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

Phorbol ester treatment of HepG2, a human tumorigenic cell line, caused rapid morphological changes characterized by a flattening and spreading of the cells that coincided with a rapid inhibition of thymidine incorporation. Within 24 h, cell division was completely inhibited, suggesting the cells had entered a quiescent state. Continued incubation in the presence of phorbol esters resulted in the resumption of thymidine incorporation and cell division, but this coincided with only a partial down-regulation of PKC activity. Seventy-two hours of treatment was required to obtain down-regulation of greater than 80% of the PKC activity, but reversal of the inhibitory effects occurred between 24 and 48 h after the addition of phorbol esters, when a large proportion of the PKC activity was still present. Northern blot analysis of a number of transcripts showed that the steady-state levels of c-myc and transforming growth factor beta 1 (TGF-beta 1) messages increased only after 3 h of phorbol ester treatment and returned to normal levels after 24 h. C-fos, albumin, and alphafetoprotein messages were not affected, suggesting the differentiation state of the cells was not altered. Therefore, phorbol ester activation of PKC causes an inhibition of HepG2 cell growth initially, but this is unlike the promotion of differentiation seen in other systems. Partial down-regulation of PKC activity causes a reversal of the growth inhibition and the cells return to a normal growth rate. This effect is also clearly different from systems in which phorbol esters have been shown to have a mitogenic effect on cells.
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PMID:Partial down-regulation of protein kinase C reverses the growth inhibitory effect of phorbol esters on HepG2 cells. 197 39

Roles of protein kinases in mediating adaptive neuronal responses to activation of signal transduction pathways are well known. Recent findings suggest that kinases may also be involved in pathological processes in the nervous system. The present study employed cultured human cerebral cortical neurons to test the hypothesis that overactivation of protein kinase C (PKC) can result in neurodegeneration. Phorbol 12-myristate 13-acetate (PMA), an activator of PKC, caused the degeneration of neurons over a period of 3-24 h. The PKC inhibitor H-7 prevented the neurodegeneration normally caused by PMA, and an inactive phorbol (4 alpha-phorbol 12,13-didecanoate; PDD) did not cause neurodegeneration. The neurodegeneration caused by PMA was independent of calcium influx. Immunoreactivity toward antibodies that recognize the microtubule-associated protein tau in Alzheimer neurofibrillary tangles (Alz-50 and 5E2) was greatly increased in neurons exposed to PMA. The antigenic changes were prevented by H-7. These findings indicate that high levels of activation of PKC can cause neurodegeneration and are consistent with the possibility that altered cellular signaling contributes to pathological neuronal degeneration in the intact nervous system.
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PMID:Evidence for the involvement of protein kinase C in neurodegenerative changes in cultured human cortical neurons. 201 10

We have compared two different methods of attenuating protein kinase C (PKC) activity in vascular smooth muscle. First, the effects of two purported PKC inhibitors, staurosporine (stauro) and H-7 [1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride], were examined on contractility of isolated, intact canine femoral artery. In arterial rings stauro was equipotent in relaxing contractions induced by phenylephrine (PE), phorbol-12,13-dibutyrate (PDBu) and KCl (IC50, 0.31 +/- 0.19; 0.35 +/- 0.2; and 0.34 +/- 0.16 microM). H-7, in comparison, was markedly less potent than stauro (IC50, 0.67 +/- 0.2, 2.33 +/- 0.24; and 6.5 +/- 5.5 microM for PE, PDBu and KCl, respectively). Pretreatment of tissues with 1 microM stauro suppressed tension development almost completely when PE and PDBu were the contractile agonists, and partially in K(+)-depolarized rings. H-7, in contrast, had no inhibitory effect on agonist-induced contraction. Neither basal nor K(+)-stimulated calcium influx was affected by 10 microM stauro. Second, prolonged exposure of canine carotid arterial rings to PDBu (1-100 nM for 24 hr), a means of depleting PKC from the tissue, caused dose-dependent attenuation of agonist-induced contractions. Preincubation with 100 nM PDBu caused complete inhibition of tension induced by norepinephrine (NE) and serotonin and partial inhibition of PDBu- and KCl-induced contractions. Lowering the concentration of PDBu during preincubation to 30, 10 or 1 nM reduced markedly the inhibitory effects. The inactive phorbolester 4 alpha-phorbol-12,13-didecanoate (4 alpha-PDD) had no effect on agonist-induced contractions. PKC activity was determined in rings contracted isometrically with PDBu or NE after prolonged exposure to vehicle, 4 alpha-PDD or PDBu.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Protein kinase C and vascular smooth muscle contractility: effects of inhibitors and down-regulation. 201 82

Phenobarbital (PB) added to the medium of cultured rat hepatocytes alters epidermal growth factor (EGF) dependent mitogenesis in a biphasic manner; PB concentrations less than 1.5 mM are growth stimulatory but higher concentrations significantly inhibit normal hepatocyte proliferation. In contrast, the growth of putative preneoplastic cells is inhibited less by high concentrations of PB. Mechanistic studies designed to test the ability of PB to alter the early events of EGF signal transduction demonstrate that PB neither competes with EGF for binding to the EGF receptor nor alters EGF-induced receptor down-regulation. However, pretreatment with PB (greater than 1 mM) results in a transient inhibition of EGF binding to hepatocytes. The kinetics of this effect are similar to those obtained when hepatocytes are exposed to the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA), a skin tumor promoter and activator of Ca2+/phospholipid-dependent protein kinase C. However, several observations suggest that distinct mechanisms mediate the responses to these two tumor promoters. First, the inhibitory effects of PB and TPA on EGF binding are additive. Also down-regulation of EGF receptors in response to TPA occurs with hepatocytes, A431 epidermal carcinoma cells, HepG2 hepatoma cells, and rat liver epithelial cells, but only hepatocytes are sensitive to PB. Furthermore, translocation of protein kinase C to the membrane occurs in hepatocytes treated with TPA but not in those treated with PB. The chronic treatment of rats with PB further sensitizes hepatocytes to EGF receptor down-regulation by in vitro PB while desensitizing them to EGF receptor down-regulation by TPA. This latter effect is correlated with a decreased ability of TPA to induce translocation of protein kinase C to the membrane. PB significantly increases the intracellular concentration of TGF-beta 1 in periportal hepatocytes but not in putative preneoplastic cells. TGF-beta 1 may therefore have an important function in regulating early stages of cell cycle progression in proliferating hepatocytes.
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PMID:Liver tumor promotion: effect of phenobarbital on EGF and protein kinase C signal transduction and transforming growth factor-beta 1 expression. 202 68

1. mdx mice do not express dystrophin, the product of the gene which is defective in Duchenne and Becker muscular dystrophy. We have previously shown that protein-synthetic rates (ks) are increased in mdx mouse muscles [MacLennan & Edwards (1990) Biochem. J. 268, 795-797]. 2. The tumour-promoting stereoisomer of phorbol 12,13-didecanoate (4 beta-PDD) acutely increased the ks of muscles from mdx and wild-type (C57BL/10) mice incubated in vitro in the absence of insulin. The effects of 4 beta-PDD are presumably mediated by activation of protein kinase C (PKC). 3. The muscle glycogen concentrations of mdx mice were higher than those of C57BL/10 mice. Studies performed in vivo and in vitro suggested that the effect might be at least partially due to increased rate of glycogen synthesis in mdx muscle. 4. 4 beta-PDD increased the glycogen-synthetic rates rates of C57BL/10, but not mdx, muscles incubated in vitro in the absence of insulin. 5. In muscles from both species incubated in the absence of insulin, treatment with 4 beta-PDD also induced increased rates of glucose uptake and lactate production. Kinetic studies of C57BL/10 and mdx muscles suggested that 4 beta-PDD raised the Vmax. of glucose uptake, but did not alter the Km for the process. 6. The possible role of PKC in controlling the protein and carbohydrate metabolism of normal and mdx mouse muscles is discussed.
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PMID:Acute effects of phorbol esters on the protein-synthetic rate and carbohydrate metabolism of normal and mdx mouse muscles. 202 27

Endothelin (ET), a peptide originally isolated from the supernatants of cultured endothelial cells, exerts a wide variety of biological effects in different tissues. Endothelial-cell-synthesized ET-1 has been proposed to act in a paracrine manner on adjacent smooth muscle cells (SMC) in vivo, with effects that include both vascular reactivity (vasodilation/vasoconstriction) and mitogenesis. This study, by the use of immunocytochemically characterized SMC (rVSMC) isolated from the aortas of spontaneously hypertensive rats, has investigated a possible autocrine role for ET in regulation of the vasculature. Although quiescent cultures of rVSMC apparently did not constitutively express prepro ET-1mRNA, ET-specific transcripts could be induced by a variety of growth factors (transforming growth factor beta [TGF-beta]; platelet-derived growth factor-AA homodimer [PDGF-A chain]) and vasoactive hormones (angiotensin II [Ang II], arginine-vasopressin, and ET-1 itself). The kinetics for prepro ET-1mRNA induction in rVSMC were characteristically rapid in onset and transient. Down-regulation of protein kinase C by 48 h pretreatment of rVSMC with phorbol ester markedly reduced the subsequent ability of rVSMC to express ET-1 transcripts and secrete ET-1 peptide in response to Ang II. Inducible prepro ET-1mRNA expression was accompanied by a cycloheximide-inhibitable release of ET-1 peptide into the medium of rVSMC. ET-1 peptide was determined by both radioreceptor- and radioimmunoassay. Stimulated rVSMC accumulated ET-1 (approximately 200 pg.10(6) cells-1 x 4 h-1) at levels that attained biological relevance (approximately 10(-10) M). Sep-pak C18 extracts of medium from stimulated rVSMC elicited contraction of isolated endothelium-denuded rat mesenteric resistance vessels, and this response was characteristically protracted and difficult to "wash out." Synthetic (porcine) ET-1 promoted the expression of transcripts for PDGF-A chain, TGF-beta, and thrombospondin in quiescent rVSMC. Such effects of ET-1 on gene expression may be relevant to the mitogenic potential of ET-1 on VSMC. Our findings imply a role for ET-1 in the control of vascular function via both paracrine and autocrine regulatory mechanisms. The expression of prepro ET-1mRNA and peptide biosynthesis by rVSMC may have both short-term (e.g., vasoconstriction) and long-term (e.g., structural remodeling) consequences. A sustained loop of autocrine stimulation by ET-1 in SMC could contribute toward the pathogenesis of vasospasm and/or atherosclerosis.
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PMID:Stimulation of endothelin mRNA and secretion in rat vascular smooth muscle cells: a novel autocrine function. 207 71

We have reported that mast cells adhere to laminin after activation with PMA. In this study, we demonstrate that the cross-linking of cell surface high-affinity IgE-R on mast cells derived from mouse bone marrow cultured for 3 wk in the presence of WEHI-3-conditioned media acts as a highly sensitive physiologic stimulus for this attachment and that receptor activation is also induced by calcium ionophore A23187. Adherence occurred at threefold log concentrations less of A23187 and Ag than required for histamine release in a selective subpopulation comprising 20 to 30% of the total cells. At higher concentrations of agonist that permitted histamine release, the time course for degranulation was shown to be more rapid than that of adherence. Adherence was inhibited by antibodies to laminin and laminin receptor and was calcium ion and temperature dependent. Treatment of cells with dibutyryl cAMP, which activates protein kinase A, inhibited both adherence and histamine release induced by Ag or calcium ionophore. Treatment of cells with staurosporin, which inhibits protein kinase C, also inhibited adherence and histamine release induced by calcium ionophore, but was not significantly active against either adherence or histamine release induced by Ag. It thus appears that agents which modulate intracellular signaling mechanisms are equally effective toward histamine release and adherence, suggesting these two events are intimately linked in stimulus secretion coupling. Specific cytokines stimulating mast cell adhesion to laminin could not be found; however, culture of mast cells with TGF-beta 1 was determined to enhance IgE-mediated adherence to laminin. Hence, the high-affinity IgE-R on the mast cell functions not only in exocytosis but also facilitates the process of mast cell adherence to laminin.
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PMID:Regulation of adhesion of mouse bone marrow-derived mast cells to laminin. 214 20

The effects of phorbol ester on cell growth inhibition by transforming growth factor beta 1 (TGF-beta 1) in human hepatoma cell lines, Mahlavu and PLC/PRF/5, were investigated. TGF-beta 1 (2.5 to 10 pM) alone could not inhibit the growth of Mahlavu cells, whereas in the presence of 12-O-tetradecanoyl phorbol 13-acetate (TPA) at 1 ng/ml, TGF-beta 1 could suppress their growth in a dose-dependent manner. The growth of PLC/PRF/5 cells could be inhibited by addition of TGF-beta 1 (2.5 to 10 pM) alone in a dose-dependent manner, and this action was not affected by TPA (1 ng/ml). The TGF-beta 1 inhibition induced by TPA in Mahlavu cells could not be cancelled by addition of protein kinase C inhibitor, 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H7) (10 microM) or staurosporin (1 nM). Thus, TPA could induce TGF-beta 1 inhibition of cell growth in Mahlavu cells which did not respond to TGF-beta 1 alone, and activation of protein kinase C does not seem to be behind this TPA action.
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PMID:Effects of phorbol ester on cell growth inhibition by transforming growth factor beta 1 in human hepatoma cell lines. 216 81

The effects of the phorbol ester, 12-tetradecanoyl-phorbol-13-acetate (TPA) and related compounds on acetylcholine (ACh)-evoked [3H]leucine-labelled protein release (secretion) were tested in isolated permeabilized rat pancreatic acini. The aim was to determine whether the diacylglycerol-like compounds can still potentiate the actions of ACh during unfluctuating supramaximal elevation of cytosolic free calcium (Ca2+) levels. TPA and R59022, an inhibitor of diacylglycerol kinase, evoked marked biphasic dose-dependent increases in 3H-labelled protein secretion from permeabilized rat pancreatic acini. Synthetic diacylglycerol (OAG) and 8-bromo cyclic GMP elicited small increases in 3H-labelled protein release while an inactive phorbol ester (4 alpha-phorbol-12,13-didecanoate; 4 alpha-PDD) and polymyxin B, an inhibitor of protein kinase C, were unable to stimulate secretion. Combining polymyxin B with TPA resulted in an inhibition of 3H-labelled protein secretion. Acetylcholine also induced a dose-dependent increase in 3H-labelled protein output, but when TPA or R59022 was combined with ACh, there was a marked potentiation of the ACh-evoked secretory response, particularly at higher concentrations of ACh. This synergism was unaffected by the protein kinase C inhibitor, polymyxin B. The results show that cytosolic free Ca2+ and protein kinase C may not be the only mediators of ACh-evoked secretion. Moreover, they indicate that protein kinase C may not be involved in the potentiation by TPA of ACh-evoked 3H-labelled protein release.
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PMID:Effects of phorbol ester and related compounds on acetylcholine-evoked [3H]leucine-labelled protein secretion in permeabilized rat pancreatic acini. 217 84

Full-grown prophase-arrested oocytes of Xenopus laevis were treated with 50 nM phorbol 12-myristate 13-acetate (PMA), an activator of protein kinase C, or with 50 nM 4 alpha-phorbol 12,13-didecanoate (4 alpha PDD) that does not activate protein kinase C. The effect on membrane currents and capacitance, inulin uptake and ouabain binding, and on membrane morphology were analyzed. (i) During application of PMA, current generated by the Na+/K+ pump decreases; in addition, Cl- and K+ channels become inhibited. This general decrease in membrane conductance reaches steady state after about 60 min. 4 alpha PDD was ineffective. (ii) Ouabain binding experiments demonstrate that PMA (K1/2 = 7 nM), but not 4 alpha PPD, induces a reduction of the number of pump molecules in the surface membrane. Permeabilization of oocytes by digitonin plus 0.02% SDS renders all binding sites present prior to PMA treatment again accessible for ouabain. The KD value for ouabain binding is not influenced. 4 alpha PDD was ineffective. (iii) Exposure of oocytes to PMA reduces membrane capacitance and stimulates uptake of inulin suggesting an increase in endocytosis. Electron micrographs show that PMA reduces the number and length of microvilli, leading finally to a smooth membrane surface with a reduced surface area. From these results we conclude that stimulation of protein kinase C leads to downregulation of the sodium pump. A major portion of this inhibition is brought about by reduction in area of surface membrane with a concomitant internalization of pump molecules. In addition to this mode of downregulation, a direct effect of stimulation of protein kinase C on the pump molecule cannot be excluded.
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PMID:Activation of protein kinase C by phorbol ester induces downregulation of the Na+/K(+)-ATPase in oocytes of Xenopus laevis. 217 38


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