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)

The biochemical mechanisms responsible for regulating cellular platelet-derived growth factor expression are incompletely understood. Our previous studies have shown that platelet-derived growth factor B/c-sis mRNA levels are induced in human renal microvascular endothelial cells by either thrombin or transforming growth factor (TGF-beta), while exposure to agents which elevate cAMP levels blocks the induction responses. The current studies use combined transcription run-off and message decay rate experiments to show greater than 3-fold increases in rate of transcription after stimulation with either thrombin or TGF-beta. c-sis message has a 70-90-min half-life under basal conditions that is effectively unaltered by thrombin or TGF-beta. Forskolin does not decrease the stability of c-sis mRNA, although it attenuates transcription increases seen with inducing agents. TGF-beta induction of c-sis transcription is mediated independent of the protein kinase C (Ca2+- and phospholipid-dependent enzyme)-mediated responses to phorbol ester, as it remains intact following down-regulation of protein kinase C response; TGF-beta and phorbol elicit additive induction. Inhibitory effects of cAMP upon transcription act distal to early thrombin-receptor-coupled increases in phosphatidylinositol turnover and are capable of turning off TGF-beta-activated transcription after activation has been established. Both inducing and suppressing agents alter endothelial platelet-derived growth factor B/c-sis mRNA expression dominantly through effects upon rates of transcription, cAMP suppression of transcription is dominant, and TGF-beta and phorbol esters mediate induction of transcription through distinct pathways.
 ...
PMID:Distinct pathways mediate transcriptional regulation of platelet-derived growth factor B/c-sis expression. 319 52

The effect of phorbol-12-myristate-13-acetate (PMA), an activator of protein kinase C (PK-C) on lipid peroxidation (LPO) in rat liver homogenates and microsomes was studied. PMA (10(-10) to 10(-6) M) produced a concentration-dependent inhibition of LPO, which was greatly decreased by polymyxin B (PxB) (an inhibitor of PK-C). The non-active analogue of PMA, 4 alpha-phorbol-12,13-didecanoate (4 alpha-PDD) exerted no inhibitory effect. The adenylate cyclase activator, forskolin (FK) (10(-6) M) abolished the inhibitory effect of PMA on LPO. PMA and FK did not inhibit LPO in liposomes. It is suggested that LPO in biomembranes could be regulated by PK-C, whose inhibitory effect might be prevented by cAMP-dependent protein kinases.
 ...
PMID:The role of secondary messengers in the regulation of lipid peroxidation in rat liver microsomes. 323 56

The ability of the tumor-promoting phorbol ester 4 beta-phorbol 12 beta-myristate 13 alpha-acetate (PMA) to induce protein kinase C (PKC) translocation and lysosomal enzyme release was examined in skin fibroblasts from normal subjects and from patients with cystic fibrosis (CF). As compared to normal fibroblasts, those CF exhibited: (i) an increased sensitivity to the effect of PMA on the disappearance of PKC from cytosolic fractions as well as a greater and earlier recovery, in the membrane fraction, of the PKC activity lost in the cytosolic fraction; (ii) an earlier response to PMA for its effect on beta-N-acetylglucosaminidase release. In contrast, the inactive phorbol ester 4 alpha-phorbol 12,13-didecanoate (4 alpha PDD) proved ineffective in inducing PKC translocation and beta-N-acetylglucosaminidase release in both normal and CF fibroblasts. The data suggest a defect in the regulation of PKC activity in CF fibroblasts, which may lead to altered secretion.
 ...
PMID:Phorbol ester-induced protein kinase C translocation and lysosomal enzyme release in normal and cystic fibrosis fibroblasts. 334 34

Binding of [3H]PDB has been measured in the present study to determine the levels of protein kinase C in the neuronal and astrocytic glial cells in culture from rat brain. Binding of [3H]PDB to homogenates of cultured neuronal cells from the brains of normotensive and hypertensive rats was time-dependent and specific. The relative potency for competition by various phorbol esters to [3H]PDB binding was TPA greater than beta-PDD greater than POE greater than alpha-PDD greater than or equal to 4 alpha phorbol. Scatchard analysis showed that neuronal cultures from normotensive rat brains contained 2-3 fold more phorbol ester receptors compared with the glial cultures from the same brains. No differences in the Kd and Bmax were observed between neuronal cultures from normotensive and spontaneously hypertensive rat brains. These studies suggest that the phorbol ester receptors are primarily localized in neuronal cells.
 ...
PMID:Receptors for phorbol esters are primarily localized in neurons: comparison of neuronal and glial cultures. 336 29

The effect of tumor promoter phorbol esters on cell proliferation was investigated in human breast cancer cell line MCF-7. During a 4-day culture period, the various phorbol ester derivatives TPA, PDD, PDBu, PDBz and PDA inhibited the proliferation of MCF-7 cells in a dose-dependent manner, with respective IC50 of 0.06, 0.75, 2.4, 3.6 and 15 X 10(-9) M. The 4-O-met-TPA, alpha PDD and alph PHR were ineffective at 2 X 10(-7) M, the highest concentration tested. Using a 3H-PDBu probe, we demonstrated the presence of specific, high affinity binding sites in intact cultured cells, with a Kd of about 9 X 10(-9) M. Unlabelled TPA, PDD, PDBU and PDBz competed with 3H-PDBu with respective IC50 of 35, 12.5, 150 and 220 X 10(-9) M. High concentrations of PDA, 4-O-met-TPA and alpha PDD slightly inhibited the 3H PDBu binding, whereas alpha PHR did not until 10(-5) M. The correlation that we observed between the relative potencies of the various phorbol derivatives for inhibiting both PDBu binding and cell proliferation, suggests that tumor promoter phorbol esters may induce growth arrest in MCF-7 cells by the mediation of protein kinase C.
 ...
PMID:Phorbol esters inhibit the proliferation of MCF-7 cells. Possible implication of protein kinase C. 346 88

The effects of two co-carcinogenic phorbol esters (phorbol myristate acetate (PMA) and phorbol dibutyrate (PDBu] and a synthetic diacylglycerol (OAG, 1-oleoyl-2-acetyl-glycerol), which all stimulate protein kinase C, were compared with two inactive phorbol compounds (4 alpha-phorbol and 4 alpha-phorbol didecanoate (4 alpha-PDD)) on three functional properties of stimulated human polymorphonuclear leukocytes (PMNs): release of granular enzymes lysozyme and beta-glucuronidase, chemokinesis, and changes in cytoplasmic free calcium [Ca2+]i. PMA, PDBu and the diacylglycerol, OAG, all caused a dose-dependent and slow (max by 15 min) release of small amounts of lysozyme with much less beta-glucuronidase and no release of cytoplasmic lactate dehydrogenase. Release was unaffected by removal of extracellular Ca2+. PMA, PDBu and OAG inhibited random movement of the cells, did not cause chemokinesis and induced a slow reduction in the basal [Ca2+]i, as measured by the quin-2 method. PMA, PDBu and OAG increased the capacity of five independently-acting stimulants (N-formyl-Met-Leu-Phe, leukotriene B4, C5a des-Arg, platelet activating factor and A23187) to cause release of lysozyme and beta-glucuronidase but strongly inhibited PMN chemokinesis induced by the same five agents and reduced the stimulant-induced increases in [Ca2+]i. PMA was always more potent than PDBu and much more potent than OAG in eliciting these stimulatory or inhibitory effects on human PMNs. In all tests, 4 alpha-phorbol and 4 alpha-PDD were inactive. The results confirm that stimulation of the diacylglycerol/protein kinase C system in human PMN, either by active phorbol esters or the synthetic diacylglycerol, causes bidirectional effects on human PMN function. In particular, activation of the C-kinase causes inhibition of stimulated neutrophil motility, whereas the secretory functions of the cells are enhanced.
 ...
PMID:Divergent effects of co-carcinogenic phorbol esters and a synthetic diacylglycerol on human neutrophil chemokinesis and granular enzyme secretion. 347 47

The effect of various concentrations of 4 beta-phorbol dibutyrate, (4-beta PDBu) phorbol myristate acetate (PMA), and 4 beta-phorbol didecanoate (4 beta-PDD) were studied on the guinea-pig parenchymal strip. The order of potency, 4 beta-PDBu greater than PMA greater than 4 beta-PDD, was the inverse of their lipid solubility. 4 beta-PDBu, 10(-9)-10(-4) M, caused a powerful, slow, sustained contraction starting within 2-3 min and reaching maximum in approximately 45 min, the maximum being 170% of the maximum histamine contraction. The responses to PMA and 4 beta-PDD were slower and less marked. 4 alpha-Phorbol dibutyrate had no effect. These results differ from those reported for guinea-pig trachea. In calcium-free Krebs solution + EGTA (1 mM) the cumulative concentration-response curve to 4 beta-PDBu was still obtained but was slower and was diminished. A23187, ionomycin and vanadate also caused contraction, the respective concentration ranges being 10(-7)-10(-5), 10(-8)-10(-6) and 10(-6)-10(-3) M. When a low concentration of 4 beta-PDBu, which on its own produced no effect, was given with a low concentration of A23187, ionomycin or vanadate, marked synergism was seen. These results are consistent with the model of smooth muscle contraction in which it was proposed that the initial response to stimulation is mediated by both the trisphosphate/calcium and diacylglycerol/protein kinase C pathways, while the sustained response is mediated by the diacylglycerol/protein kinase C pathway, only.
 ...
PMID:4 beta-PDBu contracts parenchymal strip and synergizes with raised cytosolic calcium. 347

Capacitated mouse sperm undergo the spontaneous acrosome reaction in suspension and the zona-induced acrosome reaction when bound to isolated, intact zonae pellucidae. The zona-induced acrosome reaction in the mouse resembles, in part, ligand-receptor-mediated exocytotic processes that occur in some somatic cells. Since such processes have been shown to be mediated in part by protein kinase C-catalyzed protein phosphorylation, the effects of phorbol esters, which are potent activators of this kinase, on both the spontaneous and the zona-induced acrosome reaction were examined. At concentrations up to 10 microM, 12-tetradecanoyl phorbol-13-acetate (TPA) had no effect on the time course of the spontaneous acrosome reaction as scored by the chlortetracycline (CTC) fluorescence assay. Capacitated, acrosome-intact sperm display Pattern B in the CTC assay with fluorescence on the anterior head; fully acrosome-reacted sperm display Pattern AR with no fluorescence on the head. The time course of the loss of Pattern B in the zona-induced acrosome reaction was markedly accelerated by 65 nM TPA as compared to controls, whereas the appearance of Pattern AR was retarded. The appearance of Pattern S, which is characterized by punctate fluorescence on the head and which marks an intermediate state between Pattern B and Pattern AR in the controls, was accelerated by 65 nM TPA to the same extent as the loss of Pattern B at early times post-binding to zonae. The disappearance of Pattern S at later times post-binding to zonae was retarded by 65 nM TPA to the same extent as the appearance of Pattern AR. The transitions between the fluorescence patterns, designated the B-to-S and the S-to-AR transitions, therefore define two stages of the zona-induced acrosome reaction, which are affected in opposite directions by TPA. The effects of 65 nM TPA are mimicked by 60 nM 4-beta-phorbol-12,13-didecanoate (4-beta-PDD) while the 4-alpha isomer is without effect. Such stereospecificity is similar to that reported for the activation of protein kinase C. The diacylglycerol, 1-oleyl-2-acetylglycerol, which is also known to activate protein kinase C, mimicked the effects of TPA and 4-beta-PDD on the time courses of the B-to-S and S-to-AR transitions. These results suggest that protein kinase C may play an intermediary role in the zona-induced mouse sperm acrosome reaction.
 ...
PMID:Effects of phorbol esters and a diacylglycerol on the mouse sperm acrosome reaction induced by the zona pellucida. 359 34

The mechanism by which bile salts stimulate the proliferative activity of colonic epithelium is uncertain. One of the striking cellular actions of certain bile salts that enhance the proliferative activity of colonic epithelium, such as deoxycholate (DOC) and chenodeoxycholate, is the rapid stimulation of membrane phospholipid turnover. Increased membrane phosphoinositol turnover may lead to release of diacylglycerol (DAG). The latter is an endogenous activator of the calcium phospholipid-dependent enzyme protein kinase C (PKC) whose stimulation has been correlated with enhanced proliferation in several cell systems. In the present study, we examined the effects of DOC on PKC of colonic epithelium in vitro and in vivo. When added directly in vitro to partially purified soluble preparations of phospholipid, calcium-dependent PKC from crypts isolated from rat colon, DOC suppressed activity by 20%, presumably due to calcium complex formation. By contrast, the tumor promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA), and the DAG derivative, 1-oleoyl-2-acetylglycerol (OAG), increased soluble PKC in vitro twofold. The nontumor promoters phorbol and 4 alpha-phorbol-12,13-didecanoate (4 alpha PDD) were without effect. However, in intact colonic epithelial crypt cells prelabeled with arachidonate, DOC caused rapid release of DAG and markedly increased the fraction of PKC associated with the particulate cell fraction, an index of PKC activation. TPA and OAG caused similar shifts in the subcellular distribution of PKC but did not stimulate DAG release, whereas phorbol and 4 alpha PDD were without effect on any parameter. In vivo intracolonic instillation of DOC, OAG, or TPA each induced a shift of soluble PKC to the particulate fraction of colonic mucosal scrapings.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Relationship of bile salt stimulation of colonic epithelial phospholipid turnover and proliferative activity: role of activation of protein kinase C1. 362 3

The effects of phorbol esters on serotonin release were examined in an attempt to investigate the role of protein kinase C in the regulation of serotonin release. Rat brain parietal cortical slices were incubated with [3H]5-HT in the presence of pargyline in order to label the serotonin stores. Potassium stimulated (30 s) release and spontaneous [3H]5-HT efflux were examined in slices during superfusion with Krebs-Ringer solution containing chlorimipramine. Repeated K+ stimulations elicited reproducible responses with release ratios of approximately 1.0. Introduction of phorbol 12-myristate, 13-acetate (PMA) or phorbol 12,13-dibutyrate (PDBu) 20 min prior to S2, or S3 resulted in dose-related increases in [3H]5-HT or [3H]NE release. PMA was slightly more potent (93% increase) than PDBu in potentiating K+-stimulated [3H]5-HT release. Phorbol and 4 alpha-phorbol 12,13-didecanoate (4 alpha PDD) which do not activate protein kinase C did not alter serotonin release. In contrast, basal [3H]5-HT and [3H]NE release were altered to a far lesser extent which was not always dose related. The response to the phorbol esters was reversible, Ca2+-dependent and reached maximal effect after 20 min of superfusion. The putative protein kinase C inhibitor, 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H-7) inhibited K+-induced [3H]5-HT release significantly (11%) but did not alter basal efflux. The PMA facilitation of serotonin release was, however, markedly prevented by the enzyme inhibitor. The effect of PMA on release was found not to be directly mediated through the prejunctional serotonin autoreceptors.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Protein kinase C: regulation of serotonin release from rat brain cortical slices. 366 23


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