhancing cell migration, proliferation, invasion, and apoptosis. This review discusses extracellular proteases relevant to the vasculature, their classification and function, and how protease disorders contribute to arterial plaque growth, including chronic atherosclerosis, acute coronary syndromes, restenosis, and vascular remodeling. These broad extracellular protease functions make them potentially interesting therapeutic targets.
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PMID:Extracellular proteases in atherosclerosis and restenosis. 1580 22


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