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 effect of the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) and the cytokines interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) on matrix metalloproteinases (MMP) and metalloproteinase inhibitors was studied in a variety of human cell lines. Expression of the mammalian collagenase (MMP-1), 72-kD gelatinase/type IV collagenase (MMP-2), stromelysin (MMP-3), 92-kD gelatinase/type IV collagenase (MMP-9), and tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2) was assessed by zymography and Northern blot analysis. MMP-2 and TIMP-2 activities were refractory to TPA, IL-1 and TNF-alpha treatment in most of the cell lines. In contrast, MMP-3, MMP-9 and TIMP-1 activities were markedly stimulated by TPA in most of the tumor cell lines and human umbilical vein endothelial cells (HUVEC), whereas the fibroblast lines were minimally stimulated or unresponsive to TPA. The MMP-3, MMP-9 and TIMP-1 stimulation in response to IL-1 and TNF-alpha treatment was detected in some of the tumor cell lines and HUVEC. The increase in activity was less marked than in TPA. A breast carcinoma cell line, MDA-MB-231, which did not express MMP-2, had high expression of MMP-3 and MMP-9 which were unaffected by TPA and cytokine treatment. Northern blot analysis of MMP and TIMP mRNA expression reflected the zymogram findings for most of the cell lines. TPA-mediated stimulation of MMP-1 was similar to that of MMP-3 and MMP-9. Exceptions were the fibroblast cell lines which showed either a much more marked mRNA response of MMP-9 to TPA than observed at protein level, or a high constitutive MMP-9 mRNA when MMP-9 activity was not detectable by zymography. TPA-mediated stimulation of MMP-9 and TIMP-1 activity was blocked by staurosporine, an inhibitor of protein kinase C (PKC). A non-PKC-activating phorbol ester, 4 alpha-phorbol-12,13-didecanoate, did not stimulate MMP-9 and TIMP-1 activity. TPA treatment caused the increased expression of c-fos containing AP-1-specific binding activity in selected tumor cell lines. This activity was maximal at 6 h. An association was observed between AP-1 binding activity and increased expression of MMP-1, MMP-3 and MMP-9, which possess TPA-responsive elements (TRE). TPA-sensitive MMPs and TIMP-1 were variably stimulated by biologically relevant cytokines, such as IL-1 and TNF-alpha.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Effect of phorbol ester and cytokines on matrix metalloproteinase and tissue inhibitor of metalloproteinase expression in tumor and normal cell lines. 128 26

Tumor necrosis factor (TNF) is able to induce a great diversity of cellular responses via modulating the expression of a number of different genes. The multitude of TNF activities may be explained by both structural and functional heterogeneity in TNF receptors as well as by a diversification of postreceptor signal transduction pathways. Purification of TNF receptors has revealed two major, distinct binding proteins (TR60 and TR80). TR60 seems to be an essential component for TNF signaling; the functional role of TR80 remains to be elucidated. The pathway of postreceptor signal transduction involves phospholipase A2, a phosphatidylcholine-specific phospholipase C, protein kinase C, and other serine/threonine and tyrosine-specific protein kinases with as yet unknown function. At the receiving end of TNF signaling, induction of gene expression is mediated through activation of nuclear transcription factors, such as NFkB, AP-1, IRF-1, and NF-GMa.
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PMID:Mechanisms of tumor necrosis factor action. 131 93

Chronic incubation of cultured renal tubular epithelial cells in acid medium causes an increase in Na/H antiporter activity that persists after removal from acid, is dependent on protein synthesis, and is associated with an increase in Na/H antiporter mRNA. Chronic activation of protein kinase C has similar effects in these cells. The present studies examined the role of protein kinase C in the effect of acid incubation. Incubation of MCT cells in acid for 24 h caused a 50% increase in Na/H antiporter activity. This was prevented by inhibition of protein kinase C, either with sphingosine or by protein kinase C downregulation. Pertussis toxin pretreatment did not prevent the increase in antiporter activity. Acid incubation caused an increase in transcription factor AP-1 activity, as shown by an increase in expression from a reporter gene containing six tandem AP-1 binding sites. This was associated with transient increases in c-fos and c-jun mRNAs. This response is typical of that for gene activation by protein kinase C. These studies demonstrate that acid activation of the Na/H antiporter requires protein kinase C and is associated with c-fos and c-jun expression and increased AP-1 activity.
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PMID:Role of protein kinase C and transcription factor AP-1 in the acid-induced increase in Na/H antiporter activity. 131 56

In cells, stimulation of protein kinase C (PKC) results in the dephosphorylation of specific residues proximal to the DNA binding domain of c-Jun, a major component of the AP-1 transcription factor. Since phosphorylation of this region of c-Jun inhibits interaction with DNA, this pathway may contribute to PKC activation of AP-1. To determine the mechanism(s) underlying this pathway, possible interactions between PKC and proteins implicated in c-Jun regulation are being investigated. Here it is shown that glycogen synthase kinase-3 beta (GSK-3 beta), a serine/threonine kinase that specifically targets the inhibitory c-Jun phosphorylation sites, is phosphorylated in vitro by particular forms of PKC (alpha, beta 1, gamma greater than beta 2; not epsilon). By contrast, the related GSK-3 alpha is not a substrate for any of these PKC isotypes. Phosphorylation of GSK-3 beta by PKC results in its specific inactivation. These results are consistent with a model in which activation of PKC stimulates c-Jun DNA binding by inhibiting its phosphorylation by GSK-3 beta.
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PMID:Differential regulation of glycogen synthase kinase-3 beta by protein kinase C isotypes. 132 14

Activation of either muscarinic cholinergic or thrombin receptors increases phosphoinositide turnover, Ca2+ mobilization, and redistribution of protein kinase C and induces rapid transient increases in c-fos mRNA and c-jun mRNA in 1321N1 cells. To determine whether the increases in c-fos and c-jun mRNA induced by carbachol and thrombin are sufficient to stimulate AP-1-mediated transactivation, 1321N1 cells were transfected with a reporter carrying two copies of the tetradecanoyl phorbol acetate response element and the firefly luciferase gene. Thrombin was significantly more effective than carbachol at stimulating AP-1-mediated transactivation. To identify the factors underlying the difference in AP-1 activity induced by carbachol and thrombin, members of the fos and jun families which encode components of AP-1 were examined. Carbachol and thrombin have similar effects on expression of c-fos, fosB, fra-2, junB, and junD, both acutely and over a 24-h time course. However, whereas carbachol leads only to transient induction of c-jun (maximal at 0.5 h), thrombin induces a biphasic increase in c-jun mRNA--an initial peak at 0.5 h and a second, more-prolonged increase at 12 h. Thrombin but not carbachol also induces a late increase in fra-1 mRNA, which peaks at 12 h. The secondary increase in c-jun mRNA is associated with marked increases in c-Jun protein levels and AP-1 DNA-binding activity. The late induction of c-jun and fra-1 mRNA can be prevented by adding the antagonist hirudin 30 min after thrombin, which results in loss of thrombin-stimulated increases in c-Jun protein, AP-1 DNA-binding activity, and AP-1-mediated transactivation. These findings suggest that rapid and transient conduction of c-fos and c-jun mRNA is insufficient to induce prominent changes in gene transcription, while the sustained increase in c-jun mRNA and perhaps the late induction of fra-1 mRNA are required for generation of AP-1 DNA-binding activity and transactivation through AP-1.
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PMID:Biphasic increase in c-jun mRNA is required for induction of AP-1-mediated gene transcription: differential effects of muscarinic and thrombin receptor activation. 132 61

The product of the c-jun proto-oncogene is the major component of the 12-O-tetradecanoyl phorbol 13-acetate (TPA)-inducible transcription factor AP-1. Jun binds to the TPA-responsive elements (TREs) present in a large number of TPA-inducible genes, thereby regulating their expression in response to activation of protein kinase C. Previously we have shown that Jun/AP-1 can also activate cAMP-responsive elements (CREs), indicating the existence of cross-talk in signal transduction at the transcriptional level. Here we show that Jun/AP-1 is activated by the cAMP-dependent protein kinase A (PKA). In transient transfection experiments, TRE activation by Jun is strongly enhanced by co-transfection of the catalytic subunit of PKA or forskolin treatment, although not in all cell types studied. Jun activity can be significantly inhibited by co-transfection of the regulatory subunit of PKA. Furthermore, we show a cell-specific increase in AP-1 binding in response to forskolin treatment. However, since direct phosphorylation of Jun by PKA does not occur, we suggest an indirect activation mechanism.
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PMID:Activation of Jun/AP-1 by protein kinase A. 133 36

We have previously shown that the phorbol ester, TPA, which activates protein kinase C, causes, in PC12 cells, a transcriptional activation of tyrosine hydroxylase (TH), the key enzyme in catecholamine synthesis. The study has now been extended to examine the processes that underlie this transcriptional stimulation and, in addition, to seek whether similar mechanisms are involved in long-term trans-synaptic induction of the TH gene in adrenal medullae of rats that have been given a single injection of reserpine. In both systems, it was found that the induction of c-fos gene transcription was associated with that of the TH gene but with different kinetics. The promoter of the TH gene contains (at position -207/-200) a sequence (TGATTCA) which differs from the consensus TRE or AP-1 site (TGACTCA) by one nucleotide. Experiments were carried out to investigate whether the AP-1 protein complex which is known to contain Fos and Jun binds to the putative TRE region of the TH promoter. In the gel shift assays, the nuclear protein extracts derived from TPA-treated PC12 cells and from AM of reserpine injected rats displayed a higher magnitude of binding to a 25-mer TRE-TH oligonucleotide as compared to controls. The results showed that the behaviour of TRE-TH was atypical in that two retarded complexes (A and B) were observed, which were displaced by specific competitors. Trans-activation experiments with plasmids TRE-TH/TK/CAT and -754/-19 TH/pUC18-CAT in PC12 cells showed an increase in CAT activity in response to TPA that correlates with the previously observed increase in TH transcriptional activity by TPA.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:AP-1 complex and c-fos transcription are involved in TPA provoked and trans-synaptic inductions of the tyrosine hydroxylase gene: insights into long-term regulatory mechanisms. 138 60

The expression of the beta isoenzyme for protein kinase C is regulated developmentally and in response to inducers of cell differentiation (such as phorbol esters and 1 alpha,25-dihydroxyvitamin D3). The 5' segment of the gene for protein kinase C beta was cloned from a human leukocyte genomic library in EMBL3 bacteriophage. This segment of the gene (greater than 54 kilobases in length) encompassed the coding sequence for the amino-terminal regulatory domain of the enzyme, the 5'-untranslated region, and the 5'-flanking region. Initiation of transcription was identified by S1 nuclease analysis and confirmed by RNase protection analysis at 197 base pairs 5' of the initiator ATG. Sequence analysis of the 5'-flanking region revealed it to be extremely G+C-rich (> 80%) with many features of a CpG island. Comparison of sequence with known cis-regulatory motifs disclosed a number of potential regulatory elements including an octamer binding motif at -76, Sp1-binding sites at -94 and -63, E boxes at -110, -26, and +18, an AP-1 site at -442, and an AP-2 site at -330. To demonstrate promoter activity, a 630-base pair fragment extending from -587 to +43 was subcloned in front of a promoterless luciferase gene. This fragment was able to drive the expression of luciferase in transient transfections of human hematopoietic cells. Deletion analysis demonstrated that a fragment -111 to +43 was necessary and sufficient for promoter activity; this fragment did not contain TATA or CAAT motifs. The promoter was stimulated 8-20-fold by phorbol esters accounting for the previously observed transcriptional activation of protein kinase C beta. This phorbol ester responsiveness was conferred by the basal promoter (-111 to +43) and was independent of the AP-1 site. These results define a novel mechanism of protein kinase C autoregulation at a transcriptional level.
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PMID:Cloning and characterization of the major promoter of the human protein kinase C beta gene. Regulation by phorbol esters. 140 Mar 96

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

A two-stage (initiation and promotion) model of chemical transformation of mouse embryonic fibroblasts was used to elucidate the molecular mechanisms of tumor promotion in vitro. C3H10T1/2 cells which had been initiated with a subcarcinogenic dose (0.5 micrograms ml-1) of benzo[a]pyrene (B[a]P) were isolated after 12-O-tetradecanoyl phorbol 13-acetate (TPA) treatment lasting 12, 24 or 36 days. These series of partially promoted cells were designated T-12, T-24 and T-36 cells. T-12 and T-24 cells exhibited higher anchorage-independent growth on soft agar in the presence of TPA than did the initiated or T-36 cells. Cytosolic protein kinase C (PKC) in the resting state was slightly depleted in T-24 and T-36 cells. Proteolytic down-regulation of membrane-bound PKC was enhanced in T-12 cells compared with the initiated cells after 3 h of TPA treatment. Induction of c-fos and c-jun proto-oncogene expression increased two- to threefold in T-12 cells. Moreover, the basal level of c-fos mRNA progressively increased in T-12, T-24 and T-36 cells. As compared with other cell types, T-12 cells had the highest AP-1 DNA-binding activity at both the basal level and at 30 min after TPA treatment. These results indicate that deregulation of the TPA-induced cellular responses occurs in the cells at various stages of tumor promotion, and might be associated with transforming processes.
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PMID:Differential induction of c-fos and c-jun proto-oncogenes and AP-1 activity by tumor promoter 12-O-tetradecanoyl phorbol 13-acetate in cells at different stages of tumor promotion in vitro. 143 50


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