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)

Cyclic AMP (cAMP)-responsive element-binding protein (CREB) is a transcription factor important in developing nervous system cells and is activated by a variety of signaling molecules. Aroclor 1254 (A1254), a polychlorinated biphenyl mixture, perturbs Ca(2+) homeostasis and increases CREB phosphorylation in rat neonatal cortical cell cultures in a time- and concentration-dependent manner. The present experiments determined that the cell type responding to A1254 with Ca(2+) increases and phosphorylated CREB (phospho-CREB) was predominantly of neuronal morphology and microtubule-associated protein (MAP2)-positive phenotype. Similarly, glutamate (100 microM) increased phospho-CREB immunoreactivity selectively in MAP2-immunopositive cells. Using Western blotting and immunocytochemical techniques, we identified key signal transduction pathways operative in phosphorylating CREB in cortical cell cultures and examined their participation in 3 ppm A1254-induced CREB activation. Cortical cultures treated with glutamate, forskolin or the phorbol ester phorbol 12-myristate 13-acetate exhibited robust increases in phospho-CREB. Tetrodotoxin (1 microM) completely inhibited CREB phosphorylation by A1254, suggesting that synaptic activity is involved in A1254-induced CREB activation. Buffering [Ca(2+)](i) with bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetrakis(acetoxymethyl) ester in the absence of extracellular Ca(2+) partially inhibited A1254-induced CREB phosphorylation. Inhibition of mitogen-activated protein kinase (10 microM U0126) or protein kinase C (PKC; bisindoylmaleimide, 5 microM) activation did not inhibit A1254-induced CREB phosphorylation. By contrast, inhibition of protein kinase A (PKA) with 100 microM PKA inhibitor peptide, PKI, blocked A1254-induced CREB phosphorylation. Thus, we examined whether A1254 activates PKA by increasing cAMP; 10 microM forskolin, but not A1254, elevated intracellular cAMP levels. These results indicate that in neocortical cells in culture, CREB phosphorylation occurs via Ca(2+)-, PKA-, and PKC-dependent pathways. Furthermore, A1254-induced CREB phosphorylation occurs predominantly in neurons, is dependent on synaptic activity and mediated by Ca(2+)- and PKA-dependent pathways.
 ...
PMID:Identification of calcium-dependent and -independent signaling pathways involved in polychlorinated biphenyl-induced cyclic AMP-responsive element-binding protein phosphorylation in developing cortical neurons. 1242 22

The analysis of gene changes associated with exposure to cannabinoids is critical due to the multiple possible signaling pathways potentially affected by cannabinoid receptor activation. A comparison of altered gene profiles under two different conditions, one in vivo (chronic exposure to delta-9-THC) and the other in vitro (neuroprotection mediated by WIN55212-2), was made to determine whether it was possible to identify common genes that were affected. Up and down-regulated sets of genes are described. Genes affected in one or the other circumstance include alterations in a 14-3-3 regulator protein of PKC, CREB, BDNF and GABA receptor subunit proteins, as well as several genes associated with known cannabinoid receptor-coupled signaling pathways. Unexpectedly, several genes that were altered in both circumstances were associated with synaptic and membrane structure, motility and neuron growth. These included, neuronal cell adhesion molecule (NCAM), hyloronidan motility receptor, and myelin proteolipid protein. While the basis for involvement of these particular genes in cannabinoid receptor activated functional processes within the cell is still not well understood, awareness that significant numbers of genes and presumably proteins are changed following either acute or long-term exposure may provide new insight into their effects.
 ...
PMID:Assessment of cannabinoid induced gene changes: tolerance and neuroprotection. 1250 5

Given that brain-derived neutrophic factor (BDNF) modulates both short-term synaptic function and activity-dependent synaptic plasticity in the adult hippocampus, here we examined signaling mechanisms in vivo in the hippocampus mediating BDNF modulation of long-term memory (LTM) formation of a one-trial fear-motivated learning task in rats. Bilateral infusions of function-blocking anti-BDNF antibody into the CA1 region of the dorsal hippocampus decreased extracellular-signal regulated kinase 2 (ERK2) and CREB activation and impaired LTM retention scores. Inhibition of ERK1/2 activation by PD098059 produced similar effects and also reduced CREB phosphorylation. In contrast, intrahippocampal administration of recombinant human BDNF increased ERK1/2 and CREB activation and facilitated LTM. Activated-p38, activated-PKC isoforms, and activated-AKT were unaltered after BDNF or anti-BDNF infusion. In addition, no changes were found on alphaPKA and betaPKA catalytic subunits in nuclear samples. Thus, our results suggest that BDNF exerts its role in LTM formation in vivo in CA1 region of the hippocampus, at least in part, via CREB activation. Moreover, BDNF-induced CREB activation appears to be mediated mainly through the activation of ERK1/2 signaling pathway.
 ...
PMID:Signaling mechanisms mediating BDNF modulation of memory formation in vivo in the hippocampus. 1258 86

Tyrosine hydroxylase (TH) gene transcription rate increases in response to numerous pharmacological and physiological stimuli. The AP1 site within the TH gene proximal promoter is thought to play an important role in mediating many of these responses; however, it is unclear which AP1 factors are required. To investigate whether c-Fos is essential for the response of the TH gene to different stimuli, c-Fos-deficient PC12 cell lines were produced utilizing an antisense RNA strategy. In these cell lines, stimulus-induced increases in c-Fos protein levels were dramatically attenuated, while c-Jun and CREB levels remained unchanged. TH gene transcription rate increased from four- to eight-fold in control cells after treatment with either 50 mM KCl or TPA. These responses were dramatically decreased in the c-Fos-deficient cell lines. In contrast, c-Fos down-regulation had little effect on the response of the TH gene to forskolin. Stimulation of TH gene promoter activity, which was observed in control cell lines treated with either 50 mm KCl or TPA was also dramatically inhibited in the c-Fos-deficient cells. These results suggest that c-Fos induction is essential for maximal stimulation of the TH gene in response to either depolarization or PKC activation in PC12 cells.
 ...
PMID:c-Fos is essential for the response of the tyrosine hydroxylase gene to depolarization or phorbol ester. 1278 62

Cadmium exposure increases the risk of prostate cancer. We now describe the effects of Cd2+ on signalling and proliferation in 1LN prostate cells. Cd2+ increased [3H]thymidine uptake and cell number twofold. Cd2+ elevated intracellular IP3, cytosolic-free Ca2+, phosphorylated MEK1/2, ERK1/2, p38 MAPK and JNK two- to threefold. Increased PDK1 and phosphorylation of the 85-kDa regulatory subunit of PI 3-kinase, Akt and p70s6k were also observed. Cd2+ treatment increased transcription factors NFkappaB and CREB, and the expression of c-fos and c-myc. Cd2+-induced increased uptake of [3H]thymidine was abolished by translational and transcriptional inhibitors, and Ca2+ channel blockers. Inhibition of phospholipase C and of Ca2+ binding to IP3 receptors inhibited Cd2+-induced DNA synthesis as did inhibition of tyrosine kinases, protein kinase C, PI 3-kinase, farnesyl transferase, MEK1/2, ERK1/2 and p38MAPK. Thus signalling events, which are triggered on exposure of 1LN cells to submicromolar concentrations of Cd2+, induce increased proliferation of these cells.
 ...
PMID:Induction of mitogenic signalling in the 1LN prostate cell line on exposure to submicromolar concentrations of cadmium+. 1449 49

Secalonic acid-D (SAD) is a teratogenic mycotoxin inducing cleft palate (CP) in the offspring of the exposed mice by reducing palatal shelf size secondary to reduced proliferation of the palatal mesenchymal (PM) cells. Co-administration of dimethylsulfoxide (DMSO) reversed the CP-inducing effect of SAD. Although SAD has been shown to affect both protein kinases A (PKA) and C (PKC) pathways, the relevance of each of these pathways to its CP induction is unknown. The present studies were designed to test the hypothesis that the protective effect of DMSO is mediated by its specific reversal of the effect(s) of SAD on one of these two pathways using ELISA-based activity assays, Western blot analysis, electrophoretic mobility shift assays (EMSA), and murine embryonic PM (MEPM) cell growth in culture. Within the PKA pathway, SAD inhibited the activity of the catalytic subunit of PKA and its migration into the nucleus, elevated phosphorylated cyclic AMP (cAMP) response element (CRE)-binding protein (pCREB) level, and reduced the binding of CREB to CRE. In the PKC pathway, SAD reduced the activity of PKC and the binding of transcription factors (TF) to 12-O-tetradecanoate-13 phorbol acetate-response element (TRE). SAD also inhibited MEPM cell growth and the expression of the CRE- and TRE-containing gene, proliferating cell nuclear antigen (PCNA). Reversal, by DMSO, of the effects of SAD on MEPM cell growth, on PCNA expression and on all components of the PKA, but not of PKC, pathway suggests that the perturbation of the PKA pathway by SAD is relevant to its induction of CP in mice.
 ...
PMID:Relevance of the palatal protein kinase A pathway to the pathogenesis of cleft palate by secalonic acid D in mice. 1476 83

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.
 ...
PMID:Control of tyrosine hydroxylase gene expression in chromaffin and PC12 cells. 1500 Oct 85

Stimulation of CD86 (formerly known as B7-2) and/or the beta2-adrenergic receptor on a CD40 ligand/interleukin-4-activated B cell increased the rate of mature IgG1 transcription. To identify the mechanism responsible for this effect, we determined whether CD86 and/or beta2-adrenergic receptor stimulation regulated transcription factor expression and binding to the 3'-IgH enhancer in vitro and in vivo. We showed that CD86 stimulation increased the nuclear localization of NF-kappaB1 (p50) and phosphorylated RelA (p65) and increased Oct-2 expression and binding to the 3'-IgH enhancer, in a protein kinase C-dependent manner. These effects were lost when CD86-deficient or NF-kappaB1-deficient B cells were used. CD86 stimulation also increased the level of IkappaB-alpha phosphorylation but in a protein kinase C-independent manner. Beta2-adrenergic receptor stimulation increased CREB phosphorylation, OCA-B expression, and OCA-B binding to the 3'-IgH enhancer in a protein kinase A-dependent manner, an effect lost when beta2-adrenergic receptor-deficient B cells were used. Also, the beta2-adrenergic receptor-induced increase in the level of mature IgG1 transcript was lost when OCA-B-deficient B cells were used. These data are the first to show that CD86 stimulation up-regulates the expression of the transcription factor Oct-2 in a protein kinase C- and NF-kappaB1-dependent manner, and that beta2-adrenergic receptor stimulation up-regulates the expression of the coactivator OCA-B in a protein kinase A-dependent manner to cooperate with Oct-2 binding to the 3'-IgH enhancer.
 ...
PMID:CD86 and beta2-adrenergic receptor signaling pathways, respectively, increase Oct-2 and OCA-B Expression and binding to the 3'-IgH enhancer in B cells. 1502 18

Stratified squamous epithelial cells undergo an orderly process of terminal differentiation that is characterized by specific molecular and morphological changes, including expression of the cornified envelope protein involucrin. Significant progress has been made in characterizing the upstream regulatory region of the involucrin gene. Binding sites for AP-1 (activator protein 1) and Sp1 transcription factors were shown to be important for involucrin promoter activity and tissue-specific expression. Defective terminal differentiation is often characterized by decreased or lack of involucrin expression. Recently, a dominant-negative construct of the transcriptional co-activator P/CAF [p300/CBP-associated factor, where CBP stands for CREB (cAMP-response-element-binding protein)-binding protein] was shown to inhibit involucrin expression in immortalized keratinocytes [Kawabata, Kawahara, Kanekura, Araya, Daitoku, Hata, Miura, Fukamizu, Kanzaki, Maruyama and Nakajima (2002) J. Biol. Chem. 277, 8099-8105]. Loss of expression or inactivation of other co-activators has also been demonstrated [Suganuma, Kawabata, Ohshima, and Ikeda (2002) Proc. Natl. Acad. Sci. U.S.A. 99, 13073-13078]. In the present study, we re-expressed CBP and P/CAF in immortalized keratinocyte lines that had lost expression of these co-activator proteins. Re-expression of these proteins restored calcium- and RA (retinoic acid)-responsive involucrin expression in these cells. RA and calcium signalling induced exchange of CBP and P/CAF occupancy at the AP-1 sites of the involucrin promoter. CBP and P/CAF inductions of the involucrin expression were not dependent on MEK (mitogen-activated protein kinase/extracellular-signal-regulated kinase kinase), p38, protein kinase C or CaM kinase (calcium/calmodulin-dependent kinase) signalling. Kinase-induced changes in involucrin promoter activity directly resulted from changes in AP-1 protein expression. We concluded that CBP and P/CAF are important regulators of involucrin expression in stratified squamous epithelial cells.
 ...
PMID:Regulation of the human involucrin gene promoter by co-activator proteins. 1502 63

Parathyroid hormone-related protein (PTHrP) regulates proliferation and differentiation of osteoblastic cells via binding to the parathyroid hormone receptor (PTH-1R). The cAMP-dependent protein kinase A pathway governs the majority of these effects, but recent evidence also implicates the MAPK pathway. MC3T3-E1 subclone 4 cells (MC4) were treated with the MAPK inhibitor U0126 and PTHrP. In differentiated MC4 cells, osteocalcin and bone sialoprotein gene expression were both down-regulated by PTHrP and also by inhibition of the MAPK pathway. PTHrP-mediated down-regulation of PTH-1R mRNA and up-regulation of c-fos mRNA were MAPK-independent, whereas PTHrP stimulation of fra-2 and interleukin-6 (IL-6) mRNA was MAPK-dependent. Luciferase promoter assays revealed that regulation of IL-6 involved the cAMP-dependent protein kinase A and MAPK pathways with a potential minor role of the protein kinase C pathway, and a promoter region containing an activator protein-1 site was necessary for PTHrP-induced IL-6 gene transcription. An alternative pathway, through cAMP/Epac/Rap1/MAPK, mediated ERK phosphorylation but was not sufficient for IL-6 promoter activation. Phosphorylation of the transcription factor CREB was also necessary but not sufficient for PTHrP-mediated IL-6 promoter activity. Most interesting, a bidirectional effect was found with PTHrP increasing phosphorylated ERK in undifferentiated MC4 cells but decreasing phosphorylated ERK in differentiated cells. These data indicate that inactivation of the MAPK pathway shows differential regulation of PTHrP-stimulated activator protein-1 members, blocks PTHrP-stimulated IL-6, and synergistically down-regulates certain osteoblastic markers associated with differentiation. These novel findings indicate that the MAPK pathway plays a selective but important role in the actions of PTHrP.
 ...
PMID:Impact of the mitogen-activated protein kinase pathway on parathyroid hormone-related protein actions in osteoblasts. 1512 46


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>