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)

Jun homodimers and Fos/Jun heterodimers bind to the gene for phosphoenolpyruvate carboxykinase (GTP) (EC 4.1.1.32) (PEPCK) at three sites within the first 350 base pairs of the promoter. These include CRE-1 (-82 to -90), and P3(II) and P4 (-252 to -258 and -268 to -285, respectively). Over-expression of Jun in HepG2 cells resulted in a 10-15-fold increase in the level of transcription of a chimeric PEPCK (-490 to +73)-CAT gene, while expression of Fos decreased transcription and blocked the induction of transcription from the PEPCK promoter by Jun. The action of Fos and Jun on PEPCK gene transcription involved each of the Fos/Jun-binding sites and was modulated by additional transcriptional regulatory elements within the PEPCK promoter. The ability of Fos to inhibit PEPCK transcription was dependent upon P3(I), a region of the promoter which does not bind Fos/Jun heterodimers, but does bind members of the C/EBP family of transcription factors. Stimulation of PEPCK transcription by 8-Br-cAMP or by overexpression of the catalytic subunit of protein kinase A was inhibited by Fos expression. The inhibitory effects of phorbol esters and protein kinase C on PEPCK gene expression may be mediated through the action of Fos and Jun.
 ...
PMID:Opposing actions of Fos and Jun on transcription of the phosphoenolpyruvate carboxykinase (GTP) gene. Dominant negative regulation by Fos. 132 59

gadd153 is a CCAAT/enhancer-binding protein (C/EBP)-related gene whose expression is induced in response to growth arrest and DNA damage. This investigation explored the possibility that Ca2+ might play a role in regulating expression of gadd 153. We have demonstrated that treatment of HeLa cells with the calcium ionophores A23187 and ionomycin leads to the induction of gadd153 mRNA. The induction was rapid; increases in mRNA were detected by 90 min of treatment, and near maximum levels were achieved within 5-h exposure to A23187. Elevated mRNA levels resulted from both an increase in the rate of gadd153 transcription and an increase in the stability of the gadd153 mRNA. The response was not dependent on protein kinase C nor was it coupled to c-fos expression. Buffering intracellular and extracellular Ca2+ by combined treatment with BAPTA-AM (acetoxymethyl ester form of bis(aminophenoxy)ethane N,N'-tetraacetic acid) and EGTA prevented the induction of gadd153 mRNA by A23187. In addition, these treatments prevented the induction of gadd153 mRNA in response to the DNA damaging agent methyl methanesulfonate. We conclude that intracellular Ca2+ plays a role in regulating gadd153 expression. More specifically, Ca2+ likely plays a role in the induction of gadd153 mRNA following DNA damage.
 ...
PMID:Calcium ionophore A23187 induces expression of the growth arrest and DNA damage inducible CCAAT/enhancer-binding protein (C/EBP)-related gene, gadd153. Ca2+ increases transcriptional activity and mRNA stability. 140 Mar 65

Four DNA-recombinant proteins, corresponding to the DNA-binding domain of CCAAT/enhancer binding protein (C/EBP), were phosphorylated in vitro by protein kinase C (PKC). High-performance liquid chromatography-peptide mapping of 32P-labeled C/EBP indicated the presence of three major 32P-labeled peptides: S299 (P)RDK, AKKS277 (P)VDK, and GAAGLPGPGGS248 (P)LK. Phosphorylation of C/EBP by PKC or M-kinase resulted in an attenuation of binding to a 32P-labeled CCAAT oligodeoxynucleotide. Three other truncated forms of C/EBP, C/EBP87, C/EBP87S-C, and C/EBP60, were studied to define the sites of phosphorylation affecting DNA binding. Phosphorylation of the C/EBP87, containing sites Ser299 and Ser277, and C/EBP60, containing only site Ser299, by PKC also resulted in attenuation of DNA binding. In contrast, phosphorylation of C/EBP87S-C, which retained Ser277 but had a Cys in place of Ser299, had no effect on DNA binding. Ser299 could not be phosphorylated by PKC if the protein is already bound to specific DNA. Phosphorylation of intact C/EBP from liver nuclear extract by PKC or M-kinase occurred at Ser299 and Ser277 and at an additional site, as demonstrated by immunoprecipitation and peptide mapping.
 ...
PMID:Phosphorylation of CCAAT-enhancer binding protein by protein kinase C attenuates site-selective DNA binding. 152 59

IL-8 is produced by a wide variety of cells in response to polyclonal mitogens and cytokines. Northern blotting analysis revealed that IL-1, TNF and PMA could induce rapid expression of IL-8 mRNA in the absence of new protein synthesis. Nuclear run-off assays using different cell types demonstrated that IL-8 mRNA expression could at least be partly due to the activation of transcription. Cloning and determination of the entire sequence of IL-8 genomic DNA enabled us to explore the functional significance of the 5'-flanking enhancer region of the IL-8 gene by employing CAT assays. The results indicated that the region spanning from -94 to -71 bp is minimally sufficient for conferring responsiveness to IL-1, TNF and PMA. Further analysis using point-mutations revealed that this region consisted of two distinct cis-elements; one being the potential binding site for NFkB-like and the other for a C/EBP-like factor. These results suggested that all three stimuli, IL-1/TNF/PMA, modulate the identical combination of nuclear factors possibly by phosphorylation. We previously reported that these three stimuli activated the same serine protein kinase which phosphorylates identical 65 kDa and 74 kDa cytosol proteins in human PBMC. This IL-1/TNF/PMA-activated protein kinase is distinct from protein kinase A, protein kinase C or casein kinase in substrate specificity; in Ca and phospholipid dependency; in cyclic nucleotide dependency; and sensitivity to protein kinase inhibitors. Taken collectively, IL-1/TNF/PMA may activate a common serine protein kinase and this protein kinase may in turn directly or indirectly modulate several nuclear factors.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Regulation of human interleukin 8 gene expression and binding of several other members of the intercrine family to receptors for interleukin-8. 175 77

We previously demonstrated that down-regulation of protein kinase C (PKC) by prolonged 12-O-tetradecanoylphorbol-13-acetate (TPA) treatment leads to the specific repression of GnRH transcription in GT1-7 hypothalamic neurons. Here we have investigated the regulatory sequences and cognate DNA-binding proteins that mediate this transcriptional response. The promoter-proximal section of the GnRH gene contains an evolutionarily conserved sequence that is bound along its entire length by GT1-7 nuclear proteins in DNase I protection assays. Two distinct regions within this sequence are required for PKC regulation of the GnRH gene, as excision of either region results in loss of TPA repression of transcription. Excision of either of these regions also decreases basal transcription, demonstrating their role in GnRH promoter function. One region encompasses three AT-rich protein-binding sites; the other is an extended region of continuous DNase I protection, 50 nucleotides in length, that contains consensus recognition motifs for the CCAAT/EBP and helix-loop-helix families of transcription factors. Mobility shift analysis of binding to the latter region reveals that TPA treatment of GT1-7 neurons induces the formation of a specific DNA-protein complex with kinetics of appearance consistent with a role in repression of GnRH transcription. Thus, the sequences that mediate PKC regulation of GnRH are proximal to the promoter, evolutionarily conserved, and form TPA-inducible complexes with GT1-7 nuclear proteins.
 ...
PMID:Regulation of gonadotropin-releasing hormone transcription by protein kinase C is mediated by evolutionarily conserved promoter-proximal elements. 747 68

Through its action on macrophages, bacterial lipopolysaccharide (LPS) or endotoxin can trigger responses that are protective or injurious to the host. This review examines the effects of LPS on macrophages by following events from the cell surface to the nucleus. The involvement of protein tyrosine kinases, mitogen-activated protein kinases, protein kinase C, G proteins, protein kinase A, ceramide-activated protein kinase, and microtubules in this process are reviewed. At the nuclear level, rel, C/EBP, Ets, Egr, fos, and jun family members have been implicated in activation of LPS-inducible gene expression.
 ...
PMID:Endotoxin signal transduction in macrophages. 869 27

Regulation of mRNA levels, DNA binding activities, and phosphorylation of CCAAT/enhancer-binding protein (C/EBP) family members by stimulation of glutamate receptors were studied in cultured rat cortical astrocytes. Indirect immunofluorescence and immunoblot analyses with specific antibodies to C/EBP family members revealed that both C/EBPbeta and C/EBPdelta but not C/EBPalpha are expressed in the nuclei of astrocytes. After exposure to glutamate, C/EBPbeta mRNA levels increased within 10 min, reached the maximal level at about 1 h, and returned to the basal level within 6 h. In contrast, C/EBPdelta mRNA levels decreased by 6 h and were recovered within 12 h. These changes in mRNA levels were accompanied by an increase and a decrease in proteins for C/EBPbeta and C/EBPdelta, respectively. Elevation of C/EBPbeta mRNA levels by glutamate treatment required an increase in intracellular Ca2+ concentration and depended on activations of protein kinase C and calmodulin-dependent protein kinases. Gel mobility shift analysis using nuclear extracts from the glutamate-treated cells showed increases in C/EBP site binding activities 2 h after the exposure to glutamate. Moreover, glutamate stimulated phosphorylation of C/EBPbeta in 32P-labeled astrocytes in a Ca2+-dependent manner. These results suggest that glutamate regulates functions of C/EBP family members in brain astrocytes through changes in mRNA levels of C/EBPbeta and C/EBPdelta as well as through phosphorylation of C/EBPbeta.
 ...
PMID:Regulation of CCAAT/enhancer-binding protein family members by stimulation of glutamate receptors in cultured rat cortical astrocytes. 879 61

14-3-3 protein, a brain-specific protein, is thought to be a multifunctional protein involved in the activation of tyrosine and tryptophan hydroxylases, the inhibition or activation of protein kinase C, and the activation of signal transduction. The human 14-3-3 eta chain gene was isolated and its structure was determined. It is composed of two exons separated by one long intron (approximately 8 kb) and spans about 10 kb. A transcription initiation site was identified by a combination of S1 nuclease mapping, primer extension analysis, and RACE methods. In the 5'-flanking region, we found four GC box sequences, four anti-GC box sequences, a TATA box-like sequence, CAAT box-like sequences, a C/EBP element, two AP-2 sequences, an AP-3 sequence, an Oct-6-like sequence, six E boxes, and a CRE sequence. FISH with DNA probes of the human 14-3-3 eta chain gene mapped the 14-3-3 eta chain gene to chromosome 22q12.1-q13.1.
 ...
PMID:Structural organization and chromosomal assignment of the human 14-3-3 eta chain gene (YWHAH). 881 17

1. The effect of different protein kinase inhibitors on the expression of the inducible isoform of nitric oxide (NO) synthase (iNOS) was investigated in cultured vascular smooth muscle cells (VSMC) isolated from the rat aorta. 2. The non-selective protein kinase C (PKC) inhibitor, staurosporine, but not the more selective PKC inhibitors, calphostin C and Ro 31-8820, or the tyrosine kinase inhibitors, genistein and erbstatin analogue (erbstatin A), elicited a distinct (up to six fold) up-regulation of iNOS gene expression in these cells, as demonstrated by a parallel increase in iNOS mRNA and protein abundance as well as an accumulation of nitrite (NO2-) in the conditioned medium. Actinomycin D and cycloheximide inhibited the effect of staurosporine, suggesting an involvement of both DNA transcription and de nova protein synthesis. 3. Staurosporine also synergistically potentiated the stimulating effect of interleukin-1 beta (IL-1 beta), but not that of the adenylyl cyclase activator, forskolin, on NO2- production and iNOS protein abundance. Staurosporine, on the other hand, had no effect on the IL-1 beta-mediated increase in iNOS mRNA abundance. The effect of staurosporine on both basal and IL-1 beta-stimulated NO2- production was concentration-dependent with an apparent maximum at 3 nM. Among the other protein kinase inhibitors tested, only calphostin C also enhanced the stimulant effect of IL-1 beta approximately two fold, while genistein, erbstatin A and Ro 31-8220 inhibited rather than potentiated it. 4. Staurosporine did not influence basal activity of the transcription factors CREB and nuclear factor kappa B (NF-kappa B), but increased that of C/EBP. Moreover, staurosporine significantly augmented the activation of C/EBP by IL-1 beta and forskolin. 5. These findings suggest that in cultured VSMC a staurosporine-sensitive protein kinase exists, which is unlikely to be related to PKC, that prevents iNOS gene expression presumably by suppressing basal C/EBP activity. They also indicate that NF-kappa B and a member of the C/EBP family of transcription factors, presumably C/EBP beta, act synergistically under basal conditions and possibly also following exposure to IL-1 beta in the up-regulation of iNOS gene expression in these cells. Targeting of the activation of C/EBP beta may thus represent an interesting approach to interfere selectively with the cytokine-induced over-production of NO in acute and chronic inflammatory conditions.
 ...
PMID:Induction by staurosporine of nitric oxide synthase expression in vascular smooth muscle cells: role of NF-kappa B, CREB and C/EBP beta. 913 19

Paclitaxel (Taxol) is a novel chemotherapeutic drug that is effective against breast and ovarian cancers. Although the primary target of paclitaxel is microtubules, its efficacy exceeds that of conventional microtubule-disrupting agents, suggesting that it may have additional cellular effects. Previously, we demonstrated that paclitaxel can induce interleukin-8 (IL-8) gene expression at the transcriptional level in subsets of human ovarian cancer lines. In this as well as the previous report, we present evidence that this ability is not linked to the lipopolysaccharide pathway of IL-8 gene induction. The present study identifies the cis-acting elements and trans-acting factors involved in this induction by transfecting DNA constructs containing the 5'-flanking region of the IL-8 gene linked to the chloramphenicol acetyltransferase reporter gene into paclitaxel-responsive and nonresponsive ovarian cancer cells (responsiveness refers to the IL-8 response). Paclitaxel only activated the IL-8 promoter in responsive cells. The AP-1 and NF-kappaB binding sites in the IL-8 promoter are required for activation by paclitaxel; in contrast, a C/EBP site required for IL-8 promoter activation in other cell types is not involved. Gel shift assays demonstrate that paclitaxel causes a marked increase in protein binding to the NF-kappaB and AP-1 consensus binding sequences in the paclitaxel-responsive ovarian cells, but not the nonresponsive cells. The induction of NF-kappaB and AP-1 binding is reduced by the addition of protein kinase C inhibitors and cyclic AMP effector, respectively. These results demonstrate a molecular mechanism for cell-specific paclitaxel-induced IL-8 gene expression which may have clinical relevance.
 ...
PMID:Identification of tumor-specific paclitaxel (Taxol)-responsive regulatory elements in the interleukin-8 promoter. 927 87


1 2 3 4 5 6 Next >>