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)

The potential contribution of serine/threonine-specific protein phosphatases in the transcriptional regulation of plasminogen activator and plasminogen activator inhibitor gene expression was explored in human HT-1080 fibrosarcoma and U-937 monocyte-like cells using okadaic acid, a potent and specific inhibitor of phosphatases 1 and 2A (PP1 and PP2A). In both cell types okadaic acid induced plasminogen activator type 2 (PAI-2) gene transcription and mRNA and potentiated induction mediated by phorbol-12-myristate-13-acetate and tumor necrosis factor. Okadaic acid-mediated induction of PAI-2 was inhibited by 8-bromo-cAMP in HT-1080 cells but not in U-937 cells. Okadaic acid had opposite effects on urokinase (u-PA) gene expression in the two cell lines; u-PA mRNA and gene transcription was suppressed in HT-1080 cells but transiently induced in U-937 cells. Tissue-type PA (t-PA) mRNA, although undetectable in U-937 cells, was also suppressed by okadaic acid in HT-1080 cells. This effect was selective, as constitutive and phorbol-12-myristate-13-acetate-mediated expression of plasminogen activator inhibitor type 1 mRNA was not modulated by okadaic acid in either cell type. These results indicate that PP1 and PP2A protein phosphatases are involved in signal transduction pathways modulating PAI-2, u-PA, and t-PA, and furthermore, that okadaic acid interaction with the protein kinase C and A pathways are gene- and cell type-specific.
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PMID:Cell- and gene-specific interactions between signal transduction pathways revealed by okadaic acid. Studies on the plasminogen activating system. 131 13

We investigated the effect of phorbol myristate acetate (PMA), dexamethasone (Dex) and reagents which raise intracellular cyclic AMP, on the production of plasminogen activator inhibitor type-2 (PAI-2) in human promyelocytic leukemia cell line, PL-21 and on the production of urinary type plasminogen activator (u-PA) in human pre-B cell lymphoma cell line, RC-K8. Cells were cultured in fetal bovine serum free RPMI-1640 containing the test-reagents for 48 hours. PAI-2 and u-PA antigens were measured by ELISA kits. PMA, an activator of protein kinase C (PKC), markedly increased both PAI-2 and u-PA production in each cell line. On the other hand, cAMP increased PAI-2 production in PL-21 cells, but decreased u-PA synthesis in RC-K8 cells. Similar to cAMP, Dex also increased PAI-2 production but decreased u-PA production in RC-K8 cells. Moreover, PMA and cAMP synergistically increased the PAI-2 production. This was verified by Western blot, using a monoclonal antibody against the PAI-2. These two cell lines are, therefore, useful for clarifying the role of A kinase and C kinase on PAI-2 and u-PA synthesis in human hemopoietic cells.
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PMID:[Effect of cyclic AMP and phorbol ester on PAI-2 synthesis in a leukemic cell line PL-21 and on u-PA secretion in a pre-B cell lymphoma cell line RC-K8]. 131 13

Structural requirements for binding to the bone calcitonin (CT) receptor and for CT bioactivity both in vitro and in vivo were assessed for a series of N-terminally truncated, N alpha-acetylated, fragments of salmon calcitonin (sCT). Sequential deletion of amino acid residues from the amino-terminus of [Ala7]sCT-(2-32) peptide amide first led to partial agonists and, upon deletion of residues 1 to 7, to a high affinity antagonist, N alpha-acetyl-sCT-(8-32)-NH2. The presence of two separate domains within the sCT sequence is proposed: (I) a binding domain comprising residues 9-32 and (II) an activation domain requiring residues 3 to 6. N alpha-acetyl-sCT-(8-32)-NH2, in several bioassays including plasminogen activator release from LLC-PK1 cells (pA2 = 7.31), cAMP production in UMR-106-06 cells (pA2 = 7.81) and in the fetal rat long bone resorption assay showed potent antagonistic properties.
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PMID:N-terminal truncation of salmon calcitonin leads to calcitonin antagonists. Structure activity relationship of N-terminally truncated salmon calcitonin fragments in vitro and in vivo. 132 97

Several hormones and inducers of intracellular messengers, known to affect plasminogen-activator (PA) production in other systems, were investigated for putative effects on bovine embryos. Day 8 embryos were cultured for 5 days in a humidified atmosphere of 5% CO2 in air at 37 degrees C in media containing different concentrations of progesterone, oestradiol, dexamethasone, retinoic acid, dibutyryl cyclic AMP (dbcAMP) and phorbol myristate acetate (PMA). At intervals of 24 h, the medium was recovered for PA analysis and overall embryonic diameter was measured. While none of the hormones and agents tested affected PA production (P > 0.05), dimethyl sulfoxide, which was used to dissolve PMA, inhibited PA production during the first 72 h of culture (P < 0.05). PA production was affected by duration of culture (P < 0.05). Concentrations of plasminogen activator in the media were low during the first 48 h, had increased after 72 and 96 h in culture, and either remained high or decreased slightly toward the end of the culture period. With the exceptions of dbcAMP and PMA, the hormones tested in this study did not affect embryonic size. Dibutyryl cAMP caused a progressive decrease in embryonic diameter. PMA resulted in embryo death at high concentrations but at lower concentrations it enhanced overall embryonic diameter throughout the time of culture (P < 0.05). These results suggest that cultured bovine embryos produce PA in a fixed, time-dependent manner, independent of exogenous hormonal regulation.
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PMID:Lack of effect of hormones and inducers of intracellular messengers on plasminogen activator production by bovine embryos in vitro. 133 38

Human mesangial cells in culture synthesize and secrete plasminogen activator inhibitor 1 (PAI-1) and tissue-type plasminogen activator (t-PA). Phorbol myristate acetate (PMA), a known activator of protein kinase C, induces a three to four-fold increase in t-PA and PAI-1 release over a period of 24 h, whereas cell-associated t-PA and PAI-1 levels remain relatively stable. A similar effect is obtained with oleylacetyl glycerol, a more physiologic protein kinase C activator. The effect of PMA is suppressed in the presence of H7, an inhibitor of cellular protein kinases, and by cycloheximide and actinomycin D, indicating a requirement for de novo protein and RNA synthesis, respectively. Northern blot analysis of PMA-treated cells reveals a rapid and transient increase in PAI-1 mRNA reaching a maximum after 4-8 h, whereas increase in t-PA mRNA levels requires 24 h. Activation of protein kinase A by addition of 8-bromocyclic AMP (8-bromo cAMP) has no significant effect on PAI-1 release but inhibits the PMA-mediated increases in PAI-1 antigen and mRNA. Addition of 8-bromo cAMP alone does not affect t-PA release. When added to PMA-stimulated cells, 8-bromo cAMP inhibits t-PA release in a dose-dependent manner, but causes a superinduction of t-PA mRNA. 8-bromo cAMP also induces a decrease in PMA-stimulated intracellular t-PA release. Similar inhibition is observed after stimulation of endogenous adenylate cyclase with prostaglandin E1 or isoproterenol. This indicates that protein kinase A activation may inhibit PMA-stimulated t-PA release via a post-transcriptional effect, e.g. inhibition of protein synthesis or activation of protein degradation. In conclusion, hormones or mediators which activate protein kinase C can stimulate t-PA and PAI-1 synthesis in human mesangial cells. Protein kinase A activation has no effect on the basal release of PAI-1 and t-PA by human mesangial cells, and, in contrast to endothelial cells, it inhibits both PMA-stimulated PAI-1 and t-PA releases. This cell-specific regulation of t-PA and PAI-1 seems to be mediated by differential transcriptional and post transcriptional mechanisms.
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PMID:Cell-specific regulation of plasminogen activator inhibitor 1 and tissue type plasminogen activator release by human kidney mesangial cells. 155 43

Transfection of mouse Y1 adrenal tumor cells with DNA encoding mutant type I regulatory subunit generated stable transformants in which the basal activity of cAMP-dependent protein kinase was repressed. As expected, steroidogenesis in these kinase-deficient cells was no longer stimulated by corticotropin or cAMP analogues, and the expression of three cAMP-regulated genes (ornithine decarboxylase, urokinase-type plasminogen activator, and P450 side-chain cleavage) could no longer be induced. However, in addition to the loss of hormone responsiveness, the basal level of steroidogenesis and the constitutive expression of these cAMP-inducible genes was also repressed in kinase-defective mutant clones. To verify that functional cA-PK would revert this repressed phenotype, we transfected a cA-PK defective subclone of Y1 cells, Kin 8, with DNA encoding the C alpha and C beta subunits of cAMP-dependent protein kinase. Basal levels of steroid production were restored to normal in stable transformants, and the elevation of kinase activity following induction of the C-subunit expression vectors elicited a steroidogenic response. Gene transcription was also shown to be regulated by either C alpha or C beta as measured by the induction of plasminogen activator and ornithine decarboxylase mRNA levels and transcription rates. The dominant role played by cAMP-dependent protein kinase in these adrenal cells was demonstrated by experiments showing the regulation of ornithine decarboxylase gene expression by protein kinase C requires basal cAMP-dependent protein kinase activity.
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PMID:Cyclic AMP-dependent protein kinase controls basal gene activity and steroidogenesis in Y1 adrenal tumor cells. 156 25

The effects of interleukin-1 (IL-1), forskolin, and tumor necrosis factor beta (TNF-beta) on tissue plasminogen activator (t-PA) activity were studied in the human osteoblastic osteosarcoma cell line, G292. t-PA activity was measured in the cell media using the chromogenic substrate, S-2251. After a 24 hour incubation period, IL-1 increased t-PA in a dose-dependent manner. The effect of IL-1 at 10.0 U/ml was partially inhibited in the presence of indomethacin. Forskolin (1.0 microM) increased t-PA activity after 24 hours with the effects of combined treatment of IL-1 (1.0 U/ml, 10.0 U/ml) and forskolin being apparently additive in nature. TNF-beta (10(-8)-10(-7)M) also produced increased t-PA activity in the cell media after a 24 hour incubation period. These results suggest that the cytokines, IL-1 and TNF-beta, can increase t-PA activity in G292 cells and that there is both a cAMP-dependent as well as a cAMP-independent pathway involved in the regulation of this osteoblastic cell function.
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PMID:Effects of interleukin-1, tumor necrosis factor -beta, and forskolin on tissue plasminogen activator activity in human osteoblastic osteosarcoma cells. 157 31

Adenosine 3',5'-cyclic monophosphate (cAMP) elevation in cultured rat mesangial cells causes urokinase-dependent adhesion loss, stress-fiber fragmentation, and shape change. Thrombin cleaves single-chain urokinase (scu-PA), causing its inactivation, but not two-chain u-PA [tcu-plasminogen activator (PA)] or tissue-type PA. We tested the ability of thrombin to inhibit the effects of cAMP elevation in mesangial cells and inactivate cell-associated scu-PA. In an assay of trypsin-sensitive adhesion, 65.9% of control cells and 5.5% of cells treated with isoproterenol + methylisobutylxanthine (IM) remained adherent. In the presence of 0.01, 0.1, 1.0, and 10.0 unit/ml thrombin, 20.9, 46.6, 50.4, and 53.3%, respectively, of IM-treated cells remained attached. Thrombin also inhibited stress-fiber fragmentation and shape change. The effects of thrombin were blocked by hirudin or antithrombin III plus heparin. Direct zymography in gels containing gelatin and plasminogen revealed loss of a closely spaced pair of PA bands with thrombin treatment (1.0 unit/ml). Hirudin blocked the loss. alpha-Thrombin inactivated by diisopropyl fluorophosphate neither inhibited shape change nor caused loss of the PA bands; however, gamma-thrombin was nearly as active as native alpha-thrombin in both regards. Pretreatment of the cells with as little as 1.0 unit/ml thrombin for 1.0 min caused marked inhibition of shape change and near total loss of the slower migrating u-PA band (of the doublet). The faster migrating band was inhibited less. The results indicate that the slower migrating band represents scu-PA; the nature of the faster migrating band is less certain. Thrombin reversed the adhesion loss and shape change caused by 8-(4-chlorophenylthio)-cAMP and MIX. Thus physiological concentrations of thrombin rapidly inactivate mesangial cell scu-PA and inhibit and reverse cAMP-stimulated adhesion loss and shape change.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Regulation of mesangial cell adhesion and shape by thrombin. 165 8

Epidermal growth factor (EGF) induces tissue-type plasminogen activator (t-PA) biosynthesis in HeLa cells. Based on nuclear run-on transcription assays, t-PA biosynthesis is modulated by EGF on the level of gene transcription. The effect of EGF is slow, requiring 4-8 h to induce t-PA gene transcription and up to 24 h to induce t-PA mRNA and antigen secretion. An additive response is observed when cells are treated with both phorbol 12-myristate 13-acetate and EGF, suggesting that the two pathways converge and act independently to implement their respective effects. cAMP has previously been shown to potentiate phorbol 12-myristate 13-acetate-mediated induction of t-PA biosynthesis in HeLa cells and in human endothelial cells. Akin to this observation, cAMP also potentiates the EGF-mediated increase in t-PA mRNA. Maximal levels of t-PA mRNA is seen in the presence of all three agonists. The regulation of t-PA by EGF alone and in the presence of either PMA or cAMP is consistent with a role of t-PA during growth and development, and further indicates a functional interplay between protein kinase C-, tyrosine kinase, - and cAMP-dependent signal transduction pathways during regulation of t-PA gene expression.
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PMID:Regulation of human tissue-type plasminogen activator gene transcription by epidermal growth factor and 3',5'-cyclic adenosine monophosphate. 166 1

Although the existence of plasminogen activator (PA) activity and the factors that regulate it in ovarian granulosa cells of both mammalian and avian species have been extensively documented, very little information has been generated concerning the control of PA activity in the adjacent thecal layer. This study was conducted to evaluate the effects of several physiological and pharmacological agents on PA activity in dispersed cells from the thecal layer of the largest preovulatory follicle in the hen ovary 17-16 h before ovulation. LH (50 and 100 ng) in the presence of 3-isobutyl-1-methylxanthine (0.01 mM) stimulated an approximate 25% increase in cell-associated PA activity, possibly via elevated levels of cAMP. Prostaglandin E1 and E2 (PGE1 and PGE2; 0.1 and 1 microM), but not PGI2 or PGF2 alpha (1 microM), enhanced PA activity and cAMP formation, effects that were potentiated by 0.01 mM 3-isobutyl-1-methylxanthine. Activation of Gs with cholera toxin (0.01-10 ng/tube) or adenylyl cyclase with forskolin (0.01-10 microM) stimulated cAMP formation and PA activity in a dose-dependent manner. Exposure of cells to the cAMP analog 8-bromo-cAMP (0.1-5 mM) caused similar increases in thecal cell PA activity. Incubation of cells with phorbol 12-myristate 13-acetate (PMA; 3.2-162 nM), an agonist known to activate protein kinase-C, resulted in a dose-dependent increase in PA activity. However, an equimolar concentration of phorbol 13-monoacetate (162 nM), an inactive analog of PMA that does not activate protein kinase-C, was without effect. Coincubation of cells with forskolin (1 microM) and PMA (32 nM) resulted in a synergistic stimulation of secreted PA activity, apparently via an enhancement of adenylyl cyclase activity. Treatment of cells with the calcium ionophore A23187 (0.01-1 microM) suppressed basal PA activity. However, PA activity stimulated by PMA (32 nM) was synergistically increased after coincubation with a 0.05-microM concentration of A23187, but was inhibited at doses of 0.5 and 1 microM. Taken collectively, the data indicate that PA activity is present in the thecal layer of the largest preovulatory follicle in the ovary of the domestic hen. Furthermore, several endocrine factors (i.e. LH and PGs) were found to stimulate PA activity, possibly via both the adenylyl cyclase-cAMP-protein kinase-A and phosphoinositide-protein kinase-C pathways. In light of these findings, we propose that the preovulatory increase in PGs and LH activates PA in the thecal layer of the largest preovulatory follicle, resulting in proteolytic degradation of the follicular connective tissue and, ultimately, ovulation.
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PMID:Control of plasminogen activator activity in the thecal layer of the largest preovulatory follicle in the hen ovary. 169 Jun 37


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