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)

Transcription factor AP-1 is constituted by the various products of the fos and jun proto-oncogene family members, which associate as dimers to bind with variable efficiency to 12-O-tetradecanoyl phorbol 13-acetate (TPA)-responsive promoter elements (TREs). We have recently shown that DNA binding of AP-1 is regulated by an inhibitory protein, IP-1, whose activity is modulated by phosphorylation. Here it is shown that although AP-1 has a very high affinity for its recognition sequence, its binding to the TRE can be quickly inhibited by the addition of IP-1. IP-1 is more active on AP-1 complexes formed during a shorter period of time. IP-1 activity is blocked by stimulation of the protein kinase C (PKC) signal transduction pathway, achieved by treating HeLa cells with phorbol esters or with a diacylglycerol analog. We observed an increase in AP-1-DNA binding after treatment of the cells with either the calcium ionophore A-23187 or dibutyryl cAMP; this could be ascribed to inhibition of IP-1 activity. A decreased IP-1 activity also correlates with the increase in AP-1-DNA binding after stimulating cells with serum. This suggests that IP-1 is an important target of the various signal transduction pathways. No effect on AP-1 and IP-1 was detected in cells transformed by Ki-ras or v-raf; nor could an effect of inhibition of protein synthesis be observed. We also analysed IP-1 regulation upon differentiation of P19 embryonal carcinoma cells by retinoic acid. We conclude that IP-1 regulation has a pivotal role in the final modulation of Fos-Jun by signal transduction pathways.
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PMID:AP-1 (Fos-Jun) regulation by IP-1: effect of signal transduction pathways and cell growth. 143 49

The TPA-inducible transcription factor AP-1, consisting of homo- or hetero-dimers of members of the Jun- and Fos-families, regulates transcription of a wide variety of genes containing the TPA response element (TRE). In P19 embryonal carcinoma (EC) cells, Jun D is the only component of AP-1 expressed, while in these cells until now none of the members of the jun- and fos-families have been found to be inducable by external stimuli. Here we demonstrate that Jun B is the only member of the Jun- and Fos-families that is induced by Epidermal Growth Factor (EGF) in transfected murine P19 EC cells, expressing functional human EGF receptors (hEGF-Rs). Induction of jun B can be mimicked in wild type P19 EC cells by the synergistic action of the phorbol ester TPA and the calcium ionophore A23187, through activation of signal transduction pathways, that are activated simultaneously by EGF. The EGF induced jun B expression in the hEGF-R expressing P19 EC cells is mediated by an inverted repeat (IR) sequence in the jun B promoter, previously shown to be responsive to both PKC and PKA signal transduction. Transactivation of the IR sequence by EGF can be blocked completely by prior expression of antisense Jun D, but not by antisense c-Jun. These studies therefore implicate Jun D in the regulation of immediate early gene expression by external stimuli.
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PMID:EGF-induced jun B-expression in transfected P19 embryonal carcinoma cells expressing EGF-receptors is dependent on Jun D. 173 90

Proteins encoded by the adenovirus E1A oncogene are capable of positive and negative transcriptional regulation of both viral and cellular genes. E1A regulatory function is commonly thought to involve modifications of specific cellular factors that interact with responsive promoters. In this report we present evidence that E1A induces the activity of the jun/AP-1 transcription factor in three different cell types: P19, JEG-3, and HeLa. AP-1 binds to 12-O-tetradecanoylphorbol-13-acetate (TPA)-responsive elements (TREs); therefore, E1A might modulate a specific signal transduction pathway normally induced by activation of the protein kinase C. Binding of jun/AP-1 to a TRE is induced in all cell types studied when E1A is expressed. We observe that the expression of endogenous c-jun and jun B genes is induced by E1A, which directly transactivates the promoters of c-fos, c-jun, and jun B. Similar inducibility is obtained by treatment with retinoic acid and differentiation of P19-embryonal carcinoma cells. The E1A 13S product transactivates TRE sequences and cooperates with c-jun in the transcriptional stimulation. The 12S E1A product does not activate a TRE sequence, but cotransfection with c-jun circumvents this lack of stimulation. Coexpression of c-fos and E1A 12S, however, blocks the transactivation by c-jun, suggesting an important role for fos in determining the dominance of the 12S or 13S protein.
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PMID:Positive regulation of jun/AP-1 by E1A. 182 13

After retinoic acid treatment, a large percentage of cells of the human embryonal carcinoma cell line NT2/D1 differentiate into neuronal cells. We demonstrate here that the differentiated cells, but not the undifferentiated cells, contain high levels of neurofilament mRNA. We have also measured mRNA, protein, and activity levels of two kinases, cAMP-dependent protein kinase (PKA) and protein kinase C (PKC), in order to explore the role of protein kinases in the establishment of the differentiated state. RNA levels for the catalytic (C alpha and C beta) subunits of PKA increased after differentiation. Total PKA activity levels increased 7-fold in the differentiated cells. Parallel with this, a rise in the level of catalytic subunit protein occurred. A 12-fold induction of Type 2 (beta) PKC mRNA levels was observed after neuronal differentiation. Increases in PKC activity and in Type 2 (beta) and Type 3 (alpha) PKC protein levels also accompanied differentiation. These changes in PKA- and PKC-specific RNA levels and enzyme activity may be necessary for production and maintenance of the differentiated state in these cells.
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PMID:Increased PKA and PKC activities accompany neuronal differentiation of NT2/D1 cells. 204 Oct 56

The enhancer activity of the oligomerized SV40 TC-I and TC-II sequences has been investigated in lymphoid and non-lymphoid cell lines. While the TC-I sequence had no demonstrable enhanson activity, a class C enhanson (proto-enhancer), 5'-GGAAAGTCCCC-3', overlapping the TC-II sequence and the GT-I enhanson was identified. This TC-II enhanson, which is identical to the kappa B motif from the kappa chain enhancer, was active in both lymphoid and non-lymphoid cells, which contrasts with the previously reported lymphoid cell specificity of the kappa B motif. However, its activity in non-lymphoid cells is in agreement with our previous reports describing the effect of mutations in the 'TC region' within the total SV40 enhancer in lymphoid and non-lymphoid cells. The activity of the TC-II enhanson could be moderately increased in HeLa by 12-O-tetradecanoyl-phorbol-13-acetate (TPA) and cycloheximide treatment, indicating that the protein(s) mediating its activity may be partially repressed by the previously described inhibitor protein I kappa B. The TC-II related, H-2Kb element, 5'-TGGGGATTCCCCA-3', of the histocompatibility class I H-2Kb gene promoter is also a class C enhanson which is active in both lymphoid and non-lymphoid cells. However, in contrast to the TC-II enhanson, the H-2Kb enhanson exhibits a very low activity in HeLa cells, but can be strongly induced by TPA and/or cycloheximide treatments which suggests that its cognate factor is inactivated (repressed) by an inhibitor protein. Interestingly, cycloheximide, but not TPA treatment, could induce the activity of both the TC-II and H-2Kb enhansons in F9 embryonal carcinoma cells, suggesting that these cells lack some component(s) of the protein kinase C signal transduction pathway. We also show that oligomers of the SV40 'core' sequence, which overlaps the TC-II enhanson, had no enhanson activity in any of the cell types studied, which questions the possible role of the AP-3 protein in SV40 enhancer activity in these cell types. In addition, oligomers of the AP-2 binding sites which are present in the SV40 TC region and in the human metallothionein IIA promoter show no enhanson activity, irrespective of whether the cells are treated with TPA.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The SV40 TC-II(kappa B) and the related H-2Kb enhansons exhibit different cell type specific and inducible proto-enhancer activities, but the SV40 core sequence and the AP-2 binding site have no enhanson properties. 255 64

We have recently reported that a polypeptide mitogen, the embryonal carcinoma-derived growth factor (ECDGF), induces phosphorylation of the epidermal growth factor (EGF) receptor in intact C3H 10T 1/2 mouse fibroblasts with concomittant loss of high affinity EGF binding sites. This phenomenon appears to be mediated through an activation of protein kinase C. Several groups have described an acidic 80,000 dalton protein substrate of protein kinase C. In this paper, we demonstrate that the addition of ECDGF or the phorbol ester TPA to intact C3H 10T 1/2 cells results in the enhanced phosphorylation of this 80 kd protein in vivo. Furthermore, this response is demonstrable in vitro. Thus the addition of ECDGF, the phorbol ester TPA, protein kinase C or phosphoinositidase C to crude membranes prepared from C3H 10T 1/2 cells resulted in the enhanced phosphorylation of this protein. Data obtained by phosphopeptide mapping of the 80 kd protein show that the ECDGF-induced activation of protein kinase C in our membrane preparations is comparable with that obtained in vivo. The availability of an in vitro system in which this response is preserved should now allow a detailed biochemical analysis of the steps between binding of a mitogen to its receptor and the activation of protein kinase C.
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PMID:Embryonal carcinoma-derived growth factor activates protein kinase C in vivo and in vitro. 359 64

Retinoic acid (RA) induced differentiation of F9 embryonal carcinoma cells is accompanied by changes in cellular responsiveness to extracellular signals. These changes include an increase in the AP1 transcription factor that is associated with the expression of differentiation markers (e.g., cytokeratin 18 and plasminogen activator). Since AP1 activity is a target for protein kinase C (PKC)-regulated changes in gene expression, we have examined the effects of RA on the expression and function of the PKC isozymes. F9 stem cells express PKC beta, delta, epsilon, and zeta. RA-induced differentiation to primitive endoderm led to a transition from PKC beta to PKC alpha expression. Additional treatment with dibutyryl cyclic AMP (dbcAMP), required for terminal differentiation into parietal endoderm, further increased PKC alpha expression and total PKC activity. RA and dbcAMP had negligible effects on the expression of PKC delta, epsilon, and zeta. The PKC beta to PKC alpha transition was specific for parietal endoderm; aggregation of RA-treated F9 cells induced visceral endoderm differentiation with elevated expression of PKC beta. The PKC activation with phorbol esters induced the expression of c-fos, c-jun, and junB proto-oncogenes in F9 stem cells. In the presence of either RA or RA and dbcAMP, phorbol ester treatment enhanced the expression of type IV collagen, a parietal endoderm marker. It also increased the expression of c-jun gene but not c-fos. The specific involvement of PKC beta in c-fos induction and PKC alpha in type IV collagen induction was confirmed in each PKC isozyme-transfected F9 cells. Together, our data demonstrate that the RA-induced (and dbcAMP-induced) changes in conventional PKC expression alters gene expression during parietal endoderm formation.
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PMID:Retinoic acid-induced transition from protein kinase C beta to protein kinase C alpha in differentiated F9 cells: correlation with altered regulation of proto-oncogene expression by phorbol esters. 873 69

1,25-Dihydroxyvitamin D3 (calcitriol) at 100 nmol/l elicited morphological differentiation and expression of collagen IV in mouse F9 embryonal carcinoma cells, and its effect was enhanced and accelerated by dibutyryl-cAMP (db-cAMP). The RAR beta 2 promoter was also activated, as evidenced by an increase in beta-galactosidase activity in an F9 reporter cell line with a stably integrated RAR beta 2-lacZ construct. All three effects were slower and less extensive with calcitriol than with retinoic acid, even in the presence of db-cAMP. Activation of the RAR beta 2 promoter by calcitriol required its TRE sequence, whereas db-cAMP required the CRE. TPA also activated the RAR beta 2 promoter, requiring a functional TRE. Thus, in the RAR beta 2 promoter the TRE sequence, whose function has so far been unidentified, mediates the effects of calcitriol and TPA. RAR beta 2 promoter activation by calcitriol was blocked by inhibitors of protein kinase C indicating that calcitriol elicits its effect via protein kinase C. Therefore, calcitriol induces differentiation of F9 mouse embryonal carcinoma cells at least in part by a pathway different from the classical one operative with retinoic acids.
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PMID:Induction of mouse embryonal carcinoma cell differentiation and activation of the retinoic acid receptor beta 2 promoter by 1,25-dihydroxyvitamin D3. 896 Mar 71

The histidine decarboxylase (HDC) gene is regulated transcriptionally by gastrin and phorbol 12-myristate 13-acetate (PMA) through a protein kinase C (PKC)-related pathway. To determine the role of AP-1 (fos/jun) in the regulation of the HDC promoter, gastric cancer (AGS-B) cells stably expressing the cholecystokinin-B/ gastrin receptor and the 1.8-kb human (h) HDC-luciferase (luc) construct were cotransfected with constructs expressing c-fos and c-jun. Overexpression of c-fos and c-jun activated the HDC promoter in a dose-dependent fashion in 1.8-kb hHDC-luc/AGS-B cells as well as in transfected F9 embryonal carcinoma cells, which lack endogenous AP-1 activity. PMA was unable to activate the HDC promoter in F9 cells, which were not transfected with c-fos and c-jun. Gastrin stimulation increased c-fos and c-jun mRNA abundance and AP-1-dependent transcriptional activity, as assessed by a reporter construct in which the CAT reporter gene is under the control of a 12-O-tetradecanoylphorbol-13-acetate response element multimer. Gastrin-stimulated HDC promoter activity was blocked by transfection of c-fos antisense and dominant negative c-jun expression constructs. Finally, overexpression of c-fos and c-jun activated the hHDC promoter through a downstream cis-acting element (gastrin response element), which does not bind AP-1. In conclusion, activation of AP-1 is essential for gastrin-stimulated HDC transcription, but the mechanism appears to be indirect.
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PMID:Gastrin regulates the human histidine decarboxylase promoter through an AP-1-dependent mechanism. 914 14

As F9 embryonal carcinoma cells differentiate into parietal endoderm-like cells, expression of conventional protein kinase C (PKC) changes. Undifferentiated stem cells express PKCbeta but not PKCalpha, whereas differentiated parietal endoderm cells express PKCalpha but not PKCbeta. To determine whether changes in PKCalpha and/or PKCbeta expression control retinoic acid (RA)- and dibutyryl cyclic AMP-induced F9 cell differentiation, we established cell lines stably expressing PKCalpha, PKCbeta, antisense PKCalpha, or antisense PKCbeta RNAs. Constitutive expression of PKCalpha or inhibition of PKCbeta expression in F9 stem cells enhanced RA induced differentiation, both by increasing total expression and accelerating RA-induced expression of laminins A, B1, B2, and type IV collagen. In addition, expressing PKCbeta in a parietal endoderm cell line caused these cells to retrodifferentiate into stem cells. Based on these results, we conclude that PKCbeta and PKCalpha are key targets for RA-regulated gene expression, that PKCalpha plays an important, active role in inducing and maintaining the parietal endoderm phenotype, and that PKCbeta activity is incompatible with maintaining the differentiated state of these cells.
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PMID:Distinct functions of protein kinase Calpha and protein kinase Cbeta during retinoic acid-induced differentiation of F9 cells. 948 51


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