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 production of proteolytic enzymes by osteoblasts is considered important for initiating osteoclastic bone resorption. Using the established cell line NY as an example of osteoblast-like cells, the effect of intracellular cyclic AMP (cAMP) and protein kinase C (PKC) on plasminogen activator secretion and its specific binding to the cells were investigated. HT-1080 cells were used as the control. NY cells predominantly secrete single-chain urokinase-type plasminogen activator (scu-PA) and some two-chain u-PA. Both scu-PA and u-PA were present in the cell surface and cell lysate of NY cells, and their distribution in HT-1080 cells was quite similar to that of NY cells. Exposing cells to phorbol myristate acetate (PMA) or dibutyryl cyclic AMP (db cAMP) enhanced the secretion of scu-PA and two-chain u-PA, whereas 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H7) decreased scu-PA secretion, indicating that it is enhanced by protein kinase C (PKC) as well as by cAMP in NY cells. On the other hand, in HT-1080 cells, PMA decreased the level of two-chain u-PA secretion into the conditioned medium. The binding assay of 125I-DFP-u-PA to NY cells revealed the presence of a single class of binding sites with a Kd of 2.23 nM and Bmax of 0.82 x 10(6) binding sites/cell. PMA however, altered neither the Kd nor the Bmax. Dibutyryl cAMP increased the Bmax 1.9 fold. Thus, NY cells secrete u-PA and express specific binding sites on the cell surface, which are modulated by cAMP and PKC.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Regulation of scu-PA secretion and u-PA receptor expression in osteoblast-like cells. 816 59

Immediate and sustained signal transduction is involved in mediating phorbol ester-induced changes in growth and differentiation. Activation of protein kinase C (PKC) is the initial step in phorbol ester-induced signal transduction. By virtue of preferential down-regulation of individual isoforms and generation of proteolytically derived kinase activities, the signal transduced by sustained activation of this pathway may differ substantially from that generated initially upon application of the phorbol ester. To examine the effect of chronic phorbol ester-induced activation of this pathway, the relationship between PKC activity/content and AP-1 binding activity and gene expression was studied in the U937 cell. Phorbol ester-induced differentiation of the U937 cell into a monocyte/macrophage-like cell requires sustained activation of the PKC pathway. AP-1 binding activity was enhanced by 12-O-tetradecanoylphorbol-13-acetate (TPA) and in a temporally dependent manner, with conversion of a high to low mobility band shift occurring after a 12-h exposure to TPA. After a 72-h exposure, AP-1 binding activity was maximally increased by 1 nM TPA and remained elevated to a similar degree even after treatment with 600 nM TPA. Enhanced AP-1 binding activity was dependent upon continuous exposure to TPA and was not secondary to differentiation. A 72-h treatment with one nM TPA maximally increased expression of c-jun, krox-24, and jun-B mRNA transcripts. Exposure to higher TPA concentrations decreased the content of these transcripts. Maximal expression of collagenase and plasminogen activator receptor transcripts required exposure to much higher TPA concentrations (100 nM).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of chronic phorbol ester treatment on protein kinase C activity, content, and gene expression in the human monoblastoid U937 cell. 818 Jan 29

Heparin inhibits the migration and proliferation of arterial smooth muscle cells and modifies the extracellular matrix. These effects may be the result of heparin's effects on proteinases that degrade the matrix. We have previously reported that heparin inhibits the induction of tissue-type plasminogen activator and interstitial collagenase mRNA. We have investigated the possibility that heparin affects other members of the matrix metalloproteinase family. Phorbol ester increased the levels of mRNA of collagenase, 92-kD gelatinase and stromelysin as well as the synthesis of these proteins. These effects were inhibited by heparin, but not by other glycosaminoglycans, in a dose-dependent manner. The induction of these matrix metalloproteinases was also inhibited by staurosporine and pretreatment with phorbol ester indicating the involvement of the protein kinase C pathway. In contrast, the 72-kD gelatinase was expressed constitutively and was not affected by phorbol ester or heparin. Tissue inhibitor of metalloproteinase-1 was expressed constitutively and was slightly increased by phorbol ester. It was not affected by heparin. Thus, heparin inhibits the production of four proteinases (tissue plasminogen activator, collagenase, stromelysin and 92-kD gelatinase) that form an interdependent system capable of degrading all the major components of the extracellular matrix.
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PMID:Heparin inhibits the induction of three matrix metalloproteinases (stromelysin, 92-kD gelatinase, and collagenase) in primate arterial smooth muscle cells. 818 30

Recent reports indicate that protein kinase C may play an important role in the process of gonadotropin-induced ovulation in the ovary. In the present study, we examined the effect of the protein kinase C inhibitor, 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H-7), on LH-stimulated tissue type plasminogen activator (tPA) activity in cultured rat granulosa cells. Granulosa cells were obtained from PMSG-treated rats and cultured for 48 h in the presence or absence of H-7 (0.1-60 microM) with ovine LH (30 ng/ml), phorbol 12-myristate 13-acetate (10(-8) M), phorbol 12,13-dibutyrate (10(-8) M), or (Bu)2cAMP (5 mM). After culture, tPA activity in the conditioned medium was assayed by fibrin autography technique after sodium dodecyl sulfate-polyacrylamide gel electrophoresis. H-7 (1.0-60 microM) inhibited LH-, phorbol 12-myristate 13-acetate-, or phorbol 12,13-dibutyrate-stimulated tPA activity dose dependently, and each ID50 was approximately 8 microM. However, H-7 did not inhibit (Bu)2cAMP-stimulated tPA activity. To investigate the effect of H-7 on the ovulatory process in vivo, PMSG-treated immature rats were injected with H-7 (10(-9)-10(-3) M) into the unilateral ovarian bursa just before human CG administration. After 24 h, the number of oocyte-cumulus complexes in the oviduct was counted. H-7 suppressed the number of oocytes released from treated ovaries dose-dependently. The light microscopical observation revealed that ovaries treated with H-7 contained a few corpora lutea and many large unruptured follicles. The results of the present study suggest that the suppressive effects of H-7 on human CG-induced ovulation might be partly due to the inhibition of tPA secretion by rat granulosa cells via protein kinase C inhibition.
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PMID:Possible involvement of protein kinase C in gonadotropin-induced ovulation in the rat ovary. 840 62

Previous studies have shown that high glucose levels and diabetes induce an elevation in protein kinase C (PKC) activity in vascular cells and tissues susceptible to diabetic complications. In addition, PKC activation has been shown to modulate vascular cell growth, permeability, and gene expression, processes thought to be involved in the development of vascular complications. Using two in vivo model systems, we have identified a novel inhibitor of diabetic vascular dysfunction, LY290181. LY290181 prevented glucose-induced increases in blood flow and permeability in rat granulation tissue and corresponding vascular changes in the retina, sciatic nerve, and aorta of diabetic rats. Tested for its ability to inhibit PKC-regulated processes, LY290181 inhibited phorbol ester-stimulated plasminogen activator activity in a dose-dependent manner in bovine retinal endothelial cells and in human dermal fibroblasts. In addition, LY290181 inhibited phorbol ester-stimulated activation of the porcine urokinase plasminogen activator (uPA) promoter (-4600/+398) linked to the chloramphenicol acetyltransferase (CAT) reporter gene (p4660CAT). More detailed analysis of the uPA promoter revealed that LY290181 inhibited phorbol ester-stimulated activation of the uPA phorbol response element (-2458/-2349) located upstream of the thymidine kinase promoter (puPATKCAT). LY290181 appears to inhibit uPA promoter activation by blocking phorbol ester-stimulated binding of nuclear proteins to the uPA PEA3/12-0-tetradecanoylphorbol 13-acetate responsive element (TRE). These results suggest that LY290181 may inhibit diabetes-induced vascular dysfunction by inhibiting transcription factor binding to specific PKC-regulated genes involved in vascular function.
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PMID:LY290181, an inhibitor of diabetes-induced vascular dysfunction, blocks protein kinase C-stimulated transcriptional activation through inhibition of transcription factor binding to a phorbol response element. 862 Oct 17

Neuronal cells in primary culture from the hypothalamus-brain stem areas of normotensive [Wistar-Kyoto (WKY)] and spontaneously hypertensive (SH) rat brains have been used in the present study to investigate an interaction between the brain renin-angiotensin II system and the plasminogen activator system. This is an attempt to further our understanding of the role of brain Ang II in the control of neuronal development and differentiation through its regulation of the extracellular matrix. Ang II caused a 10-fold stimulation of plasminogen activator inhibitor-1 (PAI-1) messenger RNA (mRNA) in WKY rat brain neuronal cultures. The stimulation was mediated by the AT1 receptor subtype and was accompanied by an increase in PAI-1 gene transcription and the synthesis of cellular PAI-1 protein. The stimulation involved activation of protein kinase C, and alterations in the intracellular Ca2+ pool caused a significant inhibition of Ang II stimulation of PAI mRNA. Ang II stimulation of PAI-1 mRNA succeeded its action on c-fos mRNA and was attenuated by c-fos antisense oligonucleotide. Although PAI-1 gene expression was also stimulated by Ang II in neuronal cultures of SH rat brain, two differences between WKY and SH rat brain neurons were observed: 1) the level of Ang II stimulation in SH rat neurons was 50% of that in WKY rat neurons; and 2) Ang II stimulation of c-fos was 2.4-fold higher in SH neurons than in WKY neurons, but c-fos antisense oligonucleotide did not attenuate the stimulatory action of Ang II on PAI-1 mRNA in SH neurons. These observations suggest that the changes in the Ang II-mediated signaling pathways and/or the regulatory region(s) of the PAI-1 gene may contribute to the differential actions of Ang II in WKY and SH rat brain neurons.
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PMID:Angiotensin II regulation of plasminogen activator inhibitor-1 gene expression in neurons of normotensive and spontaneously hypertensive rat brains. 864 Dec 4

Retinoic acid (RA) induced differentiation of F9 embryonal carcinoma cells is accompanied by changes in cellular responsiveness to extracellular signals. These changes include an increase in the AP1 transcription factor that is associated with the expression of differentiation markers (e.g., cytokeratin 18 and plasminogen activator). Since AP1 activity is a target for protein kinase C (PKC)-regulated changes in gene expression, we have examined the effects of RA on the expression and function of the PKC isozymes. F9 stem cells express PKC beta, delta, epsilon, and zeta. RA-induced differentiation to primitive endoderm led to a transition from PKC beta to PKC alpha expression. Additional treatment with dibutyryl cyclic AMP (dbcAMP), required for terminal differentiation into parietal endoderm, further increased PKC alpha expression and total PKC activity. RA and dbcAMP had negligible effects on the expression of PKC delta, epsilon, and zeta. The PKC beta to PKC alpha transition was specific for parietal endoderm; aggregation of RA-treated F9 cells induced visceral endoderm differentiation with elevated expression of PKC beta. The PKC activation with phorbol esters induced the expression of c-fos, c-jun, and junB proto-oncogenes in F9 stem cells. In the presence of either RA or RA and dbcAMP, phorbol ester treatment enhanced the expression of type IV collagen, a parietal endoderm marker. It also increased the expression of c-jun gene but not c-fos. The specific involvement of PKC beta in c-fos induction and PKC alpha in type IV collagen induction was confirmed in each PKC isozyme-transfected F9 cells. Together, our data demonstrate that the RA-induced (and dbcAMP-induced) changes in conventional PKC expression alters gene expression during parietal endoderm formation.
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PMID:Retinoic acid-induced transition from protein kinase C beta to protein kinase C alpha in differentiated F9 cells: correlation with altered regulation of proto-oncogene expression by phorbol esters. 873 69

The fibrinolytic activity in endothelial cells was regulated by balance of plasminogen activators and plasminogen activator inhibitors. Plasmin can specifically inhibit the biosynthesis of tissue-type plasminogen activator (t-PA), but not plasminogen activator inhibitor, type 1 (PAI-1) in endothelial cells. The PAI activity in the conditioned medium of endothelial cells was low and remained constant in 24 hours. However, the PAI activity in the conditioned medium of the plasmin-pretreated cells increased linearly in 24 hours. Pretreatment with protein kinase C inhibitors, H-7 or staurosporine, partially suppressed the PAI activity induced by plasmin. Pretreatment of endothelial cells with a G-protein inhibitor pertussis toxin resulted in an inhibition of the plasmin-induced PAI activity. The phospholipase A2 inhibitor mepacrine specifically eliminated the effect of plasmin stimulation on PAI activity. Cyclooxygenase and lipoxygenase inhibitors also partially inhibited the plasmin-stimulated PAI activity in endothelial cells. All these inhibitors did not affect the biosynthesis of the PAI-1 antigen in the presence or absence of plasmin. The results indicate that plasmin increased the PAI activity of endothelial cells via pathways in which protein kinase C, G protein, and phospholipase A2 may be involved.
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PMID:Regulation of plasminogen activator inhibitor activity by plasmin in endothelial cells. 874 22

New therapies of cerebral vasospasm aim to prevent the effects of subarachnoid haemorrhage. These effects result in red blood cell haemolysis and release of oxyhaemoglobin, free radicals formation and lipid peroxidations, imbalance in endothelial modulation of vasomotor tone and activation of the complement system. Low doses of fibrinolytic agents administered intrathecally accelerate the fibrinolysis of the clot and reduce the oxyhaemoglobin release. The tissue-type plasminogen activator has proven to be effective in preventing vasospasm, but the modalities of this therapy remain to be defined. Free radical reactions may be inhibited by free radical scavengers and inhibitors of lipid peroxidations. Tirilazad is a potent inhibitor of lipid peroxidations, which improves the patients' outcome and has gone to Phase III human trials. Superoxide dismutase and tropolone derivatives are currently evaluated in animal models. Vasomotor tone can be modified in experimental models either by blocking endothelin receptors (BQ-123), or by facilitating the release and enhancing the effect of nitric oxide using protein kinase C inhibitors, drugs that increase intracellular calcium (cyclopiazonic acid, LP-805) and free radicals scavengers (superoxide dismutase). These possibilities are being investigated. Finally, preliminary studies have demonstrated the efficacy of FUT-175, an inhibitor of the complement system, in the prevention of vasospasm. In the next years, these new therapies have to be validated by prospective and randomized clinical trials to propose guidelines for the management of patients at risk of cerebral vasospasm after aneurysmal rupture.
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PMID:[Pharmacological therapeutic prospects of cerebral vasospasm]. 875 98

In order to reach the sites of inflammation, lymphocytes leave the bloodstream and migrate into peripheral tissues, in a process involving integrin-mediated adhesion to the vascular endothelium, followed by transmigration across the endothelial barrier and through the underlying interstitial matrix. We have investigated the role of the plasminogen activator/plasmin system in normal T cell migration. Receptors for urokinase plasminogen activator (uPAR) were not expressed in resting T lymphocytes, but could be efficiently induced at the mRNA and protein level by coclustering of the antigen receptor complex and beta1 or beta2 integrins, through a signalling pathway involving both protein kinase C activation and an increase in intracellular cyclic AMP. Catalytic activation of plasminogen by uPAR-expressing T cells promoted their migration through an extracellular matrix in vitro. Plasmin-induced invasion was inhibited by plasmin-and urokinase inhibitors and by anti-uPAR antibodies. Finally, cytofluorimetric and immunohistochemical analysis of primary human tumor specimens showed the presence of uPAR positive infiltrating T cells in vivo. Collectively, these findings suggest that plasminogen activation may play a role in lymphocyte migration in vivo, and that integrin-dependent expression of membrane-associated endopeptidases could represent an additional step in the regulated process of leukocyte transmigration.
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PMID:Integrin-dependent induction of functional urokinase receptors in primary T lymphocytes. 878 76


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