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:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pretreatment of rats with tranexamic acid inhibited the rapid lowering of the plasma levels of acetone/kaolin-activated prekallikrein proactivator and prekallikrein caused by intravenous injection of dextran, but did not inhibit the reduction in the level of plasminogen, and potentiated the lowering of high molecular weight kininogen. By acetone/kaolin activation of normal rat plasma a mixture of surface-bound factor XIIa and unbound XIIf was obtained, and a BAEe-esterase (MW about 47,000) possessing weak kininogenase activity was present in addition to kallikrein. In activated plasma from dextran-treated rats the cleavage of XIIa was strongly reduced, and the second esterase was almost absent. It is suggested that dextran induces the loss of a plasma factor which is important for the cleavage of factor XIIa in the adopted procedure. This factor was not high molecular weight kininogen, and the lowering of plasminogen was too small to account for the reduction in PKA-activity.
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PMID:Dextran-induced lowering of parameters of the kallikrein-kinin system in rat plasma. 51 28

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

Interactive regulation of gene expression by retinoic acid (RA) and adenosine monophosphate (cAMP) in mammary tumor cells was explored using Shionogi mouse mammary carcinoma cells (SC115) as a model and urokinase-type plasminogen activator (uPA) as a target gene product. Twenty-four hour treatment of SC115 cells with 100 nM RA, 1 mM 8-bromo-cAMP (BrcAMP), and 100 nM RA + 1 mM BrcAMP resulted in extracellular uPA activity increases of 1.4-fold, sevenfold, and 20-fold, respectively. These effects were dose-dependent with regard to both interacting members. Similar responses were obtained if 1 nM cholera toxin or 10 microM forskolin was used instead of the cAMP analog. Retinoids lacking the carboxylic acid function were inactive. The changes in uPA activity were accompanied by similar changes in uPA antigen concentration, as seen via Western blot analysis, and uPA mRNA abundance, as seen via Northern blot analysis. Actinomycin D, an inhibitor of RNA synthesis, blocked uPA stimulation by BrcAMP, suggesting that mRNA levels were transcriptionally regulated. The effect of BrcAMP on extracellular uPA activity was first evident at 2 h and peaked at approximately 6 h; the effect of RA alone and the synergistic response to joint treatment, however, followed a slower time course, requiring at least 12 h for initial expression and increasing gradually with time up to at least 48 h. Priming with RA for 48 h followed by extensive washing of the cells resulted in a threefold enhancement of the stimulatory effect of BrcAMP on uPA. Experiments utilizing the casein/plasminogen overlay method for the detection of uPA secretion by increased rate of uPA secretion per cell rather than to an increased fraction of uPA-secreting cells. Initial investigation of the mechanism of RA potentiation of cAMP responsiveness showed that RA did not alter cellular cAMP levels or total cAMP-dependent protein kinase A activity. Finally, the tumor promoter phorbol myristate acetate, an activator of protein kinase C, also increased SC115 cell uPA activity and synergized with RA. This raised the possibility that the enhancement of cAMP responsiveness by RA was indirectly mediated via an effect on protein kinase C. Experiments with protein kinase C-depleted cells, however, showed that this was not the case. In conclusion, RA treatment of SC115 cells potentiates the effect of cAMP on uPA expression at the single cell level via a partially irreversible mechanism independent of protein kinase C. The molecular target of RA and whether SC115 cell differentiation underlies the effect of RA remain to be established.
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PMID:Retinoic acid priming potentiates the induction of urokinase-type plasminogen activator by cyclic adenosine monophosphate in mouse mammary carcinoma cells. 164 61

Proteolytic enzymes such as plasminogen activators (PAs) and collagenases are implicated in the process of ovarian follicle rupture. Data obtained in rats support the concept that PAs are both hormonally regulated and temporally related to the ovulatory process; however, such data are lacking in the human ovary. The recent identification of a family of PA inhibitors (PAIs) adds a new dimension to the control of PA activity, and in contrast to animal studies, the human preovulatory follicle is characterized by PA inhibitory activity. To initially examine the PA and PAI system in the human ovary, granulosa cells obtained from women undergoing gonadal hyperstimulation for in vitro fertilization were cultured in the presence or absence of the protein kinase-C activator, phorbol 12-myristate 13-acetate. Reverse fibrin autography of conditioned medium from control cells revealed the presence of a putative PAI with an apparent mol wt of 50,000. Phorbol ester stimulated the accumulation of this PAI in a specific and dose-dependent manner. Cumulus cells and noncumulus granulosa cells were similar in terms of presence and regulation of PAI. Immunoprecipitation with specific antisera revealed that this human granulosa cell PAI was immunochemically related to PAI-1. This identification was supported by quantitative analysis revealing a 3.7-fold increase in PAI-1 antigen, as assessed by a specific enzyme-linked immunoabsorbent assay. These findings are the first demonstration of the in vitro regulation of PAI activity in the human ovary.
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PMID:Phorbol ester increases plasminogen activator inhibitor accumulation in cultures of human granulosa cells. 172 27

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

Y1 mouse adrenal tumor cells and mutants of Y1 cells (Kin 2 and Kin 8), with defects in regulatory subunit of type 1 protein kinase (R1), were assayed for steroid, growth, and plasminogen activator after application of the tumor promoter 12-O-Tetradecanoylphorbol-13-acetate (TPA). TPA, like ACTH, caused an increase in steroid production and a decrease in growth in Y1 cells. The effects on steroidogenesis were diminished in Kin 2 and markedly diminished in Kin 8. TPA induced plasminogen activator in Y1 but not Kin 2 or Kin 8 while ACTH induced the enzyme in both Y1 and Kin 2 but not Kin 8. TPA did not produce a measurable increase in cyclic nucleotides in Y1 cells. Unlike Cytochalasin E, another agent that causes steroidogenesis without changes in cyclic AMP concentration, TPA and ACTH did not require serum for its effect on steroid production. Cytochalasin E also caused induction of plasminogen activation in Y1, but not in Kin 2 or Kin 8 cells. TPA however produced growth inhibition in both mutant cell types while ACTH produced a progressively diminishing growth inhibitory effect in Kin 2 and Kin 8. The results suggest that a portion of TPA action on Y1 cells requires R1.
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PMID:Action of 12-O-tetradecanoylphorbol-13-acetate on Y1 adrenal cells apparently requires the regulatory subunit of type 1 cyclic AMP dependent protein kinase. 610 Sep 78

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

Migration of astrocytes is thought to play a role in nerve regeneration and to be mediated, at least in part, by inflammation-associated cytokines. Plasminogen activators are secreted proteases that function in fibrinolysis and participate in cellular migration and invasion and, in some cases, are modulated by cytokines. Here, we show that two cytokines, tumor necrosis factor-alpha and interleukin-1 beta, can modulate plasminogen activation in astrocytes, each causing 90% reduction of total plasminogen activator activity. Direct and reverse zymography indicated that this reduction resulted from two simultaneous events, a pronounced decrease in tissue-type plasminogen activator activity and an induction of plasminogen activator inhibitor-1. Northern hybridization analysis indicated a 30-fold increase of the steady-state level of plasminogen activator inhibitor-1 mRNA following treatment with each of the two cytokines. Both of the cytokine-induced effects could be blocked by cycloheximide or actinomycin D. When signal transduction pathways were blocked, the results indicated the involvement of reduction in cyclic AMP levels, protein kinase activity, and arachidonic metabolites of the lipoxygenase pathway. The results thus show that the two cytokines reduce the ability of astrocytes to conduct fibrinolysis and extracellular proteolysis, and suggest that the effect of these cytokines on members of the plasminogen activation system is through a common signal transduction pathway.
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PMID:Components of the plasminogen activator system in astrocytes are modulated by tumor necrosis factor-alpha and interleukin-1 beta through similar signal transduction pathways. 756 46

Butyrate is a potent differentiating agent present in high concentrations in colonic lumen as a result of metabolic breakdown of dietary fibre and, as such, may directly influence colonic cancer progression. We have investigated the effects of butyrate on an enzyme system important in colonic tumour progression, the plasminogen-activating system, in a poorly differentiated colon cancer cell. Butyrate was found to induce a rapid and transient increase in plasminogen activator inhibitor type 1 (PAI-1) mRNA while concomitantly suppressing the constitutive production of both urokinase-type plasminogen activator (uPA) and uPA receptor (uPAR) mRNA transcripts. We have investigated the mechanisms involved in mediating these effects by run-on transcription and RNA stability analyses. Our data show that PAI-1 mRNA induction occurs through both regulation of the stability of the alternately spliced 3.3 kb PAI-1 mRNA transcript and induction of the 2.4 kb PAI-1 mRNA transcript. Studies using modulators of signal transduction pathways demonstrate that induction of PAI-1 mRNA synthesis is independent of protein kinase C but dependent on the activation of protein kinase A. Suppression of uPA mRNA by butyrate was found to occur by down-regulation of gene transcription through a process independent of de novo protein synthesis. The transcription rate of the uPAR gene was not modulated by butyrate, but rapid turnover of the uPAR gene by butyrate was dependent on ongoing protein synthesis. Our results demonstrate that butyrate can effect rapid changes in the expression of genes of the plasminogen-activating system through several different mechanisms in a gene-specific manner.
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PMID:Butyrate regulates gene expression of the plasminogen activating system in colon cancer cells. 766 35


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