Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

The mitogen-activated protein kinase (MAPK) pathway plays a pivotal role in intracellular signaling, and this cascade may impinge on cAMP response elements (CREs) of target genes. Both the MAPK pathway and chromogranin A expression may be activated by cytosolic calcium influx, and calcium-dependent signals map onto the chromogranin A promoter proximal CRE. We therefore probed the role of the MAPK pathway in chromogranin A biosynthesis after secretory stimulation of PC12 pheochromocytoma cells by the nicotinic cholinergic pathway, the physiological secretory trigger. Chemical inhibition of either MAPK or MAPK kinase blocked the response of a transfected chromogranin A promoter to nicotine or protein kinase C activation [by phorbol-12-myristate-13-acetate (PMA)], although nicotine-evoked catecholamine secretion was unaffected. Activation of the MAP kinase cascade (Ras, Raf, MAPK, or CREB kinase) by cotransfection of pathway components stimulated the chromogranin A promoter. Cotransfection of MAPK pathway dominant negative mutants (for Raf, MAPK, or CREB kinase) blocked nicotinic or PMA activation of chromogranin A, although a dominant negative Ras mutant was without effect. MAPK pathway enzymatic activity was stimulated by both nicotine and PMA. Point mutations of the chromogranin A CRE suggested that this element was necessary in cis for stimulation by nicotine, PMA, or chemical activation of the MAPK pathway. Transfer of the CRE to a heterologous promoter conferred inducibility by not only nicotine or cAMP but also MAPK activation. Expression of the CREB antagonist KCREB blocked the response of the chromogranin A promoter to nicotine, cAMP, or MAPK pathway activation by either chemical stimulation or cotransfection of active cascade components. Chromogranin A mRNA responded to MAPK pathway manipulation in a fashion similar to the transfected chromogranin A promoter, in both direction and magnitude. We conclude that the MAPK pathway is a necessary intermediate in signaling from the nicotinic receptor to secretory protein transcription, although not to catecholamine secretion. In trans, this response seems to involve the following signal cascade: protein kinase C --> Raf --> MAPK kinase --> MAPK --> CREB kinase --> CREB. In cis, activation by the cascade maps onto the chromogranin A promoter proximal CRE, which is both necessary and sufficient to confer the response.
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PMID:A crucial role for the mitogen-activated protein kinase pathway in nicotinic cholinergic signaling to secretory protein transcription in pheochromocytoma cells. 965 90

To investigate the molecular mechanisms of stimuli-induced transcriptional activation in neuronal cells, we have investigated the light-induced gene expression in the neural retina of rats. The immunoreactivity for phosphorylated cAMP responsive element binding protein (PCREB-IR) was expressed in the outer half of the inner nuclear layer (INL) and the ganglion cell layer (GCL) after 5 min exposure to steady light also in mice. In addition to these cells, PCREB-IR was also detected in the inner border of the INL after 5 min exposure to flashing light. Both steady and flashing lights induced c-fos mRNA in the same types of cells as the PCREB-IR-positive cells. Majority of PCREB immunoreactive nuclei in the outer half of the INL were also immunopositive for anti-protein kinase C alpha (PKC alpha), a marker of rod bipolar cells, while CaM kinase IV immunoreactivity was not detected in these cells. PCREB-IR and c-fos gene expression in the PKC alpha positive rod bipolar cells were lost in mice lacking metabotropic glutamate receptor 6 (mGluR6). Thus, we propose that the transcriptional response of CREB to light stimulation in rod bipolar cells is regulated via mGluR6.
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PMID:CREB-induced transcriptional activation depends on mGluR6 in rod bipolar cells. 967 22

The lactate dehydrogenase-A (LDH-A) gene, whose product plays a pivotal role in normal anaerobic glycolysis and is frequently increased in human cancers, is highly regulated at the transcriptional and posttranscriptional levels. Our laboratory has carried out extensive studies concerning the regulation of LDH-A subunit expression. We have elucidated complex regulatory mechanisms by identifying multiple cis-acting promoter elements including functional sites for Sp1 and c-Myc interactions as well as sites that interact with the protein kinase A and protein kinase C substrates, CREB and AP1, respectively. Furthermore, we have reported the existence of a CRE-dependent silencer element in the LDH-A promoter. LDH-A expression is additionally regulated through the protein kinase A and C signal pathways at the posttranscriptional level, specifically mRNA stability.
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PMID:Regulation of LDH-A gene expression by transcriptional and posttranscriptional signal transduction mechanisms. 972 76

Pap1 is a fission yeast transcription factor that activates genes related with resistance against staurosporine, a potent inhibitor of protein kinase C, and has been shown to be involved in cell growth, cell cycle, carcinogenesis and differentiation. Pap1 has the bZIP DNA-binding domain but binds to non-consensus DNA sequences for the bZIP motif. Highly ordered crystals of the DNA-binding domain complexed with a DNA fragment that has an ATF/CREB-like non-consensus sequence have been obtained. The crystals grew by the vapor-diffusion technique with polyethylene glycol 6000 and belong to space group R3 with a = b = 240.78, c = 43.85 A. A 2.0 A resolution data set was collected with a cryo-crystallographic technique.
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PMID:Crystallographic characterization of Pap1-DNA complex. 975 24

We have shown previously that the pattern of expression of the transcription factor CREB (cyclic AMP-response element binding protein) in developing oligodendrocytes (OLGs) suggests a role during a period that precedes the peak of myelination in rat brain. We have now investigated the signaling pathways that could be responsible for activating CREB by phosphorylation at different stages along OLG maturation. CREB phosphorylation was studied in short-term cultures of immature OLG precursor cells and young OLGs isolated from 4- and 11-day-old rat cerebrum, respectively. The results indicated that at both developmental stages, CREB phosphorylation could be stimulated by either increased concentrations of cyclic AMP and cyclic AMP-dependent protein kinase activation or increased Ca2+ levels and a protein kinase C activity. The results also showed that CREB phosphorylation in immature OLG precursor cells could be up-regulated by treatment with histamine, carbachol, glutamate, and ATP (neuroligands known to increase Ca2+ levels in these cells), by signaling cascade(s) that involve a protein kinase C activity, as well as the mitogen-activated protein kinase pathway. In contrast, in cells isolated from 11-day-old rats, at a developmental stage that immediately precedes the beginning of the active period of myelin synthesis, CREB phosphorylation was only stimulated by treatment with the beta-adrenergic agonist isoproterenol in a process that appears to be mediated by a cyclic AMP/cyclic AMP-dependent protein kinase-dependent pathway. These results support the idea that CREB could be a mediator of neuronal signals that, coupled to specific signal transduction cascades, may play different regulatory roles at specific stages along OLG differentiation.
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PMID:Different neuroligands and signal transduction pathways stimulate CREB phosphorylation at specific developmental stages along oligodendrocyte differentiation. 988 64

Human immunodeficiency virus (HIV) can infect human colon epithelial cell lines by both CD4-dependent and -independent mechanisms. The present studies assessed cellular factors that are important for HIV-1 transcription in human colon epithelial cells. The HIV-1 long terminal repeat (LTR) was shown to contain functional DNA cis-regulatory elements downstream of the viral transactivator-responsive element in the transcribed noncoding 5' leader sequence. These downstream regulatory elements, termed DSE, can bind c-Fos and JunD and transmit protein kinase C activation signals to the HIV LTR. Moreover, specific Jun and Fos transcription factors can transactivate HIV-1 provirus in human colon epithelial cells. The DSE also bind related proteins of the CREB/ATF family. In this regard, the DSE behave as 12-0-tetradecanoylphorbol 13-acetate responder element-like cAMP-responsive elements because they bind both AP-1 and CREB/ATF transcription factors, thereby permitting induction of the HIV-1 LTR by both protein kinase C and A activation signals.
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PMID:Human immunodeficiency virus type 1 (HIV-1) infection and expression in intestinal epithelial cells: role of protein kinase A and C pathways in HIV-1 transcription. 1009 16

Axonal contact regulates Schwann cell (SC) proliferation during development. However, the intracellular signal transduction pathways involved in the axon-induced proliferation of SC have not been described. We have previously shown that SC proliferation induced by axolemma-enriched fractions (AEF) is accompanied by increased expression of cyclic AMP-responsive element binding protein, CREB. We now report the AEF and dorsal root ganglion neuritic-induced signal transduction pathway(s) which regulate the phosphorylation of CREB that correlate with the SC proliferative response. The phosphorylated form of CREB was significantly increased after 16 hr of axonal stimulation, continued to increase for 48 hr, and subsequently decreased as monitored by immunocytochemistry and Western blot analysis. Treatment with protein kinase A (PKA) inhibitor, H89, completely abolished both the CREB activation and SC proliferation. In contrast, treatment with protein kinase C (PKC) inhibitor (bisindolylmaleimide) inhibited AEF-induced SC proliferation, but did not immediately affect CREB phosphorylation. These data are consistent with the view that PKA and PKC pathways are essential for AEF-induced SC proliferation. Since PKC can influence SC proliferation without initially affecting CREB phosphorylation, PKC may regulate SC proliferation at pathways distal to the immediate CREB activation.
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PMID:Phosphorylation of CREB in axon-induced Schwann cell proliferation. 1022 Jan 11

Activation of the mitogen-activated protein kinase (MAPK) cascade recently was discovered to play an important role in synaptic plasticity in area CA1 of rat hippocampus. However, the upstream mechanisms regulating MAPK activity and the downstream effectors of MAPK in the hippocampus are uncharacterized. In the present studies we observed that hippocampal MAPK activation is regulated by both the PKA and PKC systems; moreover, we found that a wide variety of neuromodulatory neurotransmitter receptors (metabotropic glutamate receptors, muscarinic acetylcholine receptors, dopamine receptors, and beta-adrenergic receptors) couple to MAPK activation via these two cascades. In additional studies we observed that PKC is a powerful regulator of CREB phosphorylation in area CA1. MAPK plays a critical role in transcriptional regulation by PKC, because MAPK activation is a necessary component for increased CREB phosphorylation in response to the activation of this kinase. Surprisingly, we also observed that MAPK activation is necessary for PKA coupling to CREB phosphorylation in area CA1. Overall, these studies indicate an unexpected richness of diversity in the regulation of MAPK in the hippocampus and suggest the possibility of a broad role for the MAPK cascade in regulating gene expression in long-term forms of hippocampal synaptic plasticity.
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PMID:The mitogen-activated protein kinase cascade couples PKA and PKC to cAMP response element binding protein phosphorylation in area CA1 of hippocampus. 1034 Dec 37

In this study we describe that platelet-derived growth factor (PDGF), 12-O-tetradecanoyl-phorbol-acetate (TPA), and forskolin induced CREB (cAMP-responsive element-binding protein) Ser-133 phosphorylation with comparable magnitude and kinetics in NIH 3T3 cells. While forskolin was the most potent activator of CREB, TPA or PDGF modestly increased CREB activity. The role of protein kinase C, protein kinase A, and the Raf-MEK kinase pathway in the activation and Ser-133 phosphorylation of CREB by these three stimuli was investigated. We found that inhibition of the Raf-MEK kinase pathway efficiently blocks transcriptional activation of CREB by all three stimuli. This dominant involvement of Raf-MEK in CREB transcriptional activation seems to be uncoupled from CREB Ser-133 phosphorylation. We further demonstrate that although inhibition of Raf-MEK represses forskolin-induced CREB activation, forskolin by itself failed to activate ERK1/2 and Elk-1 mediated transcription. These results suggest that a basal level of Raf-MEK activity is necessary for both PDGF- and forskolin-induced CREB activation, independent of CREB Ser-133 phosphorylation.
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PMID:A dominant role for the Raf-MEK pathway in forskolin, 12-O-tetradecanoyl-phorbol acetate, and platelet-derived growth factor-induced CREB (cAMP-responsive element-binding protein) activation, uncoupled from serine 133 phosphorylation in NIH 3T3 cells. 1040 59

Whole-cell [(32)P]-protein phosphorylation assays and two-dimensional gel electrophoresis (2-DGE) were applied to the analysis of the beta-adrenoceptor (betaAR)-linked signal transduction pathway. Rat C6 glioma cells were stimulated with isoproterenol and the protein lysates were resolved by 2-DGE. Two dimensional [(32)P]-phosphoprotein 'maps' were generated depicting the modulation of intracellular proteins after isoproterenol stimulation versus unstimulated cells. A total of 274 distinct phosphoprotein spots were detected, of which 200 were up-regulated, 69 were down-regulated, and 5 remained unchanged. An evaluation of isoproterenol's activity across several kinase pathways was performed using a computer-generated 2-DGE template incorporating the location and identification of individual signaling phosphoprotein intermediaries. The template served as a 'reference map' for drug treatment comparisons. We observed a significant increase in the phosphorylation states of several nuclear transcription factors, notably CREB-1, ATF-1, NFkappaB/IkappaBalpha and ELK-1, but not c-Jun. A parallel series of radioimmunoprecipitation studies confirmed our 2-DGE findings. Moreover, isoproterenol increased the phosphorylation state of PKC and of several MAPK-dependent pathway kinases which correlated with a significant increase in their endogenous kinase activity. Isoproterenol's effects on PKA, PKC and ERK-dependent activities were blocked by propranolol, a betaAR antagonist. In conclusion, an acute isoproterenol stimulus induced multiplex pathway modulation via the betaAR in the C6 glioma cell indicating that signaling pathway cross-talk is an essential feature for the regulation of cellular function. Moreover, the immediate advantages of the 2-DGE analytical approach were apparent, and further development of the protein database will provide a valuable tool to screen for broad-based drug-mediated signaling activities.
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PMID:Probing for drug-induced multiplex signal transduction pathways using high resolution two-dimensional gel electrophoresis: application to beta-adrenoceptor stimulation in the rat C6 glioma cell. 1040 86


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