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)

Protein kinase D (PKD), a family of serine/threonine kinases, can be activated by a multitude of stimuli in a protein kinase C-dependent or -independent manner. PKD is involved in signal transduction pathways controlling cell proliferation, apoptosis, motility, and protein trafficking. Despite its versatile functions, few genuine in vivo substrates for PKD have been identified. In this study we demonstrate that the transcription factor cAMP-response element-binding protein (CREB) is a direct substrate for PKD. PKD1 and CREB interact in cells, and activated PKD1 provokes CREB phosphorylation at Ser-133 both in vitro and in vivo. A constitutive active mutant of PKD1 stimulates GAL4-CREB-mediated transcription in a Ser-133-dependent manner, activates CRE-responsive promoters, and increases the expression of CREB target genes. PKD1 also enhances transcription mediated by two other members of the CREB family, ATF-1 and CREM. Our results describe a novel mechanism for PKD-induced signaling through activation of the transcription factor CREB and suggest that stimulus-induced phosphorylation of CREB, reported to be mediated by protein kinase C, may involve downstream activated PKD.
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PMID:Protein kinase D induces transcription through direct phosphorylation of the cAMP-response element-binding protein. 1738 98

FSH is induced by activin, and this expression is modulated by GnRH through FSHB expression. This report focuses on the inhibitory effect of GnRH on activin-induced FSHB expression. Activin-treated primary murine pituitary cultures robustly express mutant ovine FSHBLuc-DeltaAP1, a luciferase transgene driven by 4.7 kb of ovine FSHB promoter. This promoter lacks two GnRH-inducible activator protein-1 sites, making it easier to observe GnRH-mediated inhibition. Luciferase expression from this transgene was decreased 94% by 100 nM GnRH with a half-time of approximately 4 h in pituitary cultures, and this inhibition was independent of follistatin. Activators of cAMP and protein kinase C like forskolin and phorbol 12-myristate 3-acetate (PMA), respectively, mimicked GnRH action. Kinetic studies of wild-type ovine FSHBLuc in LbetaT2 cells showed continuous induction by activin (4-fold) over 20 h. Most of this induction (78%) was blocked, beginning at 6 h. cAMP response element binding protein (CREB) was implicated in this inhibition because overexpression of its constitutively active mutant mimicked GnRH, and its inhibitor (inducible cAMP early repressor isoform II) reversed the inhibition caused by GnRH, forskolin, or PMA. In addition, GnRH, forskolin, or PMA increased the expression of a CREB-responsive reporter gene, 6xCRE-37PRL-Luc. Inhibition of nitric oxide type I (NOSI) by 7-nitroindazole also reversed GnRH-mediated inhibition by 60%. It is known that GnRH and CREB induce production of NOSI in gonadotropes and neuronal cells, respectively. These data support the concept that chronic GnRH inhibits activin-induced ovine FSHB expression by sequential activation of CREB and NOSI through the cAMP and/or protein kinase C pathways.
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PMID:Chronic gonadotropin-releasing hormone inhibits activin induction of the ovine follicle-stimulating hormone beta-subunit: involvement of 3',5'-cyclic adenosine monophosphate response element binding protein and nitric oxide synthase type I. 1744 83

On incubation with epinephrine, PC12 cells stably expressing alpha2-adrenergic receptor (alpha2-AR) undergo morphological and biochemical changes characteristic of neuron-like differentiation. The present study shows that alpha2-AR stimulation increases the phosphorylation of the transcription factor cAMP-response element-binding protein (CREB), the activity of a CRE-reporter plasmid and the expression of cyclin D1 with subtype-dependent efficiency (alpha2A approximately alpha2C >> alpha2B). The effects of epinephrine were mimicked by cell exposure to forskolin or to exogenous arachidonic acid (AA) and they were abrogated by prior treatment with the inhibitor of phospholipase C (PLC) (U73122) or the inhibitor of cytochrome P450-dependent epoxygenase, ketoconazole. On the other hand, treatment of the cells with epinephrine caused activation of protein kinase A (PKA), which was fully abolished by ketoconazole. Inhibition of PKA activity with H89 or ketoconazole abolished the effects of epinephrine on CREB, suggesting that activation of the cAMP/PKA pathway by AA epoxy-derivatives is responsible for CREB activation by alpha2-ARs. The effects of epinephrine were unaffected by LY294002. Furthermore, treatment with staurosporine, tyrphostin AG1478, PP1 or PD98059 did not change the extent of CREB phosphorylation but enhanced its transcriptional activity. Altogether, our results demonstrate that, in PC12 cells, the alpha2-AR subtypes cause phosphorylation and activation of CREB through a pathway involving stimulation of PLC, AA release, generation of epoxygenase derivative and increase of PKA activity. They also suggest attenuation of CREB transcriptional activity by mitogen-activated protein kinase, protein kinase C and Src kinases.
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PMID:Alpha2-adrenergic receptors activate cyclic AMP-response element-binding protein through arachidonic acid metabolism and protein kinase A in a subtype-specific manner. 1768 Sep 88

Parathyroid hormone (PTH) stimulates bone formation when injected daily but causes severe bone loss with continuous infusion. The mechanism of its paradoxical effects is still elusive. In this study, we compared changes in the gene expression profile in bone induced by intermittent or continuous treatment with three different PTH peptides, PTH-(1-34), -(1-31), and -(3-34), in Sprague-Dawley female rats. PTH-(1-34) regulated numerous genes (approximately 1,000), but differentially, in both regimes. PTH-(1-31) regulated a similar number of genes in the intermittent regimen but fewer in the continuous regimen, consistent with its less potent catabolic effect. PTH-(3-34) regulated very few genes in both regimes, which suggests the protein kinase C pathway plays a limited role in mediating the dual effects of PTH, whereas the cAMP-dependent protein kinase A pathway appears to predominate. In the intermittent treatment, many genes encoding signaling mediators, transcription factors, cytokines, and proteases/protease inhibitors are regulated rapidly and cyclically with each PTH injection; genes associated with skeletal development show a slowly accruing pattern of expression. With continuous treatment, some genes are regulated from 6 h, and the mRNA levels are sustained with a longer infusion, whereas others show a kinetic decrease and then increase later. Significant up-regulation of genes stimulating osteoclastogenesis in the anabolic regime suggests a provocative and paradoxical theme for the anabolic effect of PTH that a full anabolic response requires a transient up-regulation of genes classically associated with a resorptive response. Ingenuity pathway analysis was performed on the microarray data. A novel signaling network was established that is differentially regulated in the two PTH treatment regimes. Key regulators are suggested to be AREG, CCL2, WNT4, and cAMP-responsive element modulator.
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PMID:Determination of dual effects of parathyroid hormone on skeletal gene expression in vivo by microarray and network analysis. 1769 Jan 3

The regulated expression of type A gamma-aminobutyric acid (GABA) receptor (GABA(A)R) subunit genes plays a critical role in neuronal maturation and synaptogenesis. It is also associated with a variety of neurological diseases. Changes in GABA(A) receptor alpha1 subunit gene (GABRA1) expression have been reported in animal models of epilepsy, alcohol abuse, withdrawal, and stress. Understanding the genetic mechanism behind such changes in alpha subunit expression will lead to a better understanding of the role that signal transduction plays in control over GABA(A)R function and brings with it the promise of providing new therapeutic tools for the prevention or cure of a variety of neurological disorders. Here we show that activation of protein kinase C increases alpha1 subunit levels via phosphorylation of CREB (pCREB) that is bound to the GABRA1 promoter (GABRA1p). In contrast, activation of protein kinase A decreases levels of alpha1 even in the presence of pCREB. Decrease of alpha1 is dependent upon the inducible cAMP early repressor (ICER) as directly demonstrated by ICER-induced down-regulation of endogenous alpha1-containing GABA(A)Rs at the cell surface of cortical neurons. Taken together with the fact that there are less alpha1gamma2-containing GABA(A)Rs in neurons after protein kinase A stimulation and that activation of endogenous dopamine receptors down-regulates alpha1 subunit mRNA levels subsequent to induction of ICER, our studies identify a transcriptional mechanism for regulating the cell surface expression of alpha1-containing GABA(A)Rs that is dependent upon the formation of CREB heterodimers.
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PMID:Surface expression of GABAA receptors is transcriptionally controlled by the interplay of cAMP-response element-binding protein and its binding partner inducible cAMP early repressor. 1818 Mar 3

The chemokine Stromal-derived factor-1alpha (SDF-1alpha) interacts with seven transmembrane (TM) G-protein-coupled receptor (GPR), CXCR4. SDF-1alpha is linked to inflammation, chemoattraction, cancer metastasis, and hematopoiesis. Tachykinin (Tac1) peptides bind seven transmembrane (TM), GPR and are involved in tumor promotion. SDF-1alpha regulates Tac1 expression in non-tumorigenic breast cells through a bimodal pattern with repression at high levels through nuclear factor-kappa B (NFkappaB) activation. This study focuses on the mechanism of activation at low SDF-1alpha in MCF12A non-tumorigenic breast cells. Reporter gene assays with the 5' flanking region of Tac1 (exon 1 omitted) and co-transfection with the repressor of cAMP response element (CREB) (ICER), and transfection with the CRE sites mutated, verified critical roles for CRE sites in SDF-1alpha-mediated Tac1 activation. Western blots and functional assays with specific inhibitors indicated that SDF-1alpha phosphorylated CREB (P-CREB) via Galpha(i)2-PI3K-protein kinase C (PKC)zeta-p38-extracellular signal-regulated kinase (ERK) and no evidence of cAMP-PKA pathway. This observation is different from previous studies that reported CREB-phosphorylated PKA pathway in the activation of Tac1 in bone marrow stromal cells. This suggests cell specificity in Tac1 expression. In conclusion, this study reports on a non-canonical pathway in Tac1 activation by SDF-1alpha. This finding is significant, since Tac1 is relevant to breast cancer metastasis, to bone marrow where stromal cells have a significant facilitating function.
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PMID:Stromal-derived factor-1alpha induces a non-canonical pathway to activate the endocrine-linked Tac1 gene in non-tumorigenic breast cells. 1831 70

Emerging evidence suggests that dietary-derived flavonoids have the potential to improve human memory and neuro-cognitive performance via their ability to protect vulnerable neurons, enhance existing neuronal function and stimulate neuronal regeneration. Long-term potentiation (LTP) is widely considered to be one of the major mechanisms underlying memory acquisition, consolidation and storage in the brain and is known to be controlled at the molecular level by the activation of a number of neuronal signalling pathways. These pathways include the phosphatidylinositol-3 kinase/protein kinase B/Akt (Akt), protein kinase C, protein kinase A, Ca-calmodulin kinase and mitogen-activated protein kinase pathways. Growing evidence suggests that flavonoids exert effects on LTP, and consequently memory and cognitive performance, through their interactions with these signalling pathways. Of particular interest is the ability of flavonoids to activate the extracellular signal-regulated kinase and the Akt signalling pathways leading to the activation of the cAMP-response element-binding protein, a transcription factor responsible for increasing the expression of a number of neurotrophins important in LTP and long-term memory. One such neurotrophin is brain-derived neurotrophic factor, which is known to be crucial in controlling synapse growth, in promoting an increase in dendritic spine density and in enhancing synaptic receptor density. The present review explores the potential of flavonoids and their metabolite forms to promote memory and learning through their interactions with neuronal signalling pathways pivotal in controlling LTP and memory in human subjects.
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PMID:Food for thought: the role of dietary flavonoids in enhancing human memory, learning and neuro-cognitive performance. 1841 98

N-butylidenephthalide (BP), isolated from the chloroform extract of Angelica sinensis, has been examined for its antitumor effects on glioblastoma multiforme brain tumors; however, little is known about its antitumor effects on hepatocellular carcinoma cells. Two hepatocellular carcinoma cell lines, HepG2 and J5, were treated with either N-butylidenephthalide or a vehicle, and cell viability and apoptosis were evaluated. Apoptosis-related mRNA and proteins expressed, including orphan receptor family Nurr1, NOR-1, and Nur77, were evaluated as well as the effect of N-butylidenephthalide in an in vivo xenograft model. N-butylidenephthalide caused growth inhibition of both the cell lines at 25 microg/ml. Furthermore, N-butylidenephthalide-induced apoptosis seems to be related to Nur77 translocation from nucleus to cytosol, which leads to cytochrome c release and caspase-3-dependent apoptosis. N-butylidenephthalide-related tumor apoptosis was associated with phosphatidylinositol 3-kinase/protein kinase B (AKT)/glycogen synthase kinase-3beta rather than the mitogen-activated protein kinase or protein kinase C pathway. Blockade of AKT activation enhanced proliferation inhibition and the induction of phosphor-Bcl-2 and Nur77 proteins. Besides, the increasing apoptosis by BP via transfection wild-type cAMP-response element-binding protein (CREB) into tumor cell was suppressed by dominant phosphorylation site mutation of CREB. This finding suggested CREB pathway was also partly involved in tumor apoptosis caused by BP. Administration of N-butylidenephthalide showed similar antitumoral effects in both HepG2 and J5 xenograft tumors. N-Butylidenephthalide induced apoptosis in hepatocellular carcinoma cells, both in vitro and in vivo, suggesting a potential clinical use of this compound for improving the prognosis of hepatocellular carcinoma cells.
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PMID:The induction of orphan nuclear receptor Nur77 expression by n-butylenephthalide as pharmaceuticals on hepatocellular carcinoma cell therapy. 1857 87

Learning-related reductions of the postburst afterhyperpolarization (AHP) in hippocampal pyramidal neurons have been shown ex vivo, after trace eyeblink conditioning. The AHP is also reduced by many neuromodulators, such as norepinephrine, via activation of protein kinases. Trace eyeblink conditioning, like other hippocampus-dependent tasks, relies on protein synthesis for consolidating the learned memory. Protein kinase A (PKA) has been shown to be a key contributor for protein synthesis via the cAMP-response element-binding pathway. Here, we have explored a potential involvement of PKA and protein kinase C (PKC) in maintaining the learning-related postburst AHP reduction observed in CA1 pyramidal neurons. Bath application of isoproterenol (1 muM), a beta-adrenergic agonist that activates PKA, significantly reduced the AHP in CA1 neurons from control animals, but not from rats that learned. This occlusion suggests that PKA activity is involved in maintaining the AHP reduction measured ex vivo after successful learning. In contrast, bath application of the PKC activator, (-) indolactam V (0.2 muM), significantly reduced the AHP in CA1 neurons from both control and trained rats, indicating that PKC activity is not involved in maintaining the AHP reduction at this point after learning.
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PMID:Learning-related postburst afterhyperpolarization reduction in CA1 pyramidal neurons is mediated by protein kinase A. 1916 84

Melanogenesis is a physiological process that results in the synthesis of melanin pigments, which play a crucial protective role in protection against skin photocarcinogenesis. Phloridzin is a phloretin 2'-glucoside that is found in many parts of the apple tree that reportedly increases tyrosinase activity and melanin contents through inhibition of protein kinase C (PKC) activity in B16 melanoma cells. In this study, we attempted to accurately determine the effects and mechanisms of action of phloridzin on melanogenesis. Specifically, we observed that phloridzin-induced a dose-dependent increase in tyrosinase activity and melanin contents, and that these changes were accompanied by an increase in the levels of tyrosinase and the tyrosinase-related proteins, TRP-1 and TRP-2. Furthermore, the cAMP-dependent protein kinase A (PKA) inhibitor H89 impaired the response of the tyrosinase activity and melanin synthesis to phloridzin. Additionally, phloridzin stimulated cAMP production and phosphorylation of the cAMP-response element binding protein (CREB). Taken together, the results of this study indicate that phloridzin increases tyrosinase gene expression through the cAMP signaling pathway, thereby leading to the stimulation of melanogenesis.
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PMID:Phloridzin-induced melanogenesis is mediated by the cAMP signaling pathway. 1957 39


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