Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

p21c-ras plays a critical role in mediating tyrosine kinase-stimulated cell growth and differentiation. However, the pathways through which p21c-ras propagates these signals remain unknown. We report that in PC12 cells, expression of a dominant inhibitory mutant of ras, c-Ha-ras(Asn-17), antagonizes growth factor- and phorbol ester-induced activation of the erk-encoded family of MAP kinases, the 85-92 kd RSKs, and the kinase(s) responsible for hyperphosphorylation of the proto-oncogene product Raf-1. In addition, we find that expression of the activated ras oncogene is sufficient to stimulate these events. These data indicate that ras mediates nerve growth factor receptor and protein kinase C modulation of MAP kinases, RSKs, and Raf-1.
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PMID:ras mediates nerve growth factor receptor modulation of three signal-transducing protein kinases: MAP kinase, Raf-1, and RSK. 131 93

MIA C51 is a rat monocytic leukemia cell line which exhibits undifferentiated monocytic phenotype in culture. The proliferation of MIA C51 cells was not inhibited by the addition of 12-O-tetradecanoyl-phorbol-13-acetate (TPA, 1 microgram/ml) or phorbol 12, 13 dibutyrate (PDBu, 10 micrograms/ml). Comparison of MIA C51 cells to a phorbol diester-sensitive human monoblastoid U-937 cell line demonstrated that MIA C51 cells contained significantly lower number of PDBu receptors, protein kinase C (PKC) activity, and PKC protein level. Further experiments demonstrated that addition of TPA to MIA C51 cells did not induce the expression of c-fos proto-oncogene; whereas incubation of MIA C51 cells with N6, O2-dibutyryl cyclic adenosine 3',5' monophosphate (Bt2cAMP) resulted in a rapid increase of c-fos mRNA level. Thus, this cell line provides a new system for studying the signal transduction mechanisms in induced monocytic differentiation.
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PMID:A phorbol diester resistant monocytic leukemia cell line is PKC deficient. 131 72

CSV3 clones of simian virus 40 large T antigen-transformed murine 3T3 T cells can be made quiescent as part of a differentiation process. In these quiescent cells, insulin- and vanadate-induced mitogenesis are both associated with the induction of the c-jun proto-oncogene (Wang and Scott 1991 J. Cell. Physiol. 147, 102-110; Wang et al. 1991 Cell Growth Differ. 2, 645-652). The current studies were therefore designed to compare the early signal transduction pathways employed by insulin and vanadate to regulate c-jun expression. In quiescent CSV3-1 cells, down-regulation of protein kinase C by prolonged exposure to 12-O-tetra-decanoylphorbol-13-acetate or inhibition of protein kinase C activity by treatment with the protein kinase C antagonist staurosporine is shown not to affect c-jun induction by insulin or vanadate. This suggests that both insulin and vanadate act in a protein kinase C-independent manner. Insulin's effect on c-jun induction does, however, involve a G protein because insulin's effect can be inhibited by pertussis toxin. In contrast, vanadate induction of c-jun is not affected by pertussis toxin. Genistein, a general tyrosine kinase inhibitor, can inhibit the ability of vanadate to induce c-jun but it does not inhibit insulin's effect. Finally, the depletion of polyamines, particularly spermidine, by DL-alpha-difluoromethylornithine treatment also prevents c-jun induction by insulin but DL-alpha-difluoromethylornithine treatment has no effect on c-jun induction by vanadate. These observations indicate that the c-jun induction by insulin and vanadate in CSV3-1 cells is mediated by different signal transduction mechanisms. Together with our previously published data, these results suggest that c-jun can be induced independent of protein kinase C activation, without involvement of pertussis toxin-sensitive G protein, independent of induction of c-fos, and without expression of high levels of intracellular polyamines.
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PMID:Induction of c-jun independent of PKC, pertussis toxin-sensitive G protein, and polyamines in quiescent SV40-transformed 3T3 T cells. 133 Jun 58

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

Incubation of non-excitable murine macrophage cell line PU5-1.8 in K+(140 mM)-Hepes buffer caused membrane depolarization as measured by bis-oxonol and 3,3'-dipropylthiodicarbocyanine. Depolarization of cell membrane produced an increase of intracellular free Ca2+ concentration ([Ca2+]i). Interestingly, short-term exogenously imposed membrane depolarization in PU5-1.8 cells in the absence of growth factors initiated the incorporation of [3H]thymidine or its analog, 5-bromo-2'-deoxyuridine, as well as the expression of early-response genes such as c-fos and c-myc. The expression of the proto-oncogene products seemed to be dependent on external Ca2+, and the [3H]thymidine incorporation was inhibited by nifedipine and verapamil at similar dosages as for Ca2+ inhibition. Calcium influx and [3H]thymidine incorporation could also be induced by Bay K 8644 or by gramicidin in the Na(+)-Hepes buffer. On the other hand, challenge of cells with sphingosine, staurosporine or 1-(5-isoquinolinesulfonyl)-2-methylpiperazine suppressed the K(+)-mediated DNA synthesis. Furthermore, preincubation of cells with phorbol 12-myristate 13-acetate (PMA) for 15 min in Na(+)-Hepes buffer enhanced the DNA synthesis. Yet, pre-incubation of cells with PMA or 1,2-dioctanoyl-sn-glycerol in K(+)-Hepes buffer suppressed the K(+)-mediated DNA synthesis and membrane depolarization. These observations suggest that a rise of [Ca2+]i is required for the initiation of DNA synthesis, and PKC may be functioning as a modulator with dual action at least on the level of ion conductance.
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PMID:Membrane depolarization induced DNA synthesis in PU5-1.8 cells. Role of voltage-operated Ca2+ channel and protein kinase C. 133 68

As the factor binding to the neu protein has been unknown, it has not been possible to confirm experimentally the proposed growth-factor receptor like functions of the neu protein. To approach this problem we constructed a recombinant receptor which enabled ligand regulation of the neu tyrosine kinase. The hybrid receptor consisted of the extracellular ligand binding, transmembrane and protein kinase C-substrate domains joined to the intracellular tyrosine kinase and carboxyl-terminal domains of the neu protein. Several properties of NIH3T3 cells carrying this construct were tested. We obtained the first experimental evidence that the neu proto-oncogene has mitogenic and transforming activities only in the presence of a ligand stimulating its tyrosine kinase activity. Various cellular and molecular biological parameters indicated that the chimeric receptor behaved very similarly to the EGFR. Also, this chimeric receptor has allowed us to compare the constitutive oncogenic and the ligand-activated non-oncogenic activities of the neu tyrosine kinase. In the future we plan to focus on characterization of possible differences between EGFR and neu signalling in more differentiated cellular backgrounds.
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PMID:A chimeric EGFR/neu receptor in functional analysis of the neu oncoprotein. 135 54

Previous work has shown that aggregating fetal brain cell cultures are able to attain a highly differentiated state, and that their development is greatly enhanced by growth and/or differentiation factors such as epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), and the protein kinase C-activating tumor promoter mezerein. The present study shows that in these 3-dimensional cultures the peptide growth factors EGF and bFGF as well as mezerein are able to induce the expression of the proto-oncogene c-fos. This induction was rapid and transient, in good agreement with observations reported from a wide variety of cell types in vitro. The maximal levels of c-fos mRNA found after stimulation were low in immature cultures and increased greatly as maturation progressed. Of the three factors tested, mezerein was the most potent inducer of c-fos. In contrast to the peptide growth factors EGF and bFGF which were found to induce c-fos only in glial cells, mezerein was stimulatory in glial cells as well as in neurons. A similar cell type specificity has been observed previously for the maturation-enhancing response in immature aggregate cultures. However, in the present study no correlation was found between the degree of c-fos induction and the extent of the maturation-enhancing stimulation. Immature cultures known to be most sensitive and responsive to these maturation-enhancing agents required relatively high doses of peptide growth factors for the induction of c-fos, and the maximal levels of c-fos mRNA elicited were much lower than those in differentiated cultures which did not show any long-term response to these stimuli.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Expression of the proto-oncogene c-fos in three-dimensional fetal brain cell cultures and the lack of correlation with maturation-inducing stimuli. 137 69

The c-kit ligand, KL, and its receptor, the proto-oncogene c-kit are encoded, respectively, at the steel (Sl) and white spotting (W) loci of the mouse. Both Sl and W mutations affect cellular targets in melanogenesis, gametogenesis, and hematopoiesis during development and in adult life. Although identified as a soluble protein, the predicted amino acid sequence of KL indicates that it is an integral transmembrane protein. We have investigated the relationship between the soluble and the cell associated forms of KL and the regulation of their expression. We show that the soluble form of KL is generated by efficient proteolytic cleavage from a transmembrane precursor, KL-1. An alternatively spliced version of KL-1, KL-2, in which the major proteolytic cleavage site is removed by splicing, is shown to produce a soluble biologically active form of KL as well, although with somewhat diminished efficiency. The protein kinase C inducer phorbol 12-myristate 13-acetate and the calcium ionophore A23187 were shown to induce the cleavage of both KL-1 and KL-2 at similar rates, suggesting that this process can be regulated differentially. Furthermore, proteolytic processing of both the KL-1 and KL-2 transmembrane protein products was shown to occur on the cell surface. The relative abundance of KL-1 and KL-2 is controlled in a tissue-specific manner. Sld, a viable steel allele, is shown to encode a biologically active secreted mutant KL protein. These results indicate an important function for both the soluble and the cell associate form of KL. The respective roles of the soluble and cell associated forms of KL in the proliferative and migratory functions of c-kit are discussed.
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PMID:Differential expression and processing of two cell associated forms of the kit-ligand: KL-1 and KL-2. 137 27

The microbial alkaloid staurosporine is a potent but nonselective inhibitor of protein kinases. The derivative CGP 41251 has been shown to exert a high degree of selectivity for inhibition of protein kinase C activity. Both compounds are powerful inhibitors of proliferation of both normal and transformed cells in vitro and exert antitumor efficacy in vivo. In this work we have studied the mode of action of these compounds by analyzing their effects on early events in the induction of proliferation by different growth stimuli. Both drugs blocked the phorbol ester-induced expression of the c-fos proto-oncogene. The effect of CGP 41251 was reversible, since its removal led to a normal expression of c-fos mRNA in response to phorbol 12-myristate 13-acetate. Submicromolar concentrations of CGP 41251 and staurosporine directly inhibited both the platelet-derived growth factor (PDGF) receptor autophosphorylation and the c-fos mRNA expression induced by PDGF stimulation of intact BALB/c 3T3 cells. In contrast, ligand-induced epidermal growth factor receptor autokinase activity in A431 carcinoma cells and epidermal growth factor-dependent c-fos mRNA expression were relatively insensitive to inhibition by CGP 41251. Staurosporine suppressed signal generation by the epidermal growth factor receptor by reducing overall levels of the receptor. We conclude that CGP 41251 is a potent reversible inhibitor of protein kinase C and PDGF-mediated signal transduction. It inhibits the kinase activity of both protein kinase C and the PDGF receptor tyrosine kinase and the subsequent signaling cascade. The broad inhibition of kinases by staurosporine is also reflected at the cellular level and might contribute to the high toxicity of this compound, in comparison to CGP 41251.
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PMID:Differential inhibition of the epidermal growth factor-, platelet-derived growth factor-, and protein kinase C-mediated signal transduction pathways by the staurosporine derivative CGP 41251. 139 40

We have shown previously that angiotensin-II (A-II) controls proto-oncogene (c-fos, jun-B and c-jun) mRNA accumulation in bovine adrenal fasciculata cells (BAC). Since BAC contain both subtypes (AT-1 and AT-2) of the A-II receptor, we have investigated which subtype was involved in the effect of A-II on proto-oncogene mRNA by using a selective antagonist for AT-1 (DUP 753) and for AT-2 (CGP 42112A). DUP 753, but not CGP 42112A, inhibited the stimulatory effect of A-II on proto-oncogene mRNA, with ID50s of 4 x 10(-7) M, 7 x 10(-7) M and 2 x 10(-6) M for c-fos, jun-B and c-jun, respectively. Neither of the two antagonists by themselves had a direct effect on proto-oncogene mRNA. As the A-II AT-1 receptors are coupled to the phospholipase C system in BAC, we have investigated whether the A-II effects on the proto-oncogenes were mediated by protein kinase C (PKC) or by Ca2+ calmodulin. First, activation of PKC by the phorbol ester, PMA, increased the level of three proto-oncogene mRNAs, whereas calcium ionophore had no effect. Second, staurosporine, a specific inhibitor of PKC, reduced the stimulatory action of A-II on proto-oncogene mRNA by 80-90%, whereas trifluoroperazine, an inhibitor of calmodulin, had no significant effect. These results demonstrate that the effects of A-II on proto-oncogene mRNA are mediated by AT1 receptor subtypes, mainly through activation of the PKC pathway.
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PMID:Angiotensin-II-induced expression of proto-oncogene (c-fos, jun-B and c-jun) mRNA in bovine adrenocortical fasciculata cells (BAC) is mediated by AT-1 receptors. 142 67


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