Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

How heparin inhibits vascular smooth muscle cell proliferation and migration has not been established. We have investigated the hypothesis that heparin inhibits vascular smooth muscle cell proliferation and migration by interfering with the expression and activity of proteases such as plasminogen activators. In an in vitro mitogenesis model, tissue-type plasminogen activator (tPA) mRNA and protein increase in baboon smooth muscle cells stimulated with fetal bovine serum or phorbol esters. Heparin inhibits smooth muscle cell proliferation and suppresses the induction of tPA mRNA and protein while it has little effect on the mRNA of urokinase-type plasminogen activator, plasminogen activator inhibitor type I, and a number of genes that are also modulated by serum and phorbol esters. The inhibitory effect on tPA mRNA is specific to heparin-like molecules and does not depend on the anticoagulation activity of heparin. The increase in tPA mRNA is due to increased transcription, which is suppressed by heparin. The induction of tPA by serum and phorbol esters is diminished by protein kinase C inhibitors such as H7 or staurosporine and by protein kinase C depletion. Since heparin suppresses the induction of the tPA gene by phorbol esters, these results suggest that heparin may interfere with the protein kinase C pathway.
 ...
PMID:Heparin selectively inhibits the transcription of tissue-type plasminogen activator in primate arterial smooth muscle cells during mitogenesis. 131 Jun 87

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.
 ...
PMID:Regulation of plasminogen activators and type-1 plasminogen activator inhibitor by cyclic AMP and phorbol ester in rat astrocytes. 133 67

A31-I-13, a clonal cell variant of nontransformed BALB/c 3T3 that is highly susceptible to chemically or physically induced malignant cell transformation but is not sensitive to cell killing or susceptible to induced somatic cell mutation compared with another less transformation-susceptible A31-I-1 cell variant, was previously found to be constitutively competent [platelet-derived growth factor (PDGF)-independent] to synthesize DNA (M. Tatsuka et al., J. Cell. Physiol., 139: 18-23, 1989). The present study has demonstrated that density-arrested, quiescent A31-I-13 cells autonomously exhibit disruption of actin filamentous bundles and perturbations of dynamic morphology. PDGF induced these cytoskeletal modulations in quiescent A31-I-1 cells, which require PDGF for the induction of DNA synthesis. Furthermore, the cytoskeletal modulations of quiescent A31-I-13 cells were not accompanied by an increased production of plasminogen activators, activation of protein kinase C, or phosphorylation of a Triton X-100-soluble protein (molecular weight, 90,000) known as 80K, a major substrate for protein kinase C. However, these modulations were accompanied by the tyrosine phosphorylation of Triton X-100-insoluble (cytoskeletal) proteins with molecular weights of 24,000, 32,000-33,000, and 36,000. These Triton X-100-insoluble proteins, as well as the 80K protein, were phosphorylated by the exposure of quiescent A31-I-1 cells to PDGF. Thus the pathway for producing the transformation-susceptible phenotype in A31-I-13 appears to coincide with the PDGF signaling pathway but does not involve the protein kinase C pathway.
 ...
PMID:Expression of platelet-derived growth factor-independent phenotypes in BALB/c 3T3 cell variant with high susceptibility to chemically or physically induced neoplastic cell transformation: dissociation from activation of protein kinase C. 163 37

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.
 ...
PMID:Retinoic acid priming potentiates the induction of urokinase-type plasminogen activator by cyclic adenosine monophosphate in mouse mammary carcinoma cells. 164 61

Highly charged polyanionic ligands of the scavenger receptor trigger macrophage secretion of urokinase-type plasminogen activator (uPA). In experiments reported here, we have investigated the intracellular and extracellular regulation of polyanion-induced macrophage plasminogen activation. Exposure of a macrophage cell line (RAW264.7) to either fucoidan or phorbol myristate acetate (PMA) stimulates the secretion of uPA, whereas calcium ionophore or dibutyryl cyclic AMP had no effect. Moreover, preincubation of macrophages with inhibitors of protein kinase C reduced (50-60%) the ability of both fucoidan and PMA to trigger the secretion of uPA, whereas aspirin and eicosatetraenoic acid had no effect. Both PMA and fucoidan treatment of RAW264.7 cells resulted in a rapid and transient increase in the steady state levels of uPA mRNA. However, in marked contrast to that observed with PMA, fucoidan-induced expression of RAW264.7 uPA activity was partially insensitive to cycloheximide and actinomycin D. In addition, fucoidan-induced uPA activity was detected in conditioned media in as little as 15 min, whereas PMA-induced uPA activity did not increase until 2 h. In addition to stimulating macrophage secretion of uPA, fucoidan bound uPA and had a small stimulatory affect on uPA activity. The binding does not interfere with the catalytic site on the B chain, or require the receptor binding or kringle domains on the A chain.
 ...
PMID:Stimulation of macrophage urokinase expression by polyanions is protein kinase C-dependent and requires protein and RNA synthesis. 165 6

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.
 ...
PMID:Characterization of myogenesis from adult satellite cells cultured in vitro. 220 56

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.
 ...
PMID:Simultaneous stimulation of urokinase and tissue-type plasminogen activators by phorbol esters in human ovarian carcinoma cells. 249 25

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.
 ...
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

Tumor growth is dependent upon angiogenesis. There is an intense search for pharmacological inhibitors of angiogenesis as a novel approach to treat angiogenic diseases, e.g., arthritis, diabetic retinopathy or cancer. A series of compounds, originally studied as potential protein kinase C inhibitors, included the diaminoanthraquinone NSC 639366 (1-[[3-(diethylamino)-2-hydroxypropyl]amino]-4-[(2,3- epoxypropyl)amino]-9,10-anthracenedione fumaric acid salt) (SPC-100097), was found to reversibly inhibit bovine endothelial cell growth with an IC50 that ranged between 1 and 4 nM. NSC 639366 reversibly inhibited endothelial cell migration, particularly endothelial cells stimulated by the potent angiogenic molecule, basic fibroblast growth factor. The activity of secreted urokinase-type plasminogen activator and active interstitial collagenase, but not gelatinase, was inhibited by NSC 639366. In vivo, angiogenesis was significantly inhibited by NSC 639366 by using the chick chorioallantoic membrane or the rat corneal bioassay. Two analogs of NSC 639366 did not inhibit endothelial cell growth. These experiments introduce a novel compound that could be clinically useful against angiogenic diseases and encourage further development of compounds that inhibit the plasminogen-plasmin system known to be a key regulator of angiogenesis.
 ...
PMID:A diaminoantraquinone inhibitor of angiogenesis. 752 34

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.
 ...
PMID:Butyrate regulates gene expression of the plasminogen activating system in colon cancer cells. 766 35


1 2 3 4 5 6 Next >>