Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.73 (urokinase-type plasminogen activator)
 10,685 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Effects of sex steroids (estradiol-17 beta, E2; progesterone, Prog) and growth factors (epidermal growth factor, EGF; transforming growth factor-alpha, TGF-alpha) on invasive activity and 5'-deoxy-5-fluorouridine (5'-dFUrd) sensitivity of ovarian adenocarcinoma OMC-3 cells were investigated. Tumor cell migration along a gradient of substratum-bound fibronectin and invasion into reconstituted basement membrane were inhibited by 10 microM Prog, but stimulated by 0.1-10 nM EGF and TGF-alpha in a concentration-dependent manner. E2 did not have any effect on tumor cell migration or invasion. The zymography of tumor conditioned medium showed that the treatment of OMC-3 cells with EGF and TGF-alpha resulted in increases of type IV collagenase, stromelysin and urokinase-type plasminogen activator (uPA). EGF and TGF-alpha up-regulated thymidine phosphorylase (dThdPase) expression of tumor cells and consequently enhanced the antiproliferative action of 5'-dFUrd, which is converted to 5-fluorouracil by dThdPase. E2 and Prog did not have significant effects on the expression of proteolytic enzymes and dThdPase, or on the 5'-dFUrd sensitivity of tumor cells. The inhibitory effect of Prog on tumor cell invasion may depend on its inhibitory action on the motility of tumor cells. These results suggest that EGF and TGF-alpha simultaneously up-regulate the potential of ovarian adenocarcinoma cells to invade extracellular matrices and their dThdPase expression, both of which are associated with the specific action of 5'-dFUrd selectively to kill tumor cells with high invasive and metastatic potential.
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PMID:Effects of sex steroids and growth factors on invasive activity and 5'-deoxy-5-fluorouridine sensitivity in ovarian adenocarcinoma OMC-3 cells. 1008 95

It has been shown that, in breast stroma, urokinase-type plasminogen activator (uPA) mRNA is predominantly expressed by myofibroblasts located at the invasive areas of the tumor. To examine which factors present in a tumor environment are candidates responsible for the induction of these uPA-producing myofibroblasts, we studied in vitro the capacity of a paired panel of normal and tumor-derived human breast fibroblasts to produce uPA protein and the myofibroblast marker alpha-smooth-muscle-actin (alpha-SMA) in response to various cytokines implicated in the process of tissue-remodeling during malignant transformation. We found that fibroblasts produced increased amounts of uPA protein after exposure to a-FGF, b-FGF, EGF, PDGF-BB, and IFN-gamma, were unaffected in this respect by IL-6, M-CSF, GM-CSF and Oncostatin M, and produced decreased amounts of uPA protein after exposure to IL-1alpha, TNF-alpha, IGF-I, and IGF-II. None of these cytokines were able to induce a striking increase in the fraction of alpha-SMA-positive fibroblasts. On the other hand, 25 pM TGFbeta1 increased the fraction of alpha-SMA-positive fibroblasts 5-fold in both normal and tumor-tissue-derived fibroblasts. Nonetheless, the normal-derived fibroblasts were unaffected in their uPA-producing capacity by TGFbeta1, and the tumor-derived fibroblasts produced decreased amounts of uPA protein after exposure to this cytokine, implying that at least in vitro the myofibroblast phenotype is not a prerequisite for the production of uPA by human breast fibroblasts. In addition, we established that the basal-uPA-production of both normal and tumor-derived fibroblasts was increased by autocrinely produced b-FGF-like activity, and that the basal-uPA-production of at least the normal-derived fibroblasts was decreased by autocrinely produced IGF-like activity. Altogether, our data suggest an active role for fibroblasts in the process of uPA-directed breast tumor proteolysis.
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PMID:Cytokine-regulated urokinase-type-plasminogen-activator (uPA) production by human breast fibroblasts in vitro. 1047 75

Pancreatic acini and islets are believed to differentiate from common ductal precursors through a process requiring various growth factors. Epidermal growth factor receptor (EGF-R) is expressed throughout the developing pancreas. We have analyzed here the pancreatic phenotype of EGF-R deficient (-/-) mice, which generally die from epithelial immaturity within the first postnatal week. The pancreata appeared macroscopically normal. The most striking feature of the EGF-R (-/-) islets was that instead of forming circular clusters, the islet cells were mainly located in streak-like structures directly associated with pancreatic ducts. Based on BrdU-labelling, proliferation of the neonatal EGF-R (-/-) beta-cells was significantly reduced (2.6+/-0.4 versus 5.8+/-0.9%, P<0.01) and the difference persisted even at 7-11 days of age. Analysis of embryonic pancreata revealed impaired branching morphogenesis and delayed islet cell differentiation in the EGF-R (-/-) mice. Islet development was analyzed further in organ cultures of E12.5 pancreata. The proportion of insulin-positive cells was significantly lower in the EGF-R (-/-) explants (27+/-6 versus 48+/-8%, P<0.01), indicating delayed differentiation of the beta cells. Branching of the epithelium into ducts was also impaired. Matrix metalloproteinase (MMP-2 and MMP-9) activity was reduced 20% in EGF-R (-/-) late-gestation pancreata, as measured by gelatinase assays. Furthermore, the levels of secreted plasminogen activator inhibitor-1 (PAI-1) were markedly higher, while no apparent differences were seen in the levels of active uPA and tPa between EGF-R (-/-) and wild-type pancreata. Our findings suggest that the perturbation of EGF-R-mediated signalling can lead to a generalized proliferation defect of the pancreatic epithelia associated with a delay in beta cell development and disturbed migration of the developing islet cells as they differentiate from their precursors. Upregulated PAI-1 production and decreased gelatinolytic activity correlated to this migration defect. An intact EGF-R pathway appears to be a prerequisite for normal pancreatic development.
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PMID:Impaired migration and delayed differentiation of pancreatic islet cells in mice lacking EGF-receptors. 1082 60

Signal transduction by urokinase-type plasminogen activator (u-PA) bound to its cell receptor has been well established. In the present study, we found, for the first time to our knowledge, that u-PA promotes its own synthesis by endothelial cells and monocytes. This phenomenon was characterized and shown to involve the u-PA receptor (u-PAR) pathway. The finding may be of general importance, since most cells that express u-PAR also produce u-PA. Human umbilical vein endothelial cells (HUVECs), U937 monocytes, and human peripheral blood monocytes (PFMCs) were incubated with diisopropylfluorophosphate (DFP)-pretreated u-PA, the amino-terminal fragment (ATF) of u-PA, or the kringle domain. A threefold up-regulation of u-PA secretion and synthesis by u-PA or ATF was found. The predominant effect was expressed in HUVECs, in which u-PA mRNA was also up-regulated. The u-PA kringle domain had no effect on u-PA synthesis, leading to the conclusion that the EGF domain was responsible. This was also consistent with the additional finding that the u-PAR, to which the EGF domain binds, was necessary for the up-regulation. The results indicate that u-PA up-regulates itself via its EGF domain and u-PAR. The possibilities that the results were related to displacement of receptor-bound u-PA or the blocking of u-PA incorporation into the cells were excluded. A modest up-regulation of u-PAR was also associated with this phenomenon.
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PMID:Urokinase-type plasminogen activator up-regulates its own expression by endothelial cells and monocytes via the u-PAR pathway. 1167 84

We report here that human astrocytoma cell line U373-MG is able to express genes of the following components of plasminogen activation system: PA1-1, PN-1, u-PA and t-PA. Treatment of these cells with IL-1beta results in accumulation of PA1-1, PN-1 and u-PA mRNAs, whereas t-PA mRNA remains unaffected. IFNy preferentially enhances PN-1 and PA1-1, EGF enhances PA1-1, u-PA and t-PA expression. Simultaneous addition of anti-inflammatory cytokines IL-4, IL-13 and IL-10 has little effect on the tested components, except induction of u-PA mRNA wich was further enhanced by IL-4. We have confirmed interesting time-dependent regulation of plasminogen activation system by EGF/IFNgamma. Cells stimulated with EGF/IFNgamma show at first increased proteolytic activity but after 24 h inhibition of proteolysis with PA1-1 would prevail. To understand the cooperative effect of EGF and IFNgamma in PA1-1 induction the kinetics of activation of STAT1 was studied. It was found that although EGF alone does not activate STAT1, the STAT1 binding activity in the cells treated with the mixture of EGF/IFNgamma was considerably prolonged. Our results indicate the importance of inflammatory cytokines and EGF in gene regulation of plasminogen activation system in astrocytoma cells.
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PMID:Cytokines regulate plasminogen activation system in astrocytoma cells. 1193 22

Osteopontin (OPN) is a secreted, integrin-binding protein which has been implicated in cancer, as well as other pathologies and some aspects of normal development. Here we focus on the role of OPN in breast cancer. We describe studies that have shown that OPN plays a role in normal mammary gland development as well as in progression of breast cancer. We also summarize studies that have shown that OPN can play a functional role in malignancy of breast cancer. At least some of these effects are mediated by specific cell surface integrins (alpha(v)beta3 vs. alpha(v)beta1 and alpha(v)beta5) and lead to increased cell migration, activation of growth factor/receptor pathways (e.g. HGF and EGF), and increased proteolytic enzyme activity (e.g. uPA). We also summarize clinical studies that show that OPN levels in tumors and blood are elevated in women with metastatic breast cancer and may offer promise as prognostic markers in breast cancer.
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PMID:The role of osteopontin in breast cancer: clinical and experimental studies. 1201 31

Pancreatic carcinogenesis is still not well characterized and no specific carcinogen has been isolated in humans. Pancreatic adenocarcinoma acquires genetic abnormalities with successive modification of genes involved in the regulation of cell proliferation and differentiation. The kinetic of genetic alterations in pancreatic cancer is not totally elucidated but experimental pancreatic cancer induced by BOP in Syrian golden hamster attempts to approach this problematic. The activating mutation of the K-ras oncogene on codon 12 seems to occur early in pancreatic carcinogenesis regarding the detection of this mutation in preneoplastic dysplastic lesions and tumors such as intraductal mucinous papillary tumors. Tumor suppressor genes are also inactivated leading commonly to the loss of an inhibitory function on cell proliferation. This inactivation occurs with gene mutation, deletion or methylation on one chromosome arm associated with a loss of heterozygosity: it concerns p53, p16/MTS-1, DPC-4/SMAD4. We recently characterized the somatostatin receptor SST2 gene as a potential suppressor gene for pancreatic carcinoma. The kinetic of these gene alterations is unknown in human. At a late stage of tumor development, an increase of telomerase activity, an over expression of growth factors and/or their receptors (EGF, NGF, gastrin, bombesin), of proangiogenic factors (VEGF, FGF, PDGF), of invasiveness factors (metalloproteinases, E-cadherin, urokinase and tissue plasminogen activators) occur. All these molecular events contribute to the progression and to the metastatic potential of this carcinoma. Recently, the identification of human genome and the large scale analysis of transcriptoma will certainly authorize a better knowledge of pancreatic carcinogenesis as well as the identification of new genetic alterations and new clinical markers.
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PMID:[Molecular pathways of pancreatic carcinogenesis]. 1248 52

Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Studies Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: Abarelix, ABX-EGF, ademetionine, agomelatine, AMGN-0007, 9-aminocamptothecin, AN-9, anecortave acetate, anidulafungin, AOD-9604, apolizumab, apomate, L-arginine hydrochloride, arzoxifene hydrochloride; Bevacizumab, BP-897, BufferGel; Capravirine, carboxyamidotriazole, carnosine, CC-4047, CEP-701, cerivastatin sodium, clofarabine, conivaptan hydrochloride, CP-461, CS-003; Daptomycin, darifenacin, decitabine, deferasirox, duloxetine hydrochloride; Eberconazole, Ecyd, efalizumab, eglumegad hydrate, EMD-72000, (-)-epigallocatechin gallate, exatecan mesilate, exenatide; Fampridine, fenretinide, ferumoxtran-10; Gadofosveset sodium, garenoxacin mesilate, genistein, glutamine, GPI-15715; Hexyl insulin M2, human insulin, HYB-165; Indisulam, irofulven; KRN-5500, L-796568, laurocapram, lidocaine/prilocaine, lonafarnib, lotrafiban; Melagatran, melatonin, 2-methoxyestradiol, metreleptin, motexafin gadoliniu, motexafin lutetium; Natalizumab, nelarabine, NO-aspirin, NSC-683864; ONO-6126; Pemetrexed disodium, pexelizumab, pirfenidone, PncCRM9, polyglutamate paclitaxel, pramlintide acetate pregabalin, PRO-2000; Ragaglitazar, ramelteon, rasagiline mesilate, rDNA insulin, recombinant glucagon-like peptide-1 (7-36) amide, recombinant human parathyroid hormone (1-84), reolysin RG228, roflumilast, roxifiban acetate, RPI-4610, rubitecan; Safinamide mesilate, solifenacin succinate, SRL-172; T-138067, tafenoquine succinate, tecadenoson, TER-286, tesaglitazar, tetrathiomolybdate, tezosentan disodium, TheraCIM, tigecycline, tipifarnib, tolvaptan, trabectedin, tributyrin, trimegestone, troxacitabine; UCN-01, urokinase alfa; Vinflunine, viscum fraxini 2; Xcellerated T cells, ximelagatran.
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PMID:Gateways to clinical trials. 1468 3

We have recently reported that tyrosine kinase, p56(lck) regulates cell motility and nuclear factor kappaB-mediated secretion of urokinase-type plasminogen activator (uPA) through tyrosine phosphorylation of IkappaBalpha following hypoxia/reoxygenation (Mahabeleshwar, G. H., and Kundu, G. C. (2003) J. Biol. Chem. 278, 52598-52612). However, the role of hypoxia/reoxygenation (H/R) on ERK1/2-mediated uPA secretion and cell motility and the involvement of p56(lck) and EGF receptor in these processes in breast cancer cells is not well defined. We provide here evidence that H/R induces Lck kinase activity and Lck-dependent tyrosine phosphorylation of EGF receptor in highly invasive (MDA-MB-231) and low invasive (MCF-7) breast cancer cells. H/R also stimulates MEK-1 and ERK1/2 phosphorylations, and H/R-induced phosphorylations were suppressed by the dominant negative form of Lck (DN Lck, K273R) as well as pharmacological inhibitors of EGF receptor and Lck indicating that EGF receptors and Lck are involved in these processes. Transfection of these cells with wild type Lck or Lck F505 (Y505F) but not with Lck F394 (Y394F) induced phosphorylations of EGF receptor followed by MEK-1 and ERK1/2, suggesting that Lck is upstream of EGF receptor and Tyr-394 of Lck is crucial for these processes. H/R also induced uPA secretion and cell motility in these cells. DN Lck and inhibitors of Lck, EGF receptor, and MEK-1 suppressed H/R-induced uPA secretion and cell motility. To our knowledge, this is the first report that p56(lck) in presence of H/R regulates MEK-1-dependent ERK1/2 phosphorylation and uPA secretion through tyrosine phosphorylation of EGF receptor, and it further demonstrates that all of these signaling molecules ultimately control the motility of breast cancer cells.
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PMID:Tyrosine kinase, p56lck-induced cell motility, and urokinase-type plasminogen activator secretion involve activation of epidermal growth factor receptor/extracellular signal regulated kinase pathways. 1469 20

Urokinase-type plasminogen activator receptor (uPAR) and epidermal growth factor receptor (EGFR) are ubiquitous receptors involved in the control of a variety of cellular processes frequently found altered in cancer cells. The EGFR has been recently described to play a transduction role of uPAR stimuli, mediating uPA-induced proliferation in highly malignant cells that overexpress uPAR. In the present work, we found for the first time that uPAR stimulation with the amino-terminal fragment (ATF) of urokinase devoid of proteolytic activity transactivates the EGFR in mammary MCF-7 cells through a mechanism involving Src and a metalloproteinase, as indicated by its sensitivity to selected inhibitors. In these cells, which express low levels of uPAR and malignancy, both ATF and EGF stimuli induced an interaction of the EGFR with uPAR and ERK activation. However, EGFR activation by uPAR stimuli mediated cellular invasion rather than proliferation, while EGFR activation by EGF led to a proliferative response. These results revealed a complex modulation of EGFR function toward different cellular responses according to the status of uPAR activity. On the other hand, we also found that MMP-mediated activation of EGFR can occur in an autocrine manner in cells which secrete uPA. All this reveals novel regulatory systems operating through autocrine loops involving uPAR stimuli, Src, MMP and EGFR activation which could mediate fine control of physiological processes as well as contribute to the expression of proliferative and invasive phenotypes of cancerous cells.
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PMID:EGF receptor transactivation by urokinase receptor stimulus through a mechanism involving Src and matrix metalloproteinases. 1472 May 19


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