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)

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

To study the signal transduction pathway leading to phorbol 12-myristate 13-acetate (PMA)-induced differentiation in human promyelocytic HL-60 leukemia cells, we examined the expression of protein kinase C (PKC) isozyme genes in HL-60 cells that are susceptible or resistant to PMA-induced differentiation. The PKC-alpha, -beta, -gamma, -delta, epsilon, and -zeta transcript levels were assessed by Northern blotting, and the PKC-alpha, -beta, and -gamma protein levels were examined by immunoblotting. The PMA-resistant cell variants HL-525 and HL-534 were found to be deficient in the PKC-beta isozyme RNA and protein as compared with the PMA-susceptible HL-60 and HL-205 cell lines. In addition, a "delta-like" PKC RNA species identified in these cells demonstrated a reduced abundance in the HL-525 and HL-534 cells. Southern blot analysis indicated that the observed reduction in PKC-beta gene expression does not appear to be due to a gross deletion or rearrangement of the gene. The expression of the early response genes junB, c-fos, and c-jun was attenuated in PMA-treated HL-525 and HL-534 cells as compared to the PMA-treated HL-60 and HL-205 cells. These results suggest that the signal transduction pathway that leads to PMA-induced differentiation in the HL-60 cell system requires PKC-beta and/or delta-like PKC for the proper expression of the early response genes, and ultimately the expression of genes that define the mature state.
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PMID:Protein kinase C beta gene expression is associated with susceptibility of human promyelocytic leukemia cells to phorbol ester-induced differentiation. 144 3

C-terminal truncation of the middle surface antigen from hepatitis B virus (MHBs) gives rise to a novel transactivating protein, called MHBst. In this study we show that MHBst like the HBx protein of HBV, can cause nuclear appearance of NF-kappa B DNA binding activity and induce various kappa B-controlled reporter genes. While an inhibitor of protein kinase C could not block gene induction by MHBst, the antioxidants N-acetyl-L-cysteine (NAC) and pyrrolidine dithiocarbamate (PDTC) could potently suppress transactivation at mM and microM concentrations, respectively. Also, kappa B-dependent gene induction by the transactivator HBx was blocked. The effects were selective because PDTC did not interfere with MHBst and HBx-induced activation of the c-fos promoter/enhancer, nor with the basal activity of several other reporter genes lacking functional NF-kappa B binding motifs. Our data suggest that induction of a prooxidant state is crucial for the activation of NF-kappa B by MHBst and HBx and might be related to the hepatocarcinogenic potential of the viral proteins. MHBst had a subcellular localization unusual for a viral transactivator: it appeared to be an integral membrane protein of the endoplasmic reticulum.
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PMID:Hepatitis B virus transactivator MHBst: activation of NF-kappa B, selective inhibition by antioxidants and integral membrane localization. 163 69

The transcription factor AP-1 is phorbol ester-regulated and, as such, is considered to be a nuclear target of the signal transduction pathway involving protein kinase C. AP-1 is constituted by the various products of the jun and fos gene family members. These genes belong to the early response class and are inducible in different ways by growth factors, phorbol esters and depolarization. We studied the transcript distribution of c-jun, junB and junD in the rat brain. Our results show that the transcripts for these three genes are differentially distributed in various neuronal tissues. We also provide evidence for developmentally regulated expression of jun genes in post-natal brain. The spatiotemporal pattern of expression of c-jun, junB and junD offers clues to the understanding of the links between gene regulation and neuronal processes.
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PMID:Differential expression of the jun family members in rat brain. 171 62

Transforming growth factor-beta 1 (TGF-beta 1) rapidly increases the expression of junB transcription factor and plasminogen activator inhibitor-1 (PAI-1) and prevents the cell cycle-dependent phosphorylation of the RB retinoblastoma susceptibility gene product during late G1 phase in Mv1Lu lung epithelial cells. These responses are shown in this report to be blocked by the potent serine/threonine protein kinase inhibitor, H7, added with TGF-beta 1. Added alone, H7 does not alter the basal junB or PAI-1 mRNA levels, the deposition of PAI-1 into the extracellular matrix, or the phosphorylation of RB in late G1 phase, suggesting that this inhibitor does not have a general nonspecific effect on the cell. The analogs H8 and H9, which are preferential inhibitors of cyclic nucleotide-dependent protein kinases, are fivefold less potent than H7 as inhibitors of the TGF-beta response. The PAI-1 response to TGF-beta 1 is not affected by the simultaneous addition of staurosporine, which is a protein kinase C inhibitor, or by the prolonged preincubation of cells with phorbol 12-myristate 13-acetate, which down-regulates protein kinase C. The results suggest the possibility that H7 and its analogs block various early TGF-beta responses by inhibiting a protein serine/threonine kinase(s).
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PMID:Evidence for the involvement of protein kinase activity in transforming growth factor-beta signal transduction. 172 3

Short-term stimulation (up to 16 hours) of interleukin-3 (IL-3)-dependent mouse bone marrow-derived mast cells, Abelson transformed mouse liver-derived mast cells, or rat basophilic leukemia cells by either IgE-Ag or calcium ionophore A23187 resulted in inhibition of their proliferation as measured by 3H-thymidine incorporation and MTT (tetrazolium) assays, and in accumulation of the mRNAs of c-fos, c-jun, junB and slightly of junD proto-oncogenes. The involvement of protein kinase C (PKC) in these responses was investigated by using several approaches of enzyme activity regulation. Direct activation of the PKC was achieved by short-term exposure of the cells to the PKC-specific activator phorbol 12-myristate-13-acetate (PMA). Inhibition of PKC activity was obtained by either prolonged treatment of the cells with PMA or by exposure of the cells to the PKC inhibitors H-7 and staurosporine. The results showed the following: (1) Short-term exposure of mast cells to PMA was sufficient to induce inhibition of proliferation. (2) An increase in PKC activity was associated with a decrease in the proliferation of IgE-dinitrophenol (DNP) or calcium ionophore A23187-stimulated cells. (3) A direct correlation was found between the increase in PKC activity and the increase in the level of the mRNAs of the jun proto-oncogenes in cells activated by both stimuli mentioned. (4) While an increase in PKC activity was associated with the upregulation of the level of c-fos mRNA during calcium ionophore A23187 stimulation, it showed the opposite effect on the expression of the mRNA of this proto-oncogene when the cells were triggered by IgE-DNP. Therefore, we concluded that PKC plays various roles in the expression of the mRNA of c-fos in activated mast cells depending on the stimulus involved. In addition, the expression of the mRNA of c-jun and junB proto-onogenes is not coordinately regulated with that of c-fos during immunologic stimulation. This discordancy, which is associated with the increase in PKC activity in mast cells, may play a role in the regulation of the transcription of AP-1-responsive genes, and therefore could be associated with the regulation of proliferation of these cells.
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PMID:Protein kinase C regulates proliferation of mast cells and the expression of the mRNAs of fos and jun proto-oncogenes during activation by IgE-Ag or calcium ionophore A23187. 193 49

Genes of higher eucaryotic cells are considered to show only a limited response to nutritional stress. Here we show, however, that omission of a single essential amino acid from the medium caused a marked rise in the mRNA levels of c-myc, c-jun, junB and c-fos oncogenes and ornithine decarboxylase (ODC) in CHO cells. There was no general accumulation of mRNAs in amino acid-starved cells, since the gamma-actin, beta-tubulin, protein kinase C, RNA polymerase II, and glyceraldehyde-3-phosphate dehydrogenase mRNAs and the total poly(A)+ mRNA were not increased. The levels of c-myc, ODC, and c-jun mRNAs were elevated more by amino acid starvation than by inhibition of protein synthesis with cycloheximide, which is known to increase the levels of these mRNAs. Importantly, however, cycloheximide present during amino acid starvation reduced the rise in the levels of the mRNAs down to the level obtained with cycloheximide alone. This implies that protein synthesis is required for the accumulation of c-myc, ODC, and c-jun mRNAs in amino acid-deprived cells. The junB and c-fos mRNAs, instead, were increased to the same extent or less by amino acid starvation than by cycloheximide treatment. The accumulation of the c-myc mRNA in amino acid-starved cells was due to both stabilization of the mRNA and increase of its transcription. The rise in the c-jun mRNA level seemed to be caused merely by stabilization of the mRNA. Further, despite the inhibition of general protein synthesis, amino acid starvation led to an increase in the synthesis of c-myc polypeptide. The results suggest that mammalian cells have a specific mechanism for registering shortages of amino acids in order to make adjustments compatible with cellular growth.
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PMID:Deprivation of a single amino acid induces protein synthesis-dependent increases in c-jun, c-myc, and ornithine decarboxylase mRNAs in Chinese hamster ovary cells. 212 33

Immediate-early genes, whose expression increases independent of de novo protein synthesis during the transition from quiescence to proliferation, are postulated to play important regulatory roles in the growth response. The complement of immediate-early genes expressed must depend on the milieu of preexisting transcription factors in the quiescent cell as well as the type of mitogenic stimulation and, thus, may differ between cell types. We have begun characterizing the immediate-early response in regenerating liver and insulin-stimulated Reuber H-35 hepatoma cells in comparison with previously published results from mitogen-stimulated Balb/c 3T3 fibroblasts. The proliferating H-35 and regenerating liver cells maintain their similarity to quiescent liver as demonstrated by their continued production of the liver-specific albumin, CCAAT/enhancer binding protein, and phosphoenolpyruvate carboxykinase messenger RNAs (mRNA). Surprisingly, the phosphoenolpyruvate carboxykinase gene, which undergoes down-regulation in insulin-treated H-35 cells, was cloned by differential screening of a subtraction-enriched regenerating liver cDNA library and is an immediate-early gene in regenerating liver. H-35 cells treated with either insulin or phorbol 12-myristate 13-acetate express elevated levels of the jun genes, and phorbol 12-myristate 13-acetate pretreatment fails to abolish the insulin response, indicating that it does not depend on protein kinase C. jun family gene expression in regenerating liver differs from that in mitogen-treated fibroblasts in that the time course of expression of c-jun and junB is prolonged, and junD mRNA levels distinctly increase. Additionally, although c-fos and egr-1 mRNAs are expressed at elevated levels in stimulated liver cells, fos-B, fra-1, and egr-2 are not, which suggests that factors in addition to the serum response factor participate in the regulation of immediate-early gene induction. Interestingly, gene 33, which was cloned from a regenerating liver cDNA library by differential screening and lacks a recognizable serum response element, functions as an immediate-early gene in regenerating liver and in mitogen-treated H-35 and Balb/c 3T3 cells. These results suggest that gene 33 participates in the transition from quiescence to proliferation in many mitogen-treated cells in addition to its previously reported involvement in hormone responses. Overall, the results presented here suggest that the immediate-early response varies considerably between regenerating liver and mitogen-stimulated fibroblasts and could involve multiple, preexisting, tissue-specific, transcription-activating proteins.
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PMID:Immediate-early gene expression differs between regenerating liver, insulin-stimulated H-35 cells, and mitogen-stimulated Balb/c 3T3 cells. Liver-specific induction patterns of gene 33, phosphoenolpyruvate carboxykinase, and the jun, fos, and egr families. 212 77

EGF was used to stimulate a chimeric receptor consisting of the epidermal growth factor receptor (EGFR) extracellular, transmembrane, and protein kinase C-substrate domains linked to the intracellular tyrosine kinase and carboxyl terminal domains of the rat neu protein in NIH/3T3 cells. EGF-induced rapid and delayed morphological changes consisted of membrane ruffling, increased pinocytosis, extension of lamellar actin-containing footpads at the cell periphery and partial reorganization of the actin stress fibers in the cells. EGF bound to the cells was rapidly internalized in a complex with the EGFR/neu protein, as shown by loss of EGF binding and EGFR antigens from the cell surface. The movement of the EGFR/neu protein was followed with indirect immunofluorescence into a vesicular intracellular compartment using antibodies against both EGFR and neu protein domains. Metabolic labeling and pulse-chase experiments indicated that the receptor was degraded soon after its internalization. EGF treatment also induced the junB transcription factor mRNA and a dose-dependent stimulation of DNA synthesis in cultures expressing the chimeric receptor. The tumor promoter TPA led to a transient loss of cell surface receptors and prevented EGF stimulation of DNA synthesis but did not completely abolish junB mRNA induction or increase degradation of the chimeric receptor. These results show that the chimeric EGFR/neu receptor undergoes typical downregulation upon ligand binding and TPA pretreatment and is capable of transducing an EGF-induced mitogenic signal.
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PMID:Receptor downregulation and DNA synthesis are modulated by EGF and TPA in cells expressing an EGFR/neu chimera. 269 32

Induction of cytochrome P4501A1 by 2,3,7,8-tetra-chlorodibenzo-p-dioxin (TCDD) is mediated by the Ah receptor (AhR) complex, a ligand-dependent DNA-binding transactivator. Recently a role for protein kinase C (PKC) in the induction response has been reported in which PKC or a related kinase positively modulates AhR activity. We have examined the role of PKC by determining the effect of two nonspecific PKC inhibitors, H7 and staurosporine, and one specific PKC inhibitor, calphostin c, on AhR functionality. Although no kinase activity was detectable in cytosol, under the conditions used for our assays, AhR transformation and DNA binding still occurred. Addition of relatively high concentrations of the kinase inhibitors also had no significant effect on TCDD:AhR:DRE complex formation. Thus, our results indicate that protein kinase activity does not appear to be necessary for TCDD-dependent AhR transformation and DNA binding and they imply that protein kinases must play a role in another step(s) in the AhR-dependent mechanism of P4501A1 induction.
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PMID:Protein kinase C is not involved in Ah receptor transformation and DNA binding. 750 16


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