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)

A plasminogen activator (PA) system is involved in ovulation, implantation, tumor invasion and metastasis. In order to clarify the regulation of this PA system in endometrial cells, we examined which agent affecting cellular function altered tissue-type plasminogen activator (t-PA) secretion by endometrial carcinoma cell line (KLE cells) in vitro. Triiodothyronine, retinoic acid, insulin, 8-bromo-cAMP, PDGF, IGF-I, basic FGF or TNF-alpha did not alter t-PA secretion while the activator of protein kinase C, phorbol myristate acetate (PMA) stimulated t-PA secretion in a dose-dependent fashion (10(-10)-10(-8) M). The time required to give a statistically significant increase in t-PA over control was 3 hours, and the maximal increase was seen after 24 hours of exposure. Another active phorbol ester, PDD also stimulated t-PA secretion while inactive forms of phorbol ester, 4 alpha-PDD and phorbol did not alter it. Cholera toxin or 8-bromo-cAMP did not affect t-PA secretion, but enhanced PMA-stimulated t-PA secretion. Cycloheximide and actinomycin D completely abolished PMA-stimulated t-PA secretion. These results suggest that (1) t-PA secretion in the endometrial carcinoma cell is modulated by a protein kinase C system, (2) This effect is through new RNA production and protein synthesis. (3) There is a complicated relationship between protein the kinase C and protein kinase A system as to the regulation of t-PA secretion. This would be a suitable model to clarify the PA system in endometrial cells.
 ...
PMID:[Effect of phorbol ester on tissue-type plasminogen activator (t-PA) secretion in endometrial carcinoma cell line in vitro]. 812 84

The generation and characterization of Swiss/3T3 cells which stably over-express protein kinase C (PKC)-alpha were previously described by us. In these cells over-expression of PKC-alpha reduced the expression of epidermal growth factor (EGF) receptor molecules [(1990) J. Biol. Chem. 265, 13290-13296]. Here we show that the expression of PDGF-alpha receptors, but not PDGF-beta receptors, was specifically decreased in these cells. Not only were the levels of PDGF-alpha receptor mRNA transcript and protein significantly diminished in the PKC-alpha over-producing cells, but their ability to respond to short- and long-term growth factor signals was appropriately compromised. This was reflected in a reduced tyrosine autophosphorylation signal in response to PDGF-AA, as well as in decreased growth rates of PKC-alpha over-expressing cells when supplied with external PDGF-AA. A similar decrease in PDGF-alpha receptors was also demonstrated in parental Swiss/3T3 cells treated with phorbol esters. Our studies imply that PKC-alpha is involved in a cellular mechanism suppressing the expression of PDGF-alpha receptors in Swiss/3T3 cells. Hence, activation of PKC-alpha or alterations in its cellular levels may affect, in turn, the expression of a specific set of cell surface receptors and their responses to external growth factors.
 ...
PMID:The expression of PDGF-alpha but not PDGF-beta receptors is suppressed in Swiss/3T3 fibroblasts over-expressing protein kinase C-alpha. 814 71

We have studied in cultured rat astroglial cells MAP kinases, known for their role in intracellular signal transduction. The MAP kinase activity was stimulated by growth factors (FGFb, FGFa, EGF, PDGF, and IGF1), by a phorbol ester (TPA) activating-protein kinase C (PKC), by a neuropeptide (endothelin-1), and by a neuromediator (carbachol). Astrocytes pretreated for 18 h with TPA were still stimulated by growth factors and endothelin, suggesting that down-regulated isoforms of PKC are not involved in MAP kinase activation. In contrast, the small effect of carbachol was suppressed by TPA pretreatment. Astrocytes contained two proteins (p41 and p44) recognized by MAP kinase antibody. These proteins were phosphorylated on tyrosine residues in the cytosols of stimulated astrocytes. The kinetics of MAP kinase activation by FGFb and IGF1 were very different. FGFb promoted a rapid activation of MAP kinase (about 10 min) plus a prolonged phase that lasted at least 12 h. IGF1 produced only a rapid transient peak of activation at about 20 min. Hence, extracellular signals might generate different effects in astrocytes by differentially modulating the MAP kinase cascade. On a Mono Q column the growth factor-stimulated MAP kinase activity was separated into two peaks containing p41 and p44. Stimulation of astrocytes altered the elution pattern of p44 as a result of its phosphorylation. An ATP-dependent MAP kinase activator (MW = 40-45 kDa) was found in fractions of FGFb-stimulated cells which were not retained on Mono Q column, indicating the existence of a MAP kinase kinase (MEK) in astrocytes. C-Raf, identified in other cells as a MAP kinase kinase kinase, was also present in astrocytes.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:MAP kinase cascade in astrocytes. 816 69

PDGF heterodimer of A and B chains, a complete mitogen for 3T3 mouse fibroblasts, exemplifies those growth factors interacting with membrane associated tyrosine kinase receptors. Its binding to the PDGF-receptors results in receptor dimerization and subsequent activation of tyrosine kinase activity in the cytoplasmic protein domain, autophosphorylation of the receptor being the first event in the transduction cascade. Before the ligand-receptor complex is internalized and degraded, receptor stimulation is transmitted to the general transduction network, in which several tyrosine kinase substrates are activated by phosphorylation and changes the cytoplasmic biochemistry. These changes include cytoplasmic alkalinization, increases in the intracellular concentration of cyclic-AMP and Ca2+ and activation of protein kinase C through the degradation of phosphoinositides. The known substrates recruited by the PDGF-receptor association are phosphatidylinositol-3'-kinase, ras-GTPase-activating protein, phospholipase C-gamma, serine-threonine kinase Raf-1 and src and src-related tyrosine kinases. Upon binding of PDGF to its receptor, transactivation of transcriptional and nuclear factors such as c-fos and c-myc genes and dephosphorylation of c-jun occurs, V-sis, the oncogen of the simian sarcoma virus (SSV), is highly homologous to the c-sis/PDGF-B gene that encodes the homodimer of the B-chain of the PDGF receptor. Cells transformed by SSV have been studied as a model system for the autocrine stimulation of the PDGF receptor.
 ...
PMID:Platelet derived growth factor/tyrosine kinase receptor mediated proliferation. 822 Jan 10

In fibroblasts, stimulation of receptor tyrosine kinases results in the activation of the extracellular signal-regulated kinase 2 (ERK2). The major signalling pathway employed by these receptors involves the activation of p21ras and raf-1 kinase. Here we show that in NIH3T3 and rat-1 fibroblasts, elevation of the intracellular cAMP level results in the inhibition of ERK2 activation induced by PDGF, EGF and insulin treatment. Analysis of various signalling intermediates shows that cAMP interferes at a site downstream of p21ras, but upstream of raf-1 kinase. Inhibition by cAMP depends on both the cAMP concentration and the absolute amount of p21ras molecules bound to GTP, suggesting a mechanism of competitive inhibition. Also TPA-induced, p21ras-independent, activation of raf-1 kinase and ERK2 is inhibited by cAMP. We have used the inhibitory effect of cAMP to investigate whether phosphorylation of mSos, a p21ras nucleotide exchange factor, is dependent on the activity of the raf-1 kinase/ERK2 pathway. We found that phosphorylation of mSos, as monitored by a mobility shift, is delayed with respect to p21ras and ERK2 activation and is inhibited by cAMP in a similar cell type- and concentration-dependent manner as the inactivation of ERK2. These results provide evidence for a model of p21ras-directed signalling towards ERK2 that feeds back on mSos by regulating its phosphorylation status and that can be negatively modulated by protein kinase A and positively modulated by protein kinase C action.
 ...
PMID:cAMP antagonizes p21ras-directed activation of extracellular signal-regulated kinase 2 and phosphorylation of mSos nucleotide exchange factor. 822 35

Fluid flow and the associated shear stress play a critical role in vascular growth and remodeling. Recent data suggest that increased endothelial cell expression of platelet-derived growth factor (PDGF) A- and B-chain by flow may participate in these events. In the present study, we examined the mechanism for flow-induced PDGF expression, focusing on protein kinase C (PKC). Bovine aortic endothelial cells were exposed to flow (shear stress = 30 dyn/cm2) in a parallel-plate flow chamber. Increases in PDGF B-chain, but not PDGF A-chain, were observed within 3 h, maximal within 6 h (13-fold increase), and sustained for 24 h. PKC appeared to be involved because phorbol 12-myristate 13-acetate induced PDGF B-chain mRNA. Activation of PKC alone, however, was insufficient to induce PDGF mRNA because the selective PKC activator, 1-oleoyl-2-acetyl-sn-glycerol, did not induce PDGF expression. A PKC-independent pathway was suggested by the fact that inhibition of PKC (downregulation with phorbol 12,13-dibutyrate or exposure to staurosporine) failed to block PMA or flow-induced PDGF B-chain expression. These results demonstrate flow-induced PDGF B-chain expression in endothelial cells that appears to be mediated, in part, by a PKC-independent pathway.
 ...
PMID:Fluid shear stress stimulates platelet-derived growth factor expression in endothelial cells. 834 46

Endothelial cell activation by thrombin is a key event in wound healing, inflammation, and hemostasis. To better define thrombin-endothelial cell interactions we synthesized several peptides of varying length corresponding to the initial 14 amino acid sequence of the cloned human platelet thrombin receptor after cleavage at an arginine41 site (R/SFLLRNPNDKYEPF). Thrombin receptor activating peptides (TRAPs) as short as 5 amino acids induced significant levels of PGI2 synthesis and expression of PDGF mRNA in human endothelium and produced dose-dependent cellular contraction and permeability of confluent human umbilical vein and bovine pulmonary artery endothelial monolayers. To explore whether TRAPs utilized similar signal transducing pathways as alpha-thrombin to accomplish endothelial cell activation, phospholipase C production of the Ca2+ secretagogue IP3 was measured and detected 10 seconds after either TRAP 7 or alpha-thrombin. Furthermore, TRAPs ranging from 5-14 residues induced significant dose-dependent increases in Fura-2 fluorescence indicative of Ca2+(1) mobilization. These results indicate that thrombin-mediated proteolytic cleavage of the human and bovine thrombin receptor initiates stimulus/coupling responses such phospholipase C activation, Ca2+ mobilization, and protein kinase C activation. The functional consequence of this cellular activation via the cleaved receptor is enhanced cellular contraction, barrier dysfunction, PGI2 synthesis, and expression of PDGF mRNA.
 ...
PMID:Thrombin receptor activating peptides induce Ca2+ mobilization, barrier dysfunction, prostaglandin synthesis, and platelet-derived growth factor mRNA expression in cultured endothelium. 836 Feb 59

Phosphatidylinositol (PtdIns) 3-kinase is composed of a catalytic p110 subunit and a regulatory p85 subunit. A synthetic phosphopeptide corresponding to the kinase insert of the human PDGF beta subunit receptor and monoclonal antibodies raised against the two described p85 isoforms, p85 alpha and p85 beta were used to isolate PtdIns 3-kinase from human T lymphocytes. We demonstrate that T cells express both p85 alpha and p85 beta proteins. Both isoforms tightly associate with a p110 protein and with PtdIns 3-kinase activity in T cells. Upon triggering of the T cell antigen receptor (TCR)/CD3 complex or activation of protein kinase C (PKC) the p110 protein complexed to p85 alpha becomes rapidly phosphorylated exclusively on serine residues. p85 alpha does not appear to undergo a change in its basal serine phosphorylation during T cell activation. In contrast, stimulation of the TCR/CD3 complex or PKC, results in a marked and rapid increase in phosphorylation of p85 beta on threonine residues. These data show that PtdIns 3-kinase can be a substrate for serine/threonine kinases in T cells. The differential phosphorylation of p85 alpha and p85 beta reveals the potential for divergent regulation and function of these two PtdIns 3-kinase isoforms during T cell activation.
 ...
PMID:Divergent regulation of phosphatidylinositol 3-kinase P85 alpha and P85 beta isoforms upon T cell activation. 838 74

We report here that angiotensin II-mediated hypertrophy of vascular smooth muscle cells (VSMC) exhibits PDGF A-chain-dependent and -independent pathways. Secretion of PDGF A-chain is required for the increase in cell size, but not for the increase in protein synthesis. Angiotensin II stimulates a hypertrophic growth response in VSMC characterized by increases in cell size and protein synthesis, but not cell number. Because angiotensin II-stimulated VSMC hypertrophy has been associated with increased PDGF A-chain expression, we studied its role in the hypertrophic response by inhibiting PDGF A-chain expression with hydrocortisone or anti-PDGF antibody. Hydrocortisone (1 microM for 48 h) inhibited basal protein synthesis by 47%, but angiotensin II-stimulated protein synthesis was enhanced (111% increase after hydrocortisone treatment vs. 25% increase in control). In contrast, hypertrophy, as measured by cell size, was completely inhibited. Although hydrocortisone had no effect on early growth signals stimulated by angiotensin II (e.g., activation of protein kinase C, stimulation of Na+/H+ exchange, and c-fos and c-myc expression), it significantly decreased angiotensin II-stimulated secretion of PDGF-like material into the medium from 0.4 to 0.1 ng/ml/24 h (p < 0.01). However, the time course for PDGF secretion (maximal at 16-24 h) was significantly slower than the time course for angiotensin II-stimulated protein synthesis (maximal at 4-12 h). To block the action of PDGF A-chain selectively, VSMC were treated with anti-PDGF A-chain antibody. The antibody completely inhibited the angiotensin II-stimulated increase in cell size, but it had no significant effect on protein synthesis at early times (< 8 h). These findings demonstrate two pathways involved in angiotensin II-stimulated VSMC hypertrophy: an increase in cell size dependent on PDGF A-chain and an increase in protein synthesis independent of PDGF A-chain.
 ...
PMID:Angiotensin II-induced vascular smooth muscle cell hypertrophy: PDGF A-chain mediates the increase in cell size. 842 18

In human renal mesangial cells, platelet derived growth factor (PDGF)-A chain is subject to regulation by protein kinase C (PKC) activator, phorbol ester (phorbol 12-myristate 13-acetate, PMA). Treatment of mesangial cells with PMA increases PDGF-A chain mRNA abundance as analyzed by Northern blot hybridization. In contrast to the effect of PMA, the inactive analog phorbol had no effect on PDGF-A chain mRNA levels, while the PKC inhibitor H7 markedly reduced the PMA-induced increment in PDGF-A chain mRNA. To determine the mechanism by which PMA increases the abundance of this gene, transcription rate was measured by nuclear transcript elongation assay. Treatment of mesangial cells with PMA resulted in a 2-fold increase in PDGF-A chain gene transcription. In addition, we analyzed the effects of PMA on PDGF-A chain mRNA half-life as measured directly by pulse-chase method. PDGF-A chain mRNA has a half-life of about 106 min. The PDGF-A chain mRNA half-life was reduced by 30% (t1/2 = 74 min) when mesangial cells were incubated with PMA. Our results demonstrate that in human renal mesangial cells, the regulation of PDGF-A chain gene expression by PMA is primarily at the level of transcription.
 ...
PMID:Platelet derived growth factor-A chain gene expression in cultured mesangial cells: regulation by phorbol ester at the level of mRNA abundance, transcription and mRNA stability. 847 49


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>