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)

When Swiss 3T3 cells are treated with Insulin-like Growth Factor I, a rapid decrease in the mass of polyphosphoinositol lipids (phosphatidylinositol 4-phosphate and phosphatidylinositol 4,5-bisphosphate) occurs within the nuclei, with a concomitant increase in nuclear diacylglycerol and translocation of protein kinase C to the nuclear region. This is in contrast to the effects of the regulatory peptide, bombesin, which causes similar inositol lipid changes in the plasma membrane, has no effect on nuclear inositide levels and causes a translocation of protein kinase C to post-nuclear membranes. These results suggest the existence of a discrete nuclear polyphosphoinositide signalling system entirely distinct from the well-known plasma membrane-located system, which is under regulatory control by cell surface-located receptors.
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PMID:The polyphosphoinositide cycle exists in the nuclei of Swiss 3T3 cells under the control of a receptor (for IGF-I) in the plasma membrane, and stimulation of the cycle increases nuclear diacylglycerol and apparently induces translocation of protein kinase C to the nucleus. 165 12

In a previous study, we found that addition of serum to confluent Clone 9 cells, a nontransformed rat liver cell line, increased the abundance of mRNA alpha 1 and mRNA beta 1 at 3 h by 2- and 2.7-fold, respectively [Bhutada et al. Am. J. Physiol. 258 (Cell Physiol. 27): C1044-C1050, 1990]. We now report that exposure of these cells to 160 nM 12-O-tetradecanoylphorbol 13-acetate (TPA) for 6 h increases mRNA alpha 1 and mRNA beta 1 by 1.7 +/- 0.2- and 2.1 +/- 0.3-fold, respectively. Incubation in the presence of 160 nM TPA for 24 h reduced high-affinity phorbol dibutyrate-binding sites [dissociation constant (Kd) = 5 nM; maximum binding (Bmax) = 1.2 pmol/mg protein] to undetectable levels. In such cells, exposure to 10% serum for 6 h still resulted in two- and fourfold increment in mRNA alpha 1 and mRNA beta 1 abundances, respectively, while further addition of TPA to these protein kinase C (PKC)-depleted cells resulted in no change in the subunit mRNA abundances. The increments in mRNA alpha 1 content in response to 10% serum and 160 nM TPA at 6 h were additive, whereas the increments in mRNA beta 1 were not. The following agents increased mRNA alpha 1 and mRNA beta 1 abundance in both control and PKC-depleted cells: epidermal growth factor, platelet-derived growth factor, basic fibroblast growth factor, insulin, dexamethasone, and hypothyroid calf serum. In contrast, N6,2'-O-dibutyryl-adenosine 3',5'-cyclic monophosphate and aldosterone had no effect.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Serum and growth factor induction of Na(+)-K(+)-ATPase subunit mRNAs in Clone 9 cells: role of protein kinase C. 165 70

Initiation and development of proliferative responses to growth factors are often associated to an activation of the Na+/H+ exchange. The present work examined the effect of endothelin (ET-1) on cell proliferation and Na+/H+ exchange in cultured vascular smooth muscle cells. In rat aortic vascular smooth muscle, ET-1 (0.1 to 10 nmol/L) increased the [3H] thymidine uptake in a dose-dependent manner. This effect was enhanced in presence of insulin (0.1 micrograms/mL to 10 micrograms/mL) as a function of concentration. The Na+/H+ exchange, which is a necessary response for mitogenesis, was dose-dependently stimulated by increasing concentrations of ET-1 (1 to 1000 nmol/L) and presented a biphasic response: a transient acidification followed by a sustained alkalinization. Alkalinization induced by ET-1 was similar to that obtained by the phorbol 12-myristate 13-acetate (PMA). An inhibitor of protein kinase C, H7, or a long-term pretreatment of cells with PMA for 24 h inhibited the effect of ET-1 and PMA on Na+/H+ exchange. These results confirm that ET-1 could act as a growth factor for vascular smooth muscle cells and suggest that its mode of action depends for a large part to protein kinase C activation.
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PMID:Proliferation and Na+/H+ exchange activation by endothelin in vascular smooth muscle cells. 165 43

Hyperglycemia causes insulin-receptor kinase (IRK) resistance in fat cells. We characterized the mechanism of IRK inhibition and studied whether it is the consequence of a glucose-induced stimulation of protein kinase C (PKC). Fat cells were incubated for 1 or 12 h in culture medium containing either a low-(5-mM) or high- (25-mM) glucose concentration. IRK was isolated, insulin binding was determined, and autophosphorylation was studied in vitro with [gamma-32P]ATP or was determined by Western blotting with anti-phosphotyrosine antibodies. Substrate phosphorylation was investigated with the artificial substrate poly(Glu80-Tyr20). Partially purified insulin receptor from rat fat cells, which were cultured under high-glucose conditions for 1 or 12 h, showed no alteration of insulin binding but a reduced insulin effect on autophosphorylation (30 +/- 7% of control) and poly(Glu80-Tyr20) phosphorylation (55.5 +/- 9% of control). Lineweaver-Burk plots of the enzyme kinetics revealed, beside a reduced Vmax, and increased KM (from 30 microM to 80 microM) for ATP of IRK from high-glucose-treated cells. Because a similar inhibition pattern was earlier found for IRK from fat cells after acute phorbol ester stimulation, we investigated whether activation of PKC might be the cause of the reduced IRK activity. We isolated PKC from the cytosol and the membrane fraction of high- and low-glucose fat cells and determined the diacylglycerol- and phospholipid-stimulated PKC activity toward the substrate histone. There was no significant change of cytosolic PKC; however, membrane-associated PKC activity was increased in high-glucose-treated cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Prevention by protein kinase C inhibitors of glucose-induced insulin-receptor tyrosine kinase resistance in rat fat cells. 165 68

The effects of 12-O-tetradecanoylphorbol-13-acetate (TPA) and insulin were compared in wild-type human insulin receptors (HIRc cells) and human insulin receptors lacking 43 COOH-terminal amino acid residues (HIR delta CT cells). TPA increased total phosphorylation of the wild-type insulin receptor and inhibited insulin-stimulated autophosphorylation by 32 +/- 10% in HIRc cells. TPA inhibited insulin-stimulated autophosphorylation by 46 +/- 14% in HIR delta CT cells and also caused a 65% decrease in basal phosphorylation. Insulin-stimulated tyrosine kinase activity for poly(Glu4/Tyr1) was inhibited by TPA in HIRc and HIR delta CT cells by 50 and 40%, respectively. TPA decreased insulin-stimulated glucose incorporation into glycogen by 50% in HIRc cells and to near basal levels in HIR delta CT cells; this inhibitory effect of TPA was reversed in both cell lines by staurosporine. In conclusion, 1) TPA-induced inhibition of insulin receptor tyrosine autophosphorylation was linked to concomitant inhibition of the biological effects of insulin in cells expressing either wild-type or COOH-terminal truncated insulin receptors; and 2) the inhibitory effects of TPA were not dependent upon phosphorylation of COOH-terminal residues and furthermore appeared to be independent of phosphorylation of any insulin receptor serine/threonine residues. These findings suggest a novel protein kinase C mechanism that results in altered insulin receptor function without increasing phosphorylation of the receptor.
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PMID:Phorbol ester-mediated protein kinase C interaction with wild-type and COOH-terminal truncated insulin receptors. 165 81

Glucose-induced changes in cytoplasmic pH (pHi) were investigated using pancreatic beta-cells isolated from obese hyperglycemic mice. Glucose, at concentrations above 3-5 mM, depolarized the beta-cell and increased pHi, cytoplasmic free Ca2+ ([Ca2+]i), and insulin release. This increase in pHi was dependent on the presence of extracellular Na+ and was inhibited by 5-(N-ethyl-N-isopropyl) amiloride, a blocker of Na+/H+ exchange. Stimulation of protein kinase C with phorbol ester also induced an alkalinization. However, when protein kinase C activity was down-regulated, glucose stimulation still induced alkalinization. At 20 mM glucose, 10 mM NH4Cl induced a marked rise in pHi, paralleled by repolarization, inhibition of electrical activity, and decreases in both [Ca2+]i and insulin release. Reduction in [Ca2+]i was prevented by 200 microM tolbutamide, but not by 10 mM tetraethylammonium. At 4 mM glucose, NH4Cl induced a transient increase in insulin release, without changing [Ca2+]i. Exposure of beta-cells to 10 mM sodium acetate caused a persistent decrease in pHi, an effect paralleled by a small transient increase in [Ca2+]i. Acidification per se did not change the beta-cell sensitivity to glucose, not excluding that the activity of the ATP-regulated K+ channels may be modulated by changes in pHi.
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PMID:Glucose-induced increase in cytoplasmic pH in pancreatic beta-cells is mediated by Na+/H+ exchange, an effect not dependent on protein kinase C. 166 Aug 75

The pathways depicted in Figure 1 summarize the data discussed in this article. In neurons, the binding of insulin and IGF-I to their respective receptors triggers autophosphorylation of the receptor beta-subunits. IGF-II binds to both neuronal insulin and IGF-I receptors and can stimulate autophosphorylation of either receptor type. In addition to enhancing insulin and IGF-I receptor autophosphorylation, all 3 peptides stimulate the tyrosine phosphorylation of a 70 kDa protein with a similar time course and dose response to receptor phosphorylation. The identity of pp70 is unknown, although the close temporal relationship between pp70 phosphorylation and neurite outgrowth suggests a potential role for this protein. Subsequent to these very early events, two neuronal serine kinases are activated by insulin. One has S6 kinase activity and may represent either the pp90rsk or pp70 class of S6 kinases. Since S6 kinases are activated by direct phosphorylation rather than by second messengers, it is likely that a neuronal S6 kinase kinase exists. The activation of S6 kinase is likely to mediate insulin's effects on neuronal protein synthesis or other growth-related processes. The second serine kinase that is activated by insulin is PKC epsilon. This enzyme is largely restricted to the nervous system, so this signalling pathway may be neuronal-specific. The mechanism of activation of PKC epsilon is unknown, although preliminary data suggests that enhanced phosphorylation of the enzyme is involved. Studies are currently underway to investigate the potential role of diacylglycerol, a potential second messenger generated from either phosphotidylinositol or phosphotidylcholine hydrolysis, in the activation of PKC epsilon by insulin.
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PMID:Regulation of protein phosphorylation by insulin and insulin-like growth factors in cultured fetal neurons. 166 64

Lutropin (LH) receptors in rat granulosa cells are expressed by activation of cAMP-dependent protein kinase in response to follitropin (FSH). In the present study, 12-O-tetradecanoylphorbol 13-acetate (TPA) could cause a dose-dependent expression of LH receptors in the presence of insulin, but not in the absence of insulin, as measured by binding of 125I-deglycosylated human choriogonadotropin (DGhCG). The synergistic action of TPA with insulin was achieved at 1 nM and 10 mIU/ml, respectively. The receptor expression induced by this synergistic action was accompanied by cAMP accumulation which was detected after a lag time of 6 h following exposure to TPA. However, a synthetic diacylglycerol and non-protein kinase C activating phorbol derivatives did not mimic the effect of TPA on the receptor expression. In addition, insulin modulated the inhibitory effect of TPA in FSH-induced LH receptor expression, indicating a peculiar action of insulin in the receptor expression. Indomethacin treatment led to a dose-dependent inhibition in the receptor expression in the cells treated with TPA plus insulin more than that in the cells with FSH plus insulin, suggesting that the synergistic action was dependent upon cyclooxygenase and/or phospholipase A2 activity. It was shown by Scatchard analysis of LH receptors and kinetic studies of hCG-stimulated cAMP formation that the synergistic action of TPA with insulin led to expression of functional LH receptors coupled with the adenylate cyclase system in cultured granulosa cells.
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PMID:Tumor-promoting phorbol ester acts synergistically with insulin to induce lutropin receptor expression in rat granulosa cells. 166 32

In vitro, activation of the cAMP signalling pathway stimulates, whereas activation of PKC inhibits, 1,25(OH)2D3 synthesis. Since PTH activates both pathways, the ultimate effect of PTH on 1 alpha-hydroxylation in vivo likely depends on other endocrine-autocrine factors that impinge onto these signal transduction cascades. For example, 1,25(OH)2D3, a known repressor of 1 alpha-hydroxylation, may increase renal PKC amount-activity, thereby enhancing the inhibitory arm and preventing PTH stimulation of the 1-OHASE. In contrast, studies with diabetic rats suggest that insulin may allow cAMP-mediated stimulation to override PKC-mediated inhibition of 1-OHASE activity. Analogous to models proposed for regulation of adrenal steroid hydroxylases, it is likely that regulation of renal vitamin D hydroxylation involves both acute (reversible phosphorylation) and chronic (modulation of gene expression) mechanisms. However, the molecular details of these regulatory mechanisms remain to be resolved.
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PMID:Regulation of renal 25(OH)D3 1 alpha-hydroxylase: signal transduction pathways. 166 75

Oxytocin (OT) produced a dose-dependent increase in somatostatin, glucagon and insulin release by isolated mouse islets. A small effect on somatostatin release was observed with 0.1 nM-OT, but 1-10 nM-OT was required to affect A- and B- cells significantly. The effects of OT on somatostatin and glucagon release were similar in the presence of 3 mM- and 10 mM-glucose. No change in insulin release was produced by OT in 3 mM-glucose, but a stimulation was still observed in the presence of a maximally effective concentration of glucose (30 mM). The increase in insulin release produced by OT (in 15 mM-glucose) was accompanied by small accelerations of 86Rb and 45Ca efflux from islet cells. Omission of extracellular Ca2+ accentuated the effect of OT on 86Rb efflux, attenuated that on 45Ca efflux, and abolished that on release. OT never inhibited 86Rb efflux. It did not affect the resting potential of B-cells, but slightly increased the Ca2(+)-dependent electrical activity induced by 15 mM-glucose. OT did not affect cyclic AMP levels, but increased inositol phosphate levels in islet cells. It is suggested that the amplification of glucose-induced insulin release that OT produces is due to a stimulation of phosphoinositide metabolism, and presumably an activation of protein kinase C, rather than to a change in cyclic AMP levels or a direct action on the membrane potential. Since OT is present in the pancreas, it is possible that it exerts a neuropeptidergic control of the islet function.
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PMID:Mechanisms of the stimulation of insulin release by oxytocin in normal mouse islets. 167 63


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