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)

The cyclic adenosine monophosphate (AMP) response element-binding protein, CREB, often modulates stress responses. Here, we report that CREB suppresses the glioblastoma proliferative effect of the stress-induced acetylcholinesterase variant, AChE-R. In human U87MG glioblastoma cells, AChE-R formed a triple complex with protein kinase C (PKC) epsilon and the scaffold protein RACK1, enhanced PKCepsilon phosphorylation, and facilitated BrdU incorporation. Either overexpressed CREB, or antisense destruction of AChE-R mRNA, PKC, or protein kinase A (PKA) inhibitors-but not CREB combined with PKC inhibition suppressed-this proliferation, suggesting that CREB's repression of this process involves a PKC-mediated pathway, whereas impaired CREB regulation allows AChE-R-induced, PKA-mediated proliferation of glioblastoma tumors.
 ...
PMID:CREB regulates AChE-R-induced proliferation of human glioblastoma cells. 1515 40

Lactate dehydrogenase A (LDH-A) is hormonally regulated in rodents, and increased expression of LDH-A is observed during mammary gland tumorigenesis. The mechanisms of hormonal regulation of LDH-A were investigated using a series of deletion and mutant constructs derived from the rat LDH-A gene promoter. Results of these studies show that constructs containing the -92 to -37 region of the LDH-A promoter are important for basal and E2-induced transactivation, and mutation of the consensus CRE motif within this region results in significant loss of basal activity and hormone-responsiveness. Gel mobility shift assays using nuclear extracts from MCF-7 cells show that both CREB and ATF-1 interact with the CRE. Studies with kinase inhibitors show that E2-induced activation of this CRE is dependent on protein kinase C, and these data indicate that LDH-A is induced through a non-genomic pathway of estrogen action.
 ...
PMID:Hormonal regulation of lactate dehydrogenase-A through activation of protein kinase C pathways in MCF-7 breast cancer cells. 1524 94

Tobacco-related lung diseases are associated with alterations in tissue remodeling and are characterized by increased matrix deposition. Among the matrix molecules found to be highly expressed in tobacco-related lung diseases is fibronectin, a cell adhesive glycoprotein implicated in tissue injury and repair. We hypothesize that nicotine, a component of tobacco, stimulates the expression of fibronectin in lung fibroblasts via the activation of intracellular signals that lead to increased fibronectin gene transcription. In support of this, we found that nicotine stimulated the expression of fibronectin in lung fibroblasts and that its stimulatory effect was associated with activation of protein kinase C and mitogen-activated protein kinases, increased levels of intracellular cAMP, and phosphorylation and DNA binding of the transcription factor CREB. Increased transcription of the gene was dependent on cAMP-response elements (CREs) present on the 5' end of its gene promoter. The stimulatory effect of nicotine on fibronectin expression was abolished by alpha-bungarotoxin, an inhibitor of alpha7 nicotinic acetylcholine receptors (alpha7 AChRs). Of note, nicotine increased the expression of alpha7 nAChRs on fibroblasts. Our data suggest that nicotine induces lung fibroblasts to produce fibronectin by stimulating alpha7 nAChR-dependent signals that regulate the transcription of the fibronectin gene.
 ...
PMID:Nicotine and fibronectin expression in lung fibroblasts: implications for tobacco-related lung tissue remodeling. 1524 49

NALP1 (also called DEFCAP, NAC, CARD7) has been shown to play a central role in the activation of inflammatory caspases and processing of pro-IL1b (pro-interleukin-1b). Previous studies showed that NALP1 is highly expressed in peripheral blood mononuclear cells. In the present study, we report that expression of NALP1 is absent from CD34+ haematopoietic blast cells, and its levels are upregulated upon differentiation of CD34+ cells into granulocytes and to a lesser extent into monocytes. In peripheral blood cells, the highest levels of NALP1 were observed in CD3+ (T-lymphocytes), CD15+ (granulocytes) and CD14+ (monocytes) cell populations. Notably, the expression of NALP1 was significantly increased in the bone marrow blast cell population of some patients with acute leukaemia, but not among tissue samples from thyroid and renal cancer. A search for consensus sites within the NALP1 promoter revealed a sequence for CREB (cAMP-response-element-binding protein) that was required for transcriptional activity. Moreover, treatment of TF1 myeloid leukaemia cells with protein kinase C and protein kinase A activators induced CREB phosphorylation and upregulated the mRNA and protein levels of NALP1. Conversely, ectopic expression of a dominant negative form of CREB in TF1 cells blocked the transcriptional activity of the NALP1 promoter and significantly reduced the expression of NALP1. Thus NALP1 is transcriptionally regulated by CREB in myeloid cells, a mechanism that may contribute to modulate the response of these cells to pro-inflammatory stimuli.
 ...
PMID:NALP1 is a transcriptional target for cAMP-response-element-binding protein (CREB) in myeloid leukaemia cells. 1528 19

The bone-related transcription factor Runx2 (Cbfa1) has been extensively shown to regulate osteoblast differentiation and function. Recent studies demonstrate that Runx2 is also a positive regulator of chondrocyte maturation and vascular invasion in cartilage. Runx2 activity can be modulated in several ways, including direct stimulation of gene expression, post-translational modification, and protein-protein interactions. We have previously reported cooperative effects between BMP and RA downstream signaling involving Smad proteins and Runx2. Furthermore, our previous studies showed that PTHrP inhibits chondrocyte maturation primarily through CREB and AP-1 signaling pathways. In the present study, we investigated the effect of PTHrP on Runx2 expression in chick upper sternal chondrocytes (USCs). We further determined the signaling pathways through which PTHrP regulates Runx2 transcription. Our results show that PTHrP inhibits Runx2 expression at both the mRNA and protein levels concomitant with a PTHrP-mediated suppression of the phenotypic marker of hypertrophy, type X collagen. We further determined potential signaling pathways through which PTHrP inhibits Runx2 expression using protein kinase inhibitors, H89 (PKA inhibitor): Go-6976 (PKC inhibitor): SB203850 (p38 MAPK inhibitor), and U0126 (MEK inhibitor). We show that pretreatment with PKA and, to a lesser extent, PKC inhibitors significantly blocked PTHrP suppression of Runx2, while p38 MAPK and MEK inhibitors had no significant effect. Furthermore, PTHrP suppression of Runx2 mRNA was partially blocked in USCs infected with RCAS-A-CREB, a dominant negative reagent that abrogates CREB activity. Overall, our results demonstrate that PTHrP downregulates Runx2 expression primarily through the PKA signaling pathway.
 ...
PMID:Parathyroid hormone-related peptide (PTHrP) inhibits Runx2 expression through the PKA signaling pathway. 1530 80

Molecular mechanisms underlying C-fiber stimulation-induced ERK (extracellular signal-regulated kinase) activation in dorsal horn neurons and its contribution to central sensitization have been investigated. In adult rat spinal slice preparations, activation of C-fiber primary afferents by a brief exposure of capsaicin produces an eightfold to 10-fold increase in ERK phosphorylation (pERK) in superficial dorsal horn neurons. The pERK induction is reduced by blockade of NMDA, AMPA/kainate, group I metabotropic glutamate receptor, neurokinin-1, and tyrosine receptor kinase receptors. The ERK activation produced by capsaicin is totally suppressed by inhibition of either protein kinase A (PKA) or PKC. PKA or PKC activators either alone or more effectively together induce pERK in superficial dorsal horn neurons. Inhibition of calcium calmodulin-dependent kinase (CaMK) has no effect, but pERK is reduced by inhibition of the tyrosine kinase Src. The induction of cAMP response element binding protein phosphorylation (pCREB) in spinal cord slices in response to C-fiber stimulation is suppressed by preventing ERK activation with the MAP kinase kinase inhibitor 2-(2-diamino-3-methoxyphenyl-4H-1-benzopyran-4-one (PD98059) and by PKA, PKC, and CaMK inhibitors. Similar signaling contributes to pERK induction after electrical stimulation of dorsal root C-fibers. Intraplantar injection of capsaicin in an intact animal increases expression of pCREB, c-Fos, and prodynorphin in the superficial dorsal horn, changes that are prevented by intrathecal injection of PD98059. Intrathecal PD98059 also attenuates capsaicin-induced secondary mechanical allodynia, a pain behavior reflecting hypersensitivity of dorsal horn neurons (central sensitization). We postulate that activation of ionotropic and metabotropic receptors by C-fiber nociceptor afferents activates ERK via both PKA and PKC, and that this contributes to central sensitization through post-translational and CREB-mediated transcriptional regulation in dorsal horn neurons.
 ...
PMID:Ionotropic and metabotropic receptors, protein kinase A, protein kinase C, and Src contribute to C-fiber-induced ERK activation and cAMP response element-binding protein phosphorylation in dorsal horn neurons, leading to central sensitization. 1538 14

Classical genomic and non-genomic signaling pathways mediated by nuclear and cell membrane estrogen receptors are considered to contribute to estrogen-induced cell proliferation. Here we propose that mitochondrial signals to the nucleus regulate estrogen-induced progression of the cell cycle. The influence of estrogen on mitochondrial oxidative phosphorylation and mitochondrial gene transcription support the idea that mitochondria are significant targets of estrogen. Mitochondria are the major source of reactive oxygen species (ROS) in epithelial cells. Estrogen redox cycling within mitochondria also generates ROS. Antioxidants inhibit estrogen-induced cell growth. A-Raf, Akt, PKC, MEK, ERK, and transcription factors AP-1, NF-kappaB, and CREB are targets of both estrogen and ROS. We provide four lines of evidence in support of our hypothesis that estrogen-induced mitochondrial ROS stimulate redox sensor kinase A-Raf, Akt or PKC, which, in turn, activate transcription factors NF-kappaB, CREB, or AP-1 via the MEK/ERK pathway. Thus, estrogen-induced mitochondrial ROS leading to the activation of cell cycle genes containing AP-1, NF-kappaB, or CREB response elements are involved in the progression of the cell cycle of the estrogen-dependent cells. Our novel concept will contribute to the development of new targets in the prevention and control of estrogen-induced disease including cancer.
 ...
PMID:Mitochondrial signals to nucleus regulate estrogen-induced cell growth. 1553 31

PTH binds to PTH/PTHrP receptor, one of seventh transmembrane receptor, which activates cAMP/PKA system through Gs protein and causes an activation of PKC and an elevation of cytosolic calcium through Gq protein. PTH affects bone cells through these dual second messenger signaling systems(cAMP/PKA and Ca/PKC system). Recent studies revealed that PTH stimulates bone resorption as well as bone formation mainly through cAMP/PKA system. Further work is necessary to clarify the downstream of the signal, such as CREB and AP-1.
 ...
PMID:[The intracellular signal transduction systems of PTH and its effects on bone resorption and formation]. 1577 65

The potent tumor promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA) induces activator protein-1 (AP-1) transcription factors, early response genes involved in a diverse set of transcriptional regulatory processes, and protein kinase C (PKC) activity. This work was designed to explore the signal transduction pathways involved in TPA regulation of 5-aminolevulinate synthase (ALAS) gene expression, the mitochondrial matrix enzyme that catalyzes the first and rate-limiting step of heme biosynthesis. We have previously reported that TPA causes repression of ALAS gene, but the signaling pathways mediating this effect remain elusive. The present study investigates the role of different cascades often implicated in the propagation of phorbol ester signaling. To explore this, we combined the transient overexpression of regulatory proteins involved in these pathways and the use of small cell permeant inhibitors in human hepatoma HepG2 cells. In these experimental conditions, we analyzed TPA action upon endogenous ALAS mRNA levels, as well as the promoter activity of a fusion reporter construct, harboring the TPA-responsive region of ALAS gene driving chloramphenicol acetyl transferase gene expression. We demonstrated that the participation of alpha isoform of PKC, phosphatidylinositol 3-kinase (PI3K), extracellular-signal regulated kinase (ERK1/2), and c-Jun N-terminal kinase (JNK) is crucial for the end point response. Remarkably, in this case, ERK activation is achieved in a Ras/Raf/MEK-independent manner. We also propose that p90RSK would be a convergent point between PI3K and ERK pathways. Furthermore, we elucidated the crosstalk among the components of the cascades taking part in TPA-mediated ALAS repression. Finally, by overexpression of a constitutively active p90RSK and the coactivator, cAMP-response element protein (CREB)-binding protein (CBP), we reinforced our previous model, that implies competition between AP-1 and CREB for CBP.
 ...
PMID:Repression of 5-aminolevulinate synthase gene by the potent tumor promoter, TPA, involves multiple signal transduction pathways. 1579 41

Thromboxane A(2) receptors (TP) were previously localized to discrete regions in the rat brain on myelinated fiber tracts and oligodendrocytes (OLGs). The present studies extended these findings and investigated the effects of TP signaling on cell proliferation, survival, and gene expression in OLG progenitor cells (OPCs) and OLGs. It was found that the TP agonist, U46619 stimulated the proliferation of OPCs and promoted the survival of mature OLGs. Examination of the early gene expression events involved in OPC proliferation, revealed that c-fos expression was substantially increased by U46619 stimulation. Treatment of OPCs or OLGs with U46619 caused activation of the mitogen-activated protein kinases (MAPK) ERK 1/2. In OPCs this activation was blocked by inhibition of src. However, in OLGs this phosphorylation was not only blocked by inhibition of src but also by inhibition of protein kinase C (PKC). Furthermore, U46619 was found to increase CREB phosphorylation in both OPCs and OLGs. Similar to ERK 1/2 activation, there was a divergence in the mechanism of the TP-mediated CREB response for each cell type. Specifically, U46619 activation was attenuated by src and protein kinase A (PKA) inhibition in OPCs, whereas in OLGs this effect was blocked by inhibition of src, PKA as well as by inhibition of PKC. Collectively, these results provide the first demonstration that TP-activated nuclear signaling events are involved in the proliferation of OPCs, the survival of mature OLGs, and the stimulation of gene expression.
 ...
PMID:Thromboxane A receptor-mediated cell proliferation, survival and gene expression in oligodendrocytes. 1581 49


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