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)

We examined the short-term regulation of the phosphorylation of the mid-sized neurofilament subunit (NF-M) by kinases which were activated in rat pheochromocytoma (PC12) cells by nerve growth factor (NGF) and/or 12-O-tetradecanoylphorbol 13-acetate (TPA). We found that NGF and TPA, alone or in combination, increased (a) the incorporation of [32P]Pi into NF-M and (b) the rate of conversion of NF-M from a poorly phosphorylated to a more highly phosphorylated form. This was not due to increased synthesis of NF-M, because NGF alone did not increase NF-M synthesis and TPA alone or TPA and NGF together inhibited the synthesis of NF-M. Further, an increase in calcium/phospholipid-dependent kinase (PKC) activity resulting from the treatment of PC12 cells with NGF and TPA was observed concomitant with the increased phosphorylation of NF-M. This PKC activity was determined to be derived from the PKC alpha and PKC beta isozymes. Finally, when PC12 cells were rendered PKC-deficient by treatment with 1 muM TPA for 24 h, NGF maintained the ability to induce an increase in NF-M phosphorylation, though not to the level attained in cells which were not PKC-deficient. These data suggest that NGF with or without TPA stimulates NF-M phosphorylation as a result of a complex series of events which include PKC-independent and PKC-dependent pathways.
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PMID:The differential role of protein kinase C isozymes in the rapid induction of neurofilament phosphorylation by nerve growth factor and phorbol esters in PC12 cells. 186 Nov 52

Adrenal chromaffin cells respond to nerve growth factor (NGF) in vitro by expressing neuronal characteristics and, over a period of 2 to 4 weeks, transdifferentiating into postmitotic sympathetic neurons. Phorbol myristate acetate (PMA) is a potent activator of protein kinase C (PKC); chronic exposure to PMA mimics the initial actions of NGF by promoting the outgrowth of neurites and increasing the incorporation of [3H] thymidine in primary cultures of adrenal chromaffin cells from young rats. PMA and NGF affect the same populations of cells and even individual neurites. These effects are specific for active phorbol ester and do not result from the release of NGF or FGF in the cultures. As in the case of NGF, the effects are inhibited by glucocorticoids. The PKC inhibitor staurosporine inhibits the effects of PMA, as well as those of NGF, in a dose-dependent manner. These results suggest that a modulation in activity of PKC is important in the neuritogenic and proliferative effects of NGF, at least for an initial period of approximately 1 week.
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PMID:Chronic exposure to an activator of protein kinase C mimics early effects of NGF in chromaffin cells. 186 71

The effects of neurotransmitters and peptides on phosphoinositide hydrolysis were studied by measuring [3H]inositol monophosphate ([3H]IP) and protein kinase C (PKC) activity in the sympathetic and sensory neuronal cultures of the chick embryo. [3H]IP was increased in sympathetic neurons by acetylcholine (ACh), muscarine, serotonin (5-HT), and vasoactive intestinal polypeptide. ACh, muscarine, 5-HT, and bradykinin increased [3H]IP in sensory neuronal cultures. Dopamine, norepinephrine, histamine, and nerve growth factor did not stimulate [3H]IP formation in both cultures. ACh and phorbol 12,13-dibutyrate (PDB) increased the PKC activity by two- to sevenfold in the particulate fraction of both cultures. In sympathetic neurons, PKC activity was increased in the particulate fraction; activity in the cytosolic fraction was not affected. There was a 50% decline in the protein kinase C activity of the cytosolic fraction after PDB and ACh treatment of sensory cultures. The decline in PKC activity in the cytosolic fraction was attributed to the presence of nonneuronal cells in sensory cultures. To confirm this, the enzyme activity was determined in tissues that contain a heterogeneous population of cells. PDB activated PKC in the adrenal medulla and the brain of the rat. In both tissues there was a 65% decline in the PKC activity of the cytosolic fraction and about a 75% increase in the particulate fraction. We conclude that the mechanism of activation of protein kinase C in pure cultures of sympathetic neurons is different than in tissues containing a mixed population of neurons and nonneuronal cells.
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PMID:Effects of neurotransmitters and peptides on phospholipid hydrolysis in sympathetic and sensory neurons. 197 Jul 91

The role of protein kinase C (PKC) in mediating nerve growth factor (NGF) or basic fibroblast growth factor (bFGF)-stimulated SCG10 and c-fos expression as well as neurite outgrowth was studied in PC12 cells. Activators of PKC such as phorbol 12-myristate 13-acetate (PMA) or 1-oleoyl 2-acetyl glycerol mimicked the stimulatory effect of NGF and bFGF on SCG10 mRNA levels. Induction involved a protein synthesis-dependent mechanism and was maximal within 12-24 h of exposure. Chronic treatment of the cells with PMA for up to 8 days resulted in a substantial decrease (approximately 90%) in total PKC activity in the continued presence of PMA. PKC depletion did not affect NGF- or bFGF-stimulated SCG10 mRNA induction and bFGF-stimulated c-fos mRNA induction. However, NGF-stimulated c-fos mRNA induction was attenuated. In addition, induction of neurite outgrowth was not abolished in PKC-depleted cells. The results imply that PKC is not involved in NGF- and bFGF-stimulated SCG10 mRNA induction and neurite outgrowth. Furthermore, while the effect of bFGF on c-fos mRNA induction is PKC-independent, that of NGF is mediated by PKC-dependent and -independent pathways.
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PMID:Effect of nerve growth factor and fibroblast growth factor on SCG10 and c-fos expression and neurite outgrowth in protein kinase C-depleted PC12 cells. 210 18

A dominant inhibitory mutation of Ha-ras which changes Ser-17 to Asn-17 in the gene product p21 [p21 (Asn-17)Ha-ras] has been used to investigate the role of ras in neuronal differentiation of PC12 cells. The growth of PC12 cells, in contrast to NIH 3T3 cells, was not inhibited by p21(Asn-17)Ha-ras expression. However, PC12 cells expressing the mutant Ha-ras protein showed a marked inhibition of morphological differentiation induced by nerve growth factor (NGF) or fibroblast growth factor (FGF). These cells, however, were still able to respond with neurite outgrowth to dibutyryl cyclic AMP and 12-O-tetradecanoylphorbol-13-acetate (TPA). Induction of early-response genes (fos, jun, and zif268) by NGF and FGF but not by TPA was also inhibited by high levels of p21(Asn-17)Ha-ras. However, lower levels of p21(Asn-17) expression were sufficient to block neuronal differentiation without inhibiting induction of these early-response genes. Induction of the secondary-response genes SCG10 and transin by NGF, like morphological differentiation, was inhibited by low levels of p21(Asn-17) whether or not induction of early-response genes was blocked. Therefore, although inhibition of ras function can inhibit early-response gene induction, this is not required to block morphological differentiation or secondary-response gene expression. These results suggest that ras proteins are involved in at least two different pathways of signal transduction from the NGF receptor, which can be distinguished by differential sensitivity to p21(Asn-17)Ha-ras. In addition, ras and protein kinase C can apparently induce early-response gene expression by independent pathways in PC12 cells.
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PMID:Effect of a dominant inhibitory Ha-ras mutation on neuronal differentiation of PC12 cells. 211 94

Serum-free mouse embryo cells cultured in medium supplemented with insulin, transferrin, high-density lipoprotein, and fibronectin are dependent on epidermal growth factor for survival. Cycloheximide or actinomycin D prevented cell death caused by growth factor deprivation, suggesting that cell death required the synthesis of RNA and protein, a phenomenon similar to that reported for neuronal cell death in the absence of nerve growth factor. Orthovanadate, an inhibitor of phosphotyrosine phosphatases, and 12-O-tetradecanoylphorbol-13-acetate, an activator of protein kinase C, also prevented serum-free mouse embryo cell death in the absence of epidermal growth factor.
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PMID:Death of serum-free mouse embryo cells caused by epidermal growth factor deprivation is prevented by cycloheximide, 12-O-tetradecanoylphorbol-13-acetate, or vanadate. 215 51

Past work established a cell-free assay for a nerve growth factor (NGF)-activated protein kinase activity (designated N-kinase) that utilizes tyrosine hydroxylase and histone H1 as substrates and that is distinct from a variety of well-characterized kinases. This study explores the specificity and mechanistic pathway(s) by which N-kinase activity is regulated in PC12 rat pheochromocytoma cells. N-kinase is rapidly activated in these cells by treatment with NGF, epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), phorbol ester, or dibutyryl cyclic AMP. Our data indicate that the stimulated activity is the same for each agent by several criteria: It exhibits the same characteristic biphasic elution pattern by Mono S fast protein liquid chromatography (FPLC), except for the case of dibutyryl cyclic AMP in which one of the activity peaks is somewhat shifted; it shows the same elution pattern by FPLC on a Superose 12 column; it possesses identical substrate specificity; and, except in the case of dibutyryl cyclic AMP, it does not show additivity when each agent is added simultaneously with NGF. The multiple forms of N-kinase are interconvertible in that rechromatography on a Mono S column yields a single peak of activity. Also, when NGF and dibutyryl cyclic AMP are simultaneously presented to cells, the chromatographic profile resembles that with NGF alone. Activation occurs through several independent initial pathways. Down-regulation of protein kinase C by phorbol ester pretreatment prevents N-kinase activation by phorbol ester, but not by the other agents. A PC12 cell-derived line deficient in cyclic AMP-dependent protein kinase II activity exhibits N-kinase activation by all treatments except dibutyryl cyclic AMP. The properties of N-kinase suggests that it is similar or identical to the ribosomal S6 protein kinase described by Blenis and Erikson. Additional experiments revealed that N-kinase activity can be stimulated in several cell lines in addition to PC12 cells. These findings indicate that the N-kinase can be activated via multiple second-messenger pathways and that it could therefore potentially play a significant role in mediating shared intracellular responses to various extracellular signals.
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PMID:Multiple pathways of N-kinase activation in PC12 cells. 215 51

A newly synthesized isoquinolinesulfonamide, H-89 (N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinoline-sulfonamide), was shown to have a potent and selective inhibitory action against cyclic AMP-dependent protein kinase (protein kinase A), with an inhibition constant of 0.048 +/- 0.008 microM. H-89 exhibited weak inhibitory action against other kinases and Ki values of the compound for these kinases, including cGMP-dependent protein kinase (protein kinase G), Ca2+/phospholipid-dependent protein kinase (protein kinase C), casein kinase I and II, myosin light chain kinase, and Ca2+/calmodulin-dependent protein kinase II were 0.48 +/- 0.13, 31.7 +/- 15.9, 38.3 +/- 6.0, 136.7 +/- 17.0, 28.3 +/- 17.5, and 29.7 +/- 8.1 microM, respectively. Kinetic analysis indicated that H-89 inhibits protein kinase A, in competitive fashion against ATP. To examine the role of protein kinase A in neurite outgrowth of PC12 cells, H-89 was applied along with nerve growth factor (NGF), forskolin, or dibutyryl cAMP. Pretreatment with H-89 led to a dose-dependent inhibition of the forskolin-induced protein phosphorylation, with no decrease in intracellular cyclic AMP levels in PC12D cells, and the NGF-induced protein phosphorylation was not not inhibited. H-89 also significantly inhibited the forskolin-induced neurite outgrowth from PC12D cells. This inhibition also occurred when H-89 was added before the addition of dibutyryl cAMP. Pretreatment of PC12D cells with H-89 (30 microM) inhibited significantly cAMP-dependent histone IIb phosphorylation activity in cell lysates but did not affect other protein phosphorylation activity such as cGMP-dependent histone IIb phosphorylation activity, Ca2+/phospholipid-dependent histone IIIs phosphorylation activity, Ca2+/calmodulin-dependent myosin light chain phosphorylation activity, and alpha-casein phosphorylation activity. However, this protein kinase A inhibitor did not inhibit the NGF-induced neurite outgrowth from PC12D cells. Thus, the forskolin- and dibutyryl cAMP-induced neurite outgrowth is apparently mediated by protein kinase A while the NGF-induced neurite outgrowth is mediated by a protein kinase A-independent pathway.
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PMID:Inhibition of forskolin-induced neurite outgrowth and protein phosphorylation by a newly synthesized selective inhibitor of cyclic AMP-dependent protein kinase, N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide (H-89), of PC12D pheochromocytoma cells. 215 66

The regulation of the preproneuropeptide Y gene (NPY gene) by nerve growth factor (NGF) and second messenger systems in PC12 rat pheochromocytoma cells was studied by means of steady state NPY mRNA and nuclear run-on transcription analyses. Treatment of cells with 2.5S NGF increased the NPY mRNA abundance up to 100-fold over 1-6 days. Glucocorticoids (e.g. dexamethasone) potentiated by up to 3-fold the stimulation by NGF at early times (less than or equal to 7 h), but strongly suppressed it at later times (greater than or equal to 25 h). The response to NGF was blocked by cycloheximide, indicating a requirement for ongoing protein synthesis. Treatment of cells for 24-48 h with combinations of NGF, forskolin to elevate cAMP levels, and phorbol-12-myristate-13-acetate (PMA) to activate protein kinase C synergistically elevated NPY mRNA levels. The rate of NPY gene transcription in PC12 nuclei was increased by NGF, forskolin plus PMA, or NGF plus forskolin plus PMA, indicating that these regulators act at least in part at a transcriptional level. beta-Actin gene transcription also was elevated synergistically by forskolin and PMA. In summary, NPY gene transcription and NPY mRNA levels are controlled by multiple, potentially interacting regulatory systems. The striking antagonism between NGF and glucocorticoids may reflect the hormonal control of phenotypic choice during neural crest differentiation.
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PMID:Transcriptional regulation of the neuropeptide Y gene by nerve growth factor: antagonism by glucocorticoids and potentiation by adenosine 3',5'-monophosphate and phorbol ester. 216 Jun 1

The cell line A126-1B2 is a PC12-derived mutant that is resistant to the toxic effects of dibutyryladenosine 3':5'-cyclic monophosphate (dbcAMP) and is deficient in adenosine 3':5'-cyclic monophosphate (cAMP)-dependent protein kinase II (PKAII). This mutant formed neurites in response to nerve growth factor (NGF), but not in response to dbcAMP; and dbcAMP did not increase the rate of NGF-dependent neurite formation. Thus, while PKAII is essential for process formation in response to agents that act through the cAMP-dependent pathway, activation of PKAII is not essential for NGF-dependent neurite formation. Unexpectedly, NGF and phorbol 12-myristate 13-acetate (PMA; 10-1,000 nM) synergistically stimulated the formation of short processes that were apparent within 30 min of NGF addition in 85% of these mutant cells. These processes were similar, but not identical, in appearance to the NGF-dependent neurites that formed only after a period of 24-48 hr. This effect is dependent on the activation of protein kinase C (PKC) because an inactive phorbol ester was without effect. In contrast, there was only a small effect of NGF and/or PMA on process formation in wild type cells within the first few hours. The effect of PMA is not augmented by dbcAMP in the A126-1B2 mutant cells. After several hours, PMA caused a concentration-dependent decrease in cell adhesion; and higher concentrations of PMA resulted in a transient detachment of the cells and a loss of neurites. These experiments suggest a role for PKC in the regulation of process formation.
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PMID:Role of the cAMP-dependent protein kinase and protein kinase C in regulating the morphological differentiation of PC12 cells. 216 31


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