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)

PC12 cells were used to compare signaling pathways activated by alpha1-adrenergic receptor (AR) subtypes. PC12 cells were transfected with human alpha1A, alpha1B, or alpha1D-ARs, and subclones stably expressing receptor densities in physiological ranges isolated and characterized. Norepinephrine (NE) activated a large number of signaling pathways in transfected cells, including inositol phosphate formation, intracellular calcium, all three arms of the mitogen activated protein kinase pathways, and a number of tyrosine kinases. Activation of mitogen activated protein kinase pathways and tyrosine kinases was not blocked by chelation of intracellular calcium with BAPTA or inhibition of protein kinase C. NE also activated luciferase reporter constructs for seven different transcription factors (AP1, SRE, CRE, NFkappaB, NFAT, Stat, GAS) following transfection into alpha1A-AR expressing PC12 cells. However, similar increases in inositol phosphate formation and intracellular Ca2+ caused by purinergic P2Y2 receptor activation did not activate any of these reporters. Comparison of alpha1-AR subtypes showed that the alpha1A activated all seven reporters, the alpha1B showed smaller effects, while the alpha1D was ineffective. NE caused differentiation of alpha1A, but not alpha1B or alpha1D, -AR expressing PC12 cells similar to that caused by NGF. This NE-induced differentiation was reduced or blocked by all inhibitors tested. We conclude that alpha1-ARs activate many signaling pathways and transcriptional responses in PC12 cells, which are not linearly related to second messenger production, and which may differ for different alpha1-AR subtypes.
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PMID:Signaling pathways activated by alpha1-adrenergic receptor subtypes in PC12 cells. 1135 36

Atypical protein kinase Cs zeta and lambda/iota play a functional role in the regulation of NGF-induced differentiation and survival of pheochromocytoma, PC12 cells [Coleman and Wooten, 1994; Wooten et al., 1999]. Here we demonstrate an NGF-dependent interaction of aPKC with its binding protein, ZIP/p62. Although, ZIP/p62 was not a PKC-iota substrate, the formation of a ZIP/p62-aPKC complex in PC12 cells by NGF occurred post activation of PKC-iota and was regulated by the tyrosine phosphorylation state of aPKC. Furthermore, NGF-dependent localization of ZIP/p62 was observed within vesicular structures, identified as late endosomes by colocalization with a Rab7 antibody. Both ZIP/p62 as well as PKC-iota colocalized with Rab7 upon NGF stimulation. Inhibition of the tyrosine phosphorylation state of PKC-iota did not prevent movement of ZIP/p62 to the endosomal compartment. These observations indicate that the subcellular localization of ZIP/p62 does not depend entirely upon activation of aPKC itself. Of functional importance, transfection of an antisense p62 construct into PC12 cells significantly diminished NGF-induced neurite outgrowth. Collectively, these findings demonstrate that ZIP/p62 acts as a shuttling protein involved in routing activated aPKC to an endosomal compartment and is required for mediating NGF's biological properties.
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PMID:Nerve growth factor stimulates the interaction of ZIP/p62 with atypical protein kinase C and targets endosomal localization: evidence for regulation of nerve growth factor-induced differentiation. 1150 Sep 22

Herein, we employed a combined approach of molecular modeling and site-directed mutagenesis to address the role of tyrosine phosphorylation in transport of atypical protein kinase C (aPKC) into the nucleus. Computer modeling of the three-dimensional structure of the aPKC catalytic core, reveals that tyrosine 256 (Tyr256) is located at the lip of the activation loop and is conserved among members of the aPKC family, iota/lambda and zeta. Based on these findings, we examined whether tyrosine phosphorylation of aPKC on the activation lip may facilitate nuclear import. An antiserum was generated that selectively recognizes the phosphorylated Tyr256 residue in aPKC. By isolating nuclei of PC12 cells and immunoprecipitating aPKC with Ab-PY256, we observed that Tyr256 is rapidly phosphorylated upon NGF treatment prior to entry of aPKC into the nucleus. aPKC was observed to exclusively bind to importin-beta. The interaction between importin-beta and aPKC was enhanced upon tyrosine phosphorylation of aPKC and binding was abrogated when Tyr256 was mutated to phenylalanine. We propose that phosphorylation of aPKC at Tyr256 induces a conformation, whereby, the arginine-rich NLS is exposed, which then binds importin-beta leading to import of aPKC into the nucleus. Altogether, these findings document a novel role for the tyrosine phosphorylation in regulating import of atypical PKC into the nucleus.
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PMID:Phosphorylation of tyrosine 256 facilitates nuclear import of atypical protein kinase C. 1189 49

Panax ginseng is a traditional Chinese herb with a wide range of therapeutic benefits. Recent studies focusing on its effect on the central nervous system have revealed that ginseng has neurotrophic effects including differentiation of neurons. However, most studies involve use of the water-soluble fraction called saponin, and little is known about the effect of the lipophilic fraction. In the present study, we have shown that the lipophilic fraction of ginseng at a concentration of between 0.1 and 50 microg/ml can induce neurite outgrowth of PC12 cells in a dose-dependent manner. Nearly all cells showed morphological differentiation in response to the lipophilic fraction. This morphological differentiation of PC12 cells appeared to be similar to that of NGF. The lipophilic fraction of ginseng also induced neurite extension and promoted survival of rat cortical neurons at a concentration of between 0.025 and 1 microg/ml. These neurotrophic effects on PC12 cells and cortical neurons were not inhibited by K252b, which selectively blocks neurotrophin actions by inhibiting trk-type receptor tyrosine phosphorylation. This suggests that trks do not participate in the neurotrophic action of the lipophilic fraction. However, the effects were completely attenuated by sphingosine, polymyxin B or staurosporin, known inhibitors of protein kinase C (PKC) and calmodulin-dependent kinases. Our results suggest that the lipophilic fraction of ginseng exerts its neurotrophic effects via PKC-dependent pathways.
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PMID:Lipophilic fraction of Panax ginseng induces neuronal differentiation of PC12 cells and promotes neuronal survival of rat cortical neurons by protein kinase C dependent manner. 1223 Dec 51

We used serial analysis of gene expression to identify new NGF-responsive immediate early genes (IEGs) with potential roles in neuronal differentiation. Among those identified was MafK, a small Maf family basic region and leucine zipper transcriptional repressor and coactivator expressed in immature neurons. NGF treatment elevates the levels of both MafK transcripts and protein. In contrast, there is no effect on expression of the closely related MafG. Unlike many other NGF-responsive IEGs, MafK regulation shows selectivity and is unresponsive to epidermal growth factor, depolarization, or cAMP derivatives. Inhibitor studies indicate that NGF-promoted MafK regulation is mediated by an atypical isoform of PKC but not by mitogen-activated kinase kinase, phospholipase Cgamma, or phosphoinositide 3'-kinase. Interference with MafK expression or activity by small interfering RNA and dominant negative strategies, respectively, suppresses NGF-promoted outgrowth and maintenance of neurites by PC12 cells and neurite outgrowth by immature telencephalic neurons. Our findings support a role for MafK as a novel regulator of neuronal differentiation.
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PMID:The basic region and leucine zipper transcription factor MafK is a new nerve growth factor-responsive immediate early gene that regulates neurite outgrowth. 1238 4

It has been previously shown that 5-HT uptake inhibition produced by tetanus toxin (TeTx) corresponds to a non-competitive inhibition, and it is preceded by phosphorylation of the tyrosine-kinase receptor trkA, phospholipase C activation and translocation of protein kinase C isoforms [FEBS Lett. 481 (2000) 177; FEBS Lett. 486 (2000) 136]. In the present work, it is shown that agonists of tyrosine-kinase receptors (NGF, EGF, basic FGF) enhance Na(+)-dependent, 5-hydroxytryptamine (serotonin, 5-HT) uptake in the synaptosomal-enriched P(2) fraction from rat-brain, suggesting a divergence in the intracellular signal pathways triggered by TeTx and by agonists of TyrK receptors. Co-applications of TeTx and agonists of TyrK receptors result in a mutual and partial reversion of their effects on 5-HT transport. In spite of their differences on transport, TeTx, TPA and NGF produce an increase in serotonin transporter phosphorylation in Ser separately, which is abolished by the PKC-inhibitor bisindolylmaleimide-1. Co-application of sodium vanadate, a tyrosine-phosphatase inhibitor, partially abolishes the effect produced by TeTx, whereas genistein, a tyrosine-kinase inhibitor, does not exert any variation of TeTx inhibition. Analyses by immunoblotting of the activation of specific PKC isoforms activation, determined as translocation to the membrane compartment, reveals differences in the pattern produced by NGF and TeTx. PKC gamma, delta, and epsilon isoforms are equally activated by both compounds, whereas the beta isoform is activated in a sustained manner only by TeTx, and the alpha isoform is only down-regulated by NGF. The aim of the present work was to explore whether NGF have the same effect on 5-HT transport than TeTx, since both compounds share the ability of activate part of the same transduction pathways. In spite of this, growth factors and TeTx show an opposite effect on 5-HT transport, even though SERT phosphorylation is enhanced in both cases. The differential effect on alpha- and beta-PKC isoenzymes found between NGF and TeTx action could explain this apparent discrepancy.
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PMID:Serotonin transport is modulated differently by tetanus toxin and growth factors. 1259 Sep 35

It has been well established that exposure to Pb during critical periods of brain development results in both cognitive and behavioral deficits. Although the mechanism by which Pb induces developmental neurotoxicity is unknown, it may involve alterations in transcription of genes that are essential for growth and differentiation. Recent studies reveal that Pb interferes with growth and differentiation by acting on the transcription factor Sp1. Pb-induced changes in the activity of Sp1 may be consequent to alterations in intermediates in signal transduction pathways. This study examines both in vivo and in vitro the role of signaling factors in mediating the effects of Pb on Sp1 DNA-binding. Hippocampal developmental profiles of Sp1 DNA-binding, PKC, and MAPK protein levels were monitored in Pb-exposed rats. Pb exposure resulted in an induction of Sp1 DNA-binding during PND 5-10 followed by a subsequent decline on PND 15-20. The protein expression profiles for PKCalpha and MAPK followed a relatively similar pattern. To examine the interdependence between Sp1 DNA-binding, PKCalpha, and MAPK, PC12 cells were exposed to Pb and/or NGF. Pb or NGF exposure increased Sp1 DNA-binding. Addition of the PKC inhibitor (staurosporine) diminished NGF and Pb-induced Sp1 DNA-binding, while the MAPK inhibitor (PD 98059), completely abolished both basal and induced Sp1 DNA-binding. These findings demonstrate that Sp1 DNA-binding is regulated by PKC and MAPK, which may serve as mediators through which Pb may indirectly modulate Sp1 DNA-binding.
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PMID:Intracellular signaling pathways involved in mediating the effects of lead on the transcription factor Sp1. 1285 56

The mechanism to enhance nerve growth factor (NGF, 2 ng/ml)-induced neurite outgrowth from PC12D cells by nardosinone isolated from Nardostachys chinensis was examined. It was shown that the potentiation of the NGF-induced neurite outgrowth by nardosinone was mitogen-activated protein (MAP) kinase-dependent, but was not accompanied by stimulation of NGF-induced increase in MAP kinase phosphorylation. Furthermore, this augmentation of NGF-induced neurite outgrowth was abolished by GF109203X, a protein kinase C (PKC) inhibitor. These results suggest that the enhancement of NGF-induced neurite outgrowth from PC12D cells by nardosinone involves activation of a down-stream step of the MAP kinase-dependent cascade of NGF coupled with PKC.
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PMID:Nardosinone enhances nerve growth factor-induced neurite outgrowth in a mitogen-activated protein kinase- and protein kinase C-dependent manner in PC12D cells. 1450 Nov 62

We have recently shown that the presence of albumin in astrocytes triggers the synthesis and release of oleic acid, which behaves as a neurotrophic factor for neurons. Thus, oleic acid promotes axonal growth, neuronal clustering, and the expression of the axonal growth-associated protein, GAP-43. In this work we show that oleic acid upregulates GAP-43 expression by a protein kinase C (PKC)-dependent mechanism. Since GAP-43 expression has been shown to be upregulated by several neurotrophins, we investigated the relationship between the effect of oleic acid and that of NGF, neurotrophin-3 (NT-3) and neurotrophin-4/5 (NT-4/5) on GAP-43 expression. Our results indicate that NGF is not involved in the neurotrophic effect of oleic acid because the addition of NGF did not modify the effect of oleic acid on GAP-43 expression. Neither NT-3 nor NT-4/5 alone modified GAP-43 expression. However, NT-3 and NT-4/5 acted synergistically with oleic acid to increase GAP-43 expression. The lack of effect of NGF as compared to other neurotrophins is not unexpected since we have not found TrkA expression under our experimental conditions. The effect of oleic acid on GAP-43 expression must be independent of autocrine factors synthesized by neurons because this effect was also observed at low cellular densities. In conclusion, our results indicate that oleic acid behaves as a neurotrophic factor, inducing GAP-43 expression through a PKC-mediated mechanism that is not mediated by other neurotrophic factors but that is strongly synergized by NT-3 and NT-4/5.
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PMID:Oleic acid induces GAP-43 expression through a protein kinase C-mediated mechanism that is independent of NGF but synergistic with NT-3 and NT-4/5. 1451 21

Chromaffin and PC12 cells were used to elucidate mechanisms of stimulation of gene expression of tyrosine hydroxylase (TH), the pivotal enzyme in catecholamine biosynthesis. A plethora of treatments elevate TH gene expression. Elevated cAMP triggers increased TH gene expression, primarily by an increase in mRNA transcription. Although a variety of treatments that elevate [Ca(2+)](i), increase TH transcription, there are important differences among them, indicating different calcium signalling pathways in regulating TH gene expression acting at the CRE/CaRE (cyclic AMP/calcium response element). Several complexes, such as ATF-1/jun and CREB/AT-1 heterodimers bind this element. Activation of protein kinase C by phorbol esters, NGF and EGF activate TH transcription through the AP-1 site. TH transcription is also stimulated by glucocorticoids, increased cell density, hypoxia, and several other treatments. In some instances, post-transcriptional mechanisms also contribute to the intricate fine tuning of regulation of TH gene expression.
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PMID:Control of tyrosine hydroxylase gene expression in chromaffin and PC12 cells. 1500 Oct 85


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