UNIPROT:P00750 - FACTA Search

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Query: UNIPROT:P00750 (PLA)
16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Two plasminogen activators (PAs): tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA), as well as the type-1 plasminogen activator inhibitor (PAI-1) are synthesized and secreted by rat astrocytes. Preliminary studies suggest that PA activity plays a role in astrocyte development and differentiation. We have examined the regulation of the PA system by the cAMP-dependent protein kinase (PKA) and protein kinase C (PKC) in purified rat astrocyte cultures. PKA activity was increased by exposing cultured astrocytes to forskolin or dibutyryl cyclic AMP, whereas PKC activity was stimulated with phorbol-12-myristate 13-acetate (PMA). Activation of both second-messenger pathways produced a time- and dose-dependent increase in the total PA activity. However, based on SDS-PAGE/zymography we found that forskolin increased t-PA activity and reduced u-PA activity, whereas PMA treatment caused a significant increase in u-PA activity without altering t-PA activity. Reverse zymography analysis revealed that astrocyte PAI-1 activity is decreased by forskolin and increased by PMA. Together, these results demonstrate that the components of the PA system in rat astrocytes are independently and reciprocally regulated by PKA and PKC. Our findings raise the possibility that the plasminogen activator system could be involved in some of the actions of growth factors and/or neuromodulators that modulate PKC or PKA in astrocytes.
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PMID:Regulation of plasminogen activators and type-1 plasminogen activator inhibitor by cyclic AMP and phorbol ester in rat astrocytes. 133 67

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 sequence of events within the ovary during the process of ovulation discussed in this review is schematically represented in Fig. 1. It is obvious that LH, perhaps with some contribution from FSH, is the normal physiological trigger for the ovulatory sequence of events, and it appears from the available information that the effects of LH are mainly mediated via adenylate cyclase and increased cAMP levels. The cAMP in turn, via cAMP-dependent protein kinase, influences at least three distinct steps in the ovulatory process which seem to be of crucial importance, namely 1) the stimulation of steroidogenesis; 2) the stimulation of cyclooxygenase/lipooxygenase leading to increased prostaglandin/leukotriene synthesis; and 3) the stimulation of plasminogen activator which catalyzes the conversion of plasminogen to plasmin. A fourth crucial step in the ovulatory mechanism is the LH-induced increase in latent collagenase, but it remains to be determined if this step is mediated via cAMP. Concomitant with the increase in latent collagenase, there also appears to be an LH-dependent increase in collagenase inhibitors. The latent collagenase is then activated, and it appears that leukotrienes and prostaglandins, as well as plasmin, may be involved in this process. The active collagenase causes a digestion of the collagen in the follicle wall, and plasmin, as well as possibly other proteolytic enzymes such as proteoglycanases, may cause a further dissociation of the follicular wall. These processes of digestion of collagen and dissociation of the collagen fibers result in an opening in the follicular wall with the formation of the stigma and rupture. While the weakening of the follicular wall takes place throughout the entire wall, rupture remains for the most part a localized process at the apex of the follicle. This localization of the rupture may be explained on the basis of mechanical factors operating when the follicle wall thins and weakens. While it is clear that prostaglandins and leukotrienes can influence smooth muscle by causing contractions and that these compounds can cause vascular changes such as increased permeability, vasodilation, and vasoconstriction, it is not clear what the exact role of these latter processes are in ovulation. It appears that progesterone and not estrogen play an important role in the mechanism of LH-induced follicular rupture, but the locus of action of progesterone and its mechanism of action remains to be determined.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Mechanism of mammalian ovulation. 255 97

The sequence of ovarian events during the process of ovulation discussed in this review is schematically represented in Figure 1. It is obvious that LH, perhaps with some contribution from FSH, is the normal physiological trigger for the ovulatory sequence of events and it appears from the available information that LH's effects are mainly mediated via adenylate cyclase and increased cAMP. The cAMP in turn, via cAMP-dependent protein kinase, influences at least three distinct steps in the ovulatory process which seem to be of crucial importance, namely 1) the stimulation of steroidogenesis; 2) the stimulation of cyclooxygenase/lipooxygenase leading to increased prostaglandin/leukotriene synthesis; and 3) the stimulation of plasminogen activator which catalyzes the conversion of plasminogen to plasmin. A fourth crucial step in the ovulatory mechanism is the LH-induced increase in latent collagenase, but it remains to be determined if this step is mediated via cAMP. Concomitant with the increase in latent collagenase, there also appears to be an LH-dependent increase in collagenase inhibitors. The latent collagenase is then activated and it appears that leukotrienes and prostaglandins as well as plasmin may be involved in this process. The active collagenase causes a digestion of the collagen in the follicle wall. Plasmin as well as possibly other proteolytic enzymes such as proteoglycanases (Too et al., 1984) may cause a further dissociation of the follicular wall. These processes of digestion of collagen and dissociation of the collagen fibers result in an opening in the follicular wall with the formation of the stigma and rupture. While the weakening of the follicular wall takes place throughout the entire wall, rupture remains for the most part a localized process at the apex of the follicle. This localization of the rupture may be explained on the basis of mechanical factors operating when the follicle wall thins and weakens (Rodbard, 1984). While it is clear that prostaglandins and leukotrienes can influence smooth muscle by causing contractions and that these compounds can cause vascular changes such as increased permeability, vasodilatation and vasoconstriction, it is not clear what the exact role of these latter processes are in ovulation. It appears that progesterone and not estrogen play an important role in the mechanism of LH induced follicular rupture, but the locus of action of progesterone and its mechanism of action remains to be determined.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Mechanism of mammalian ovulation. 265 83

Plasminogen activators are highly selective proteases that activate the proenzyme plasminogen to the general protease, plasmin. We studied a porcine kidney cell line, originally isolated as a high producer of plasminogen activator, in which activities of cellular adenylate cyclase and cAMP-dependent protein kinase are increased in response to calcitonin. We found that salmon calcitonin, in the concentration range 0.03-300 nM, increased plasminogen activator production up to approximately 1,000-fold and concurrently inhibited cell multiplication; both of these effects were reversible. Human calcitonin was approximately 0.01 times as potent as salmon calcitonin, corresponding to potency differences observed in other biological systems. Plasminogen activator production was also stimulated by other agents that raise cellular cAMP levels such as cholera toxin, phosphodiesterase inhibitors, and vasopressin, but not to the same extent as by calcitonins. The rapidity and sensitivity of the plasminogen activator determination and other cellular responses may make it possible in the future to use this cell stain in a convenient bioassay for calcitonins and their analogues.
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PMID:Calcitonin stimulates plasminogen activator in porcine renal tubular cells: LLC-PK1. 627 91

Retinoic acid induces the differentiation of many murine teratocarcinoma stem cell lines. To elucidate the molecular mechanism of action of retinoic acid, we have selected a series of mutants which exhibit altered differentiation responses to retinoic acid. All of the mutants display abnormal morphology following addition of 5 X 10(-7) M retinoic acid (RA) and dibutyryl cAMP. In addition, none of the mutants are resistant to the cytotoxic effects of higher concentrations of retinoic acid (greater than 75 microM). After the addition of retinoic acid, one mutant, RA-3-10, does not differentiate by any of the biochemical criteria we have used; this mutant also possesses less than 5% of the wild type level of cellular retinoic acid binding protein (CRABP). Other mutants, such as RA-3-3, RA-3-4, and RA-5-1, contain the same amount of CRABP as wild type F9 cells. However, the mutants RA-3-3 and RA-3-4 exhibit lower levels of plasminogen activator activity, and RA-3-4 also exhibits only 10-20% of the wild type synthesis and secretion of laminin and collagen IV following treatment with RA. After RA treatment of the mutant RA-5-1, laminin and collagen IV are synthesized and secreted at reduced rates relative to wild type cells, and the secreted collagen IV has a lower molecular weight than that of wild type; this suggests that RA-5-1 cells have a mutation in one of the enzymes responsible for post-translational modification of collagen IV. None of the mutants tested exhibits alterations in either cytosolic or membrane bound cAMP-dependent protein kinase activity. These studies provide genetic evidence that the CRABP is required for the differentiation of F9 teratocarcinoma stem cells by retinoic acid. However, even in the presence of CRABP, other types of alterations, such as synthesis of collagen IV with an abnormal molecular weight, appear to cause alterations in the differentiation response of cells to retinoic acid.
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PMID:Selection and characterization of F9 teratocarcinoma stem cell mutants with altered responses to retinoic acid. 632 55

In addition to its intra-cellular functions, cAMP-dependent protein kinase (PKA) may well have an extra-cellular regulatory role in blood. This suggestion is based on the following experimental findings: (a) Physiological stimulation of blood platelets brings about a specific release of PKA, together with its co-substrates ATP and Mg++; (b) In human serum, an endogenous phosphorylation of one protein (p75, M(r) 75 kDa) occurs; this phosphorylation is enhanced by addition of cAMP and blocked by the Walsh-Krebs specific PKA inhibitor; (c) No endogenous phosphorylation of p75 occurs in human plasma devoid of platelets, but the selective labeling of p75 can be reproduced by adding to plasma the pure catalytic subunit of PKA; (d) p75 was shown to be vitronectin (V), a multifunctional protein implicated in processes associated with platelet activation, and thus a protein whose function may require modulation for control; (e) The phosphorylation of vitronectin occurs at one site (Ser378) which, at physiological pH, is buried in its two-chain form (V65 + 10) but it becomes 'exposed' in the presence of glycosaminoglycans (GAGs) e.g. heparin or heparan sulfate. Such a transconformation may be used for targeting the PKA phosphorylation to vitronectin molecules bound to GAGs, for example in the extracellular matrix or on cell surfaces; (f) From the biochemical point of view (Km values and physiological concentrations) the phosphorylation of vitronectin can take place at the locus of a hemostatic event; (g) The phosphorylation of Ser378 in vitronectin alters its function, since it significantly reduces its ability to bind the inhibitor-1 of plasminogen activator(s) (PAI-1).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Evidence for an extra-cellular function for protein kinase A. 752 49

This study was undertaken to investigate, in freshly isolated rat Sertoli cells, the physiological function of the type I and type II cyclic adenosine monophosphate (cAMP)-dependent protein kinase isozymes in tissue-type plasminogen activator secretion and the regulation of this cAMP process by follicle-stimulating hormone (FSH). Follicle-stimulating hormone-induced tissue-type plasminogen activator secretion depends upon intracellular cAMP levels. The changes in cAMP amounts required to activate maximally the tissue-type plasminogen activator secretion are extremely small, a cAMP threshold having to be reached for triggering the tissue-type plasminogen activator output. Intact Sertoli cells were incubated with combinations of cAMP analogs specific for each cAMP-dependent protein kinase type and complementary in their cAMP binding site on the cAMP-dependent protein kinase regulatory subunits: 8-aminohexylamino-cAMP = type 1, site 1; 8-thiomethyl-cAMP = type II, site 1 and N6-benzoyl-cAMP = types I/II, site 2. This allowed us to activate selectively each cAMP-dependent protein kinase type in a synergistic manner and then to evaluate their respective influence in the specific tissue-type plasminogen activator response. We establish that both of the cAMP-dependent protein kinase types are present and functional; the activity of the type I isozyme is preponderant (60%) in the cAMP-dependent tissue-type plasminogen activator secretion. Likewise, when these cAMP analogs were coupled with endogenously generated cAMP by FSH or forskolin, both of the cAMP-dependent protein kinase types were involved in the tissue-type plasminogen activator production.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Involvement of cyclic adenosine monophosphate-dependent protein kinase isozymes in tissue plasminogen activator secretion by rat Sertoli cells stimulated with follicle-stimulating hormone in vitro. 768 8

Rat astrocytes synthesize and secrete two types of plasminogen activators (PAs), tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA), whose functions are related to cell proliferation, migration, and differentiation during development. The regulation of PAs produced by brain astrocytes is poorly understood. In a previous report we demonstrated that t-PA and u-PA are each independently regulated by cAMP-dependent protein kinase and protein kinase-C. In the present study we examined the effects of three well characterized astrocyte mitogens, insulin-like growth factor-I (IGF-I), epidermal growth factor (EGF), and platelet-derived growth factor (PDGF), on the PA activities produced and secreted by rat astrocytes in vitro. We found that IGF-I and EGF increase cell-associated total PA activity in astrocyte-conditioned medium (CM). The effects of both growth factors were dose and time dependent, and maximal stimulation was achieved after 72 h of treatment with the highest dose tested (100 nM). IGF-I stimulated the cell-associated PA activity more than the CM activity, whereas EGF showed an opposite pattern, suggesting that the secretion of PA is differentially modulated by IGF-I and EGF. PDGF had no effect on astrocyte PA activities at any dose or time point included in the study. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis/zymography showed type-specific changes in CM and cell-associated PA activity after growth factor treatment. IGF-I stimulated only t-PA, whereas EGF induced a marked increase in u-PA activity and a more limited increase in t-PA. PDGF did not modify either t-PA or u-PA activity. In summary, our results show that IGF-I and EGF each had different effects on PA activities, whereas PDGF had no effect. This diversity in the patterns of growth factor regulation of PAs suggests that the production of astrocyte PAs is not simply related to mitogenesis. More likely, astrocyte PAs are involved in a wide range of growth factor-mediated actions in the developing brain.
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PMID:Differential regulation of astrocyte plasminogen activators by insulin-like growth factor-I and epidermal growth factor. 819 86

The effects of endothelin-1 (ET-1) on the production of plasminogen activator inhibitor 1 (PAI-1) and tissue plasminogen activator (t-PA) by human brain-derived endothelial cells in culture were studied. At 100 nmol/L, ET-1 increased PAI-1 production by 88+/-6% within 72 hours, and increased PAI-1 mRNA expression within 1 hour of stimulation; there was no significant effect on t-PA production. PAI-1 activity was also examined and found to increase with ET-1 treatment. Suboptimal concentrations of ET-1 and tumor necrosis factor-alpha (TNF-alpha) acted synergistically to increase PAI-1 production. ET-1 activated protein kinase C and cAMP-dependent protein kinase pathways within 3 to 5 minutes of treatment, with the peak at 10 minutes. Activation of protein kinase C by phorbol-12-myristate-13-acetate (PMA) resulted in increased PAI-1 production, whereas activation of the cAMP-dependent protein kinase by forskolin or dibutyryl cAMP (dBu-cAMP) significantly decreased PAI-1 production. However, simultaneous activation of protein kinase C by PMA and cAMP-dependent protein kinase by dBu-cAMP only slightly attenuated PMA-induced PAI-1 increase. Inhibition of protein kinase C by GF-109213X abolished the effects of ET-1. These results demonstrate that ET-1 and TNF-alpha function synergistically to induce procoagulant activity of brain endothelial cells in a process that involves a protein kinase C-dependent pathway.
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PMID:Endothelin-1 enhances plasminogen activator inhibitor-1 production by human brain endothelial cells via protein kinase C-dependent pathway. 1039 97

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