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)

Human fibrinogen, either untreated or previously phosphorylated by protein kinase C, was incubated with plasmin generated by streptokinase, urokinase or tissue plasminogen activator and the resulting fragments were separated by gel electrophoresis. Plasmin degradation resulted in the expected X, Y and D fragments, but the degradation rates differed. In vitro phosphorylation of fibrinogen was seen to inhibit the plasmin digestion. Treatment with alkaline phosphatase did not reverse the inhibition.
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PMID:Plasmin digestion of human fibrinogen previously phosphorylated by protein kinase C or dephosphorylated by alkaline phosphatase in vitro. 214 Sep 13

Secretion of urokinase-type plasminogen activator (uPA) by chicken embryo fibroblasts (CEF) is increased approximately 50-fold following transformation by Rous sarcoma virus (RSV). Using a cloned and fully sequenced chicken uPA cDNA probe, we have established that this increase in plasminogen activator production can be largely accounted for by an increase in cellular uPA mRNA. CEF contained on average less than 1 molecule of uPA mRNA/cell, whereas RSV-CEF contained 25-60 molecules/cell. The increase in cellular uPA mRNA levels was dependent on the activity of the RSV-encoded transforming protein, protein-tyrosine kinase pp60v-src. Cells infected with an RSV mutant encoding a temperature-sensitive form of the src protein (ts-NY68) contained low uPA mRNA levels when cultured at the nonpermissive temperature and high uPA mRNA levels when maintained at the permissive temperature. Temperature shift studies with tsNY68-CEF demonstrated that changes in pp60v-src activity rapidly altered uPA mRNA levels; the uPA mRNA content of total RNA extracts increased and decreased with half-time kinetics of 3-5 h. Serine/threonine-specific protein kinases also appear to modulate uPA mRNA levels in CEF cultures. Exposure of CEF and RSV-CEF for 24 h to the protein kinase C activating agent phorbol myristate acetate (PMA) increased cellular uPA mRNA levels to 20 and 260 molecules/cell, respectively. These data are consistent with the previously observed synergism between RSV and PMA in increasing plasminogen activator secretion. Nuclear run-on transcription analyses established that both RSV and PMA increase cellular uPA mRNA levels by way of increased uPA gene expression.
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PMID:Plasminogen activator gene expression is induced by the src oncogene product and tumor promoters. 215 28

We describe several characteristics of in vitro myogenesis from adult skeletal muscle satellite cells from the rat and several amphibian species. The timing of cell proliferation and fusion into myotubes was determined, and in urodeles, myogenesis from satellite cells was clearly demonstrated for the first time. Growth factors are known to stimulate satellite cell proliferation. Acidic FGF mRNA was present in rat satellite cells during proliferation but it was not detected in myotubes. Fibronectin was synthesized in satellite cells during proliferation and expelled into the extracellular medium when the myotubes differentiated. We suggest that fibronectin plays a part in the formation of myotubes, as this process was inhibited by anti-fibronectin IgG. Adult satellite cells might differ from fetal myoblasts since they were observed to exhibit the opposite response to a phorbol ester (TPA) to that of the myoblasts. We therefore examined the possibility that the different levels of protein kinase C activity and different phorbol ester binding characteristics in the two cell types account for these opposite responses. Our results suggest that the difference is not connected with the phorbol ester receptor but might be caused by events subsequent to protein kinase C activation. Localized extracellular proteolytic activity might have a role in cell mobilization and/or fusion when satellite cells are activated. We showed that the content of plasminogen activators, chiefly urokinase, was larger in tissues from slow twitch muscles which regenerate more rapidly than fast muscles. The urokinase level rose sharply in cultures when cells fused into myotubes, and was twice as high in slow muscle cells as in fast ones. We also found that, in vitro, slow muscle satellite cells displayed greater myogenicity, but that phorbol ester inhibited their mitosis and myogenicity. We conclude that satellite cells acquire characteristics which differentiate them from myoblasts and correspond to the fast and slow muscles from which they originate.
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PMID:Characterization of myogenesis from adult satellite cells cultured in vitro. 220 56

Human neuronal brain cultures established from 12- and 14-week-old fetuses synthesize and secrete urokinase-type plasminogen activator (uPA) and limited amounts of tissue-type plasminogen activator (tPA). These cells also produce and secrete the endothelial cell-type PA inhibitor (PAI-1), which forms sodium dodecyl sulfate-stable tPA/PAI-1 complexes in the culture medium. Immunocytochemistry shows a predominant localization of uPA, tPA, and PAI-1 in neuronal cells, with only a very weak positivity detectable in the few glial cells present in these cultures. The protein kinase C (PKC) activator 12-O-tetradecanoylphorbol 13-acetate (TPA) stimulates the synthesis of both uPA and PAI-1, resulting in a final increase in the plasmin-generating capacity of neuronal cell cultures. No significant effect is observed, however, when cells are treated with the TPA analogue 4 alpha-phorbol 12,13-didecanoate, which is inactive as a PKC inducer, or with the neurotrophic polypeptide basic fibroblast growth factor. These data represent the first characterization of the plasmin-generating system in human fetal brain neurons and suggest a role for PKC in the modulation of uPA and PAI-1 synthesis.
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PMID:Synthesis of urokinase-type plasminogen activator and of type-1 plasminogen activator inhibitor in neuronal cultures of human fetal brain: stimulation by phorbol ester. 221 17

The chicken urokinase-type plasminogen activator (uPA) cDNA and gene have been isolated and the complete nucleotide sequence of each established. cDNA sequence and Northern blot RNA analysis indicate that the chicken uPA mRNA is approximately 2500 nucleotides in size and contains a large 3'-noncoding region (998 nucleotides). The predicted amino acid sequence of the chicken uPA primary translation product (434 residues) suggests a domain architecture comparable to the mammalian uPA proteins with the form: (i) signal peptide, (ii) growth factor domain (GF), (iii) kringle domain (K), and (iv) serine protease domain (C). The overall sequence identity between the chicken and human proteins is 43.1%, with 56.3, 48.5, and 45.6% identity in the GF, K, and C domains, respectively. The chicken uPA gene is similar to the mammalian uPA genes in both size (8158 base pairs between transcription initiation and polyadenylation sites) and organization (11 exons). However, the sequence of the chicken uPA gene is similar to the mammalian uPA genes only within the protein-coding portions of exons. The transcription initiation site is flanked by a remarkably G/C-rich region (77% between nucleotides -1 and -300) which contains a TATA element and several potential transcription factor Spl-binding sites. The promoter region also contains several repeat elements, including two 11-nucleotide repeats that encompass six potential transcription factor AP-2-binding sites. This work provides a foundation for exploring the mechanism(s) by which protein-tyrosine kinase pp60v-src and protein kinase C modulate uPA gene transcription.
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PMID:The chicken urokinase-type plasminogen activator gene. 229 32

OVCA 433 human ovarian carcinoma cells secrete both mammalian plasminogen activators (PAs) urokinase (UK) and tissue-type PA (tPA). Treatment of cells with 4 beta-phorbol-12-myristate-13-acetate (PMA), a stimulator of protein kinase C (PKC), leads to large increases in the secretion rates of both PA types. PA stimulation by PMA is time- and concentration-dependent, with maximal effects occurring between 12 and 24 h at PMA concentrations of 1-10 ng/ml. The PMA effect is mimicked by mezerein, another known PKC stimulator, but not by 4 alpha-phorbol or 4 alpha-phorbol-12,13-didecanoate, two phorbol compounds that do not stimulate PKC. PA activity is virtually unaffected by 1-oleoyl-2-acetylglycerol (OAG), a synthetic diacylglycerol that stimulates PKC in vitro but has variable effects on whole cells. PMA stimulation of PA activity is blocked by both actinomycin D and cycloheximide, indicating requirements for new RNA and protein synthesis. When analyzed individually, the relative PMA-induced increases in UK and tPA activities are identical. Increased UK activity is fully accounted for by increased UK antigen secretion, whereas increased tPA secretion accounts for only about one-half of the increased tPA activity. Similarly, PMA induces large increases in steady-state UK mRNA levels, while its effects on tPA mRNA levels are only modest. Thus, while increases in secretion rates and mRNA levels can completely account for UK stimulation, other mechanisms augmenting these processes must exist specifically for tPA. Since the relative increases in UK and tPA activities are identical despite the probable existence of multiple mechanisms contributing to tPA regulation, our data suggest the possibility of interrelationships between the two pathways such that equivalent degrees of UK and tPA activity stimulation are ultimately achieved.
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PMID:Simultaneous stimulation of urokinase and tissue-type plasminogen activators by phorbol esters in human ovarian carcinoma cells. 249 25

In LLC-PK1 porcine epithelial cells, the urokinase-type plasminogen activator (u-PA) mRNA and protein can be induced either by stimulation of the protein kinase C (PKC) pathway using a tumor promoter (PMA) or by stimulation of the protein kinase A (PKA) pathway with calcitonin (SCT). By contrast, addition of 10(-7) M staurosporine, an inhibitor of PKC, to LLC-PK1 cells also stimulated urokinase production. In contrast to the in vitro situation (where staurosporine inhibited PKC activity), in the cell-culture system the microbial agent caused an early translocation of PKC and inhibited PKA. Addition of staurosporine together with PMA or with SCT further increased urokinase mRNA and protein synthesis. Maximal stimulation was obtained when all 3 agents were added together. We thus assume that in LLC-PK1 cells the PKA and PKC signal-transferring pathways can function independently.
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PMID:Staurosporine stimulates expression of the urokinase-type (u-PA) plasminogen activator in LLC-PK1 cells. 258 67

Gonadotropin-releasing hormone (GnRH) acts directly on the ovary to induce ovulation in hypophysectomized proestrous rats. Because plasminogen activators (PAs) are implicated in gonadotropin-induced ovulation, we have studied the effect of GnRH on ovarian PA synthesis. GnRH induced tissue-type PA (tPA) secretion by cultured rat granulosa cells, but inhibited the secretion of urokinase-type PA. These effects were blocked by co-treatment with a GnRH antagonist, suggesting that stereospecific GnRH receptors are involved. Follicle-stimulating hormone (FSH) also induced tPA in granulosa cells but with a different time course than GnRH; the combined effect of FSH and GnRH was additive. The GnRH effect was mimicked by the calcium- and phospholipid-dependent protein kinase C activator, phorbol myristate acetate. In isolated cumulus-oocyte complexes and cumulus cells, GnRH treatment also increased tPA activity. In contrast, treatment of denuded oocytes with GnRH did not increase enzyme activity. After GnRH stimulation of the cumulus-oocyte complexes, tPA content in the denuded oocyte was elevated, suggesting that the cumulus cells mediate the action of GnRH to increase the oocyte enzyme levels. Hybridization experiments using a labeled rat tPA-specific DNA probe showed that both FSH and GnRH increased the level of tPA mRNA in cultured granulosa cells; the stimulatory effect of GnRH was blocked by the GnRH antagonist. Our results indicate that GnRH treatment increases tPA secretion by cultured granulosa cells and cumulus-oocyte complexes. The stimulation of enzyme activity in the granulosa cells is accompanied by increases in tPA mRNA levels.
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PMID:Regulation of tissue-type plasminogen activator activity and messenger RNA levels by gonadotropin-releasing hormone in cultured rat granulosa cells and cumulus-oocyte complexes. 311 54

The effects of insulin, the tumour promotor tetradecanoyl phorbol acetate (TPA), TSH and combinations of these factors on growth and DNA synthesis have been examined in the FRTL-5 cell strain and in sheep thyroid cells. In addition the regulation of the production by sheep thyroid cells of the insulin-like growth factors (IGF) by TSH and their possible autocrine roles have been investigated. We found that insulin and the IGF's stimulated DNA synthesis in both rat FRTL-5 cells and sheep cells. TPA also stimulated growth in both cell types, and its effects were additive to those of insulin. In the FRTL-5 cells, TPA was a less potent stimulator of growth than TSH, but the effects of TPA and TSH were not additive which may imply growth stimulation through a common pathway. In sheep cells TSH was not mitogenic and did not appear to activate protein kinase C, the receptor for TPA. Sheep cells, unlike FRTL-5 cells, were found to produce IGF-I and IGF-II, and their syntheses were regulated by TSH. Sheep cells were also found to produce IGF-binding proteins which may modulate the biologic effects of the IGF's. Sheep thyroid IGF binding proteins were found to copurify with urokinase-like plasminogen activator on immunoaffinity chromatography. The production of this serine protease has also been shown to be regulated by TSH.
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PMID:Role of non-TSH factors in thyroid cell growth. 347 6

Tumor promoting phorbol esters and mezerein strongly induced plasminogen activator (urokinase, uPA) synthesis in porcine kidney cell cultures (LLC-PK1). Induction was due to increased uPA-mRNA levels which rose from 10 to 300 molecules/cell within 2 h of exposure to 16 nM phorbol myristate acetate. We have compared the action of tumor promoters with that of 8-bromo-cAMP, another potent inducer of uPA; the similarities between the two kinds of induction were: both involved transcriptional activation of the uPA gene; both were rapid in onset, changes in transcription rate being detectable within 10-20 min; the initial rates of transcription and uPA-mRNA accumulation were substantial and in the same order of magnitude; neither class of inducer required protein synthesis to stimulate uPA transcription. The main contrast between the two types of agents was that the uPA response to tumor promoters was transient whereas that to cAMP compounds was sustained: cultures rapidly lost their response to tumor promoters within 2 h after initial exposure while retaining responsiveness to cAMP-related agents. The cells developed a specific drug-induced desensitization which was slowly reversed after tumor promoters were removed from the culture medium. Since protein kinase C is now well established as the receptor for phorbol-derived and several other tumor promoters it will be of interest to determine whether desensitization occurs at the level of receptor.
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PMID:Induction and desensitization of plasminogen activator gene expression by tumor promoters. 386 68


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