Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Polypeptide growth factors that stimulate cell proliferation bind to cell surface receptors and activate intracellular signal transduction pathways. One major signalling pathway, initiated by phosphatidylinositol (PI) turnover, involves activation of protein kinase C. Some polypeptide growth factors, including mitogens that activate protein kinase C, induce a rapid increase in expression of the proto-oncogenes, c-myc and c-fos. In order to characterize the signal transduction pathways responsible for proto-oncogene activation, we treated Swiss 3T3 cells with the tumor promoter phorbol dibutyrate to generate cells deficient in protein kinase C. These cells were then stimulated with platelet extract, bombesin, or epidermal growth factor (EGF) and the levels of c-myc and c-fos mRNA were determined. Platelet extract or bombesin, which stimulate PI turnover, were substantially weaker inducers of c-myc and c-fos mRNA levels in the protein kinase C-depleted cells, although some variability with platelet extract was noted. EGF, which does not stimulate PI turnover in several cell systems, was by contrast a potent inducer of both proto-oncogenes whether or not the cells were deficient in protein kinase C. Pretreatment of cells with phorbol dibutyrate caused little or no change in the basal levels of c-myc or c-fos mRNA, but led to a small but significant increase in basal levels of ornithine decarboxylase mRNA. These results demonstrate that EGF and growth factors that activate PI turnover induce expression of the c-myc and c-fos proto-oncogenes through different pathways.
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PMID:Two independent growth factor-generated signals regulate c-fos and c-myc mRNA levels in Swiss 3T3 cells. 349 94

We have studied the effect of the potent mitogen bombesin on the expression of c-fos and c-myc genes in quiescent mouse fibroblasts. We have demonstrated that bombesin rapidly induces a transient expression of c-fos mRNA followed by a more protracted elevation in c-myc mRNA levels. The intensity of the induction of expression of both proto-oncogenes depended on the dose of bombesin used. Prolonged treatment of the cells with TPA, which causes a selective decrease in protein kinase C activity, partially inhibited the induction of c-fos and c-myc gene expression by bombesin, similar to what has been observed with PDGF. However, a dramatic inhibition of the mitogenic response to bombesin--but not to PDGF--was found in TPA-treated cells. In contrast, TPA-treated cells showed an increased response to EGF with regard to proto-oncogene expression. The role of protein kinase C and Ca2+-dependent pathways in proto-oncogene induction by bombesin is discussed.
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PMID:Bombesin induces c-fos and c-myc expression in quiescent Swiss 3T3 cells. Comparative study with other mitogens. 349 22

We compared the abilities of the muscarinic agonist carbachol, epidermal growth factor (EGF), and phorbol 12-myristate 13-acetate (PMA) to induce proto-oncogene mRNA accumulation and other cellular responses in normal and protein kinase C-deficient 1321-N1 human astrocytoma cells. PMA, carbachol, and EGF all stimulated rapid accumulation of mRNA for the proto-oncogenes c-fos and c-myc in the normal cells; in the protein kinase C-deficient cells, carbachol and EGF, but not PMA, retained this effect, which was not mimicked by the calcium ionophore A23187. Both carbachol and PMA activated protein kinase C in these cells, as evidenced by the stimulated phosphorylation of an acidic Mr 80,000 protein kinase C substrate protein with phosphoamino acid and peptide map identity. This response was mimicked by several other neurotransmitters in these cells, including epinephrine, histamine, oxotremorine, and serotonin, and was abolished in cells made protein kinase C-deficient by preincubation with high concentrations of PMA. Both PMA and carbachol promoted the phosphorylation of the ribosomal protein S6 and activated an S6 protein kinase in the normal but not in the protein kinase C-deficient cells. EGF, in contrast, did not appear to activate protein kinase C, but promoted the phosphorylation of S6 and activation of the S6 kinase in both normal and protein kinase C-deficient cells. We conclude that, in 1321-N1 cells, induction of c-fos and c-myc mRNA can occur through a protein kinase C-dependent pathway and one or more independent pathways, exemplified by the responses to carbachol and EGF in the protein kinase C-deficient cells.
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PMID:Protein kinase C-dependent and -independent pathways of proto-oncogene induction in human astrocytoma cells. 349 33

We have examined the role of protein kinase C in the anti-proliferative effects of interferon in Swiss 3T3 cells. Treatment of these cells with interferon did not stimulate the phosphorylation of an acidic Mr 80,000 cellular protein which serves as a substrate for protein kinase C. In addition, interferon did not inhibit the binding of 125I-epidermal growth factor to specific receptors or induce the expression of the proto-oncogene, c-fos in Swiss 3T3 cells. Thus, interferon does not activate protein kinase C. Moreover, interferon can still inhibit DNA synthesis in protein kinase C down-regulated 3T3 cells, indicating that the presence of this phosphotransferase is not essential for the anti-proliferative effects of interferon.
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PMID:Interferon inhibition of DNA synthesis in Swiss 3T3 cells: dissociation from protein kinase C activation. 349 78

Treatment of five human myeloid leukemic cell lines (KG1, ML3, HL-60, U-937, and HEL) with TPA was followed by macrophage differentiation and was accompanied by an early and transient increase in the mRNA level of c-fos proto-oncogene. The induction of c-fos was also observed in human cell lines K562 and K-Gla that did not respond to TPA with terminal macrophage differentiation. The treatment of HL-60 and U-937 cell lines with 1-oleoyl-2-acetylglycerol, a synthetic analog of diacylglycerol that, like TPA, stimulates protein kinase C activity, was followed by early and transient induction of c-fos mRNA in the absence of terminal macrophage differentiation. Finally, treatment of HL-60 with TPA in the presence of retinal, an inhibitor of protein kinase C, drastically reduced the induction of c-fos mRNA but had no effect on the terminal macrophage differentiation that is induced in this cell line by TPA. These results indicate that the induction of c-fos and terminal macrophage differentiation in response to TPA treatment can be dissociated in the in vitro models provided by human myeloid leukemic cell lines. Moreover, these findings suggest that the induction of c-fos is not only insufficient but may also be unnecessary for the differentiation along the monocyte-macrophage pathway.
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PMID:Dissociation of c-fos induction from macrophage differentiation in human myeloid leukemic cell lines. 354 82

We studied the inhibitory effects of heparin, thrombin inhibitor, and protein kinase C (PKC) inhibitor on basal and thrombin-induced preproendothelin-1 (prepro-ET-1) and proto-oncogene c-fos mRNA expression in cultured bovine endothelial cells (ECs). Northern blot analysis using cDNA for bovine prepro-ET-1 as a probe showed that heparin lowered not only the basal but also the stimulated expression of prepro-ET-1 mRNA by thrombin. A selective thrombin inhibitor (argatroban) and a PKC inhibitor (staurosporine) also inhibited thrombin-induced but not basal prepro-ET-1 mRNA expression. Heparin similarly inhibited thrombin-induced c-fos proto-oncogene mRNA expression in ECs. These data suggest that heparin, in addition to its antithrombin effect, has an inhibitory effect on prepro-ET-1 mRNA expression, possibly via a PKC-dependent pathway.
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PMID:Heparin inhibits endothelin-1 and proto-oncogene c-fos gene expression in cultured bovine endothelial cells. 750 97

The mast cell growth factor (MGF) affects migration, proliferation and differentiation of erythroid and myeloid progenitor cells by binding to a transmembrane receptor tyrosine kinase encoded by the c-Kit proto-oncogene. By using MGF-dependent human myeloid cell lines (M-07e and TF-1), here we show that a Kit-related 100 kDa protein is associated with the cell but it undergoes release into the medium upon treatment with the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA), an activator of protein kinase C. Immunological analysis with a series of antibodies to Kit indicated that the released protein (p100Kit) contains the whole glycosylated extracellular portion of the transmembrane Kit protein (p145Kit). The secreted protein retained the ability to specifically bind MGF. Moreover, p100Kit was able to block the mitogenic effect of MGF on cultured M-07e cells, suggesting that the soluble protein may function as a physiological antagonist of MGF.
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PMID:Protein kinase C-dependent release of a functional whole extracellular domain of the mast cell growth factor (MGF) receptor by MGF-dependent human myeloid cells. 751 83

Prostanoids induce expression of several immediate-early genes, but the molecular mechanisms underlying these responses remain poorly characterized. We studied induction of the proto-oncogene c-fos by PGE2 in mesangial cells as a model of gene regulation by prostanoids. PGE2 induced marked and transient accumulation of c-fos mRNA. Addition of exogenous 8-bromo-cAMP or forskolin failed to induce c-fos mRNA, suggesting that activation of an EP2 receptor linked to adenylate cyclase did not account for induction of c-fos by PGE2. These data contrast with previous experiments in NIH 3T3 cells in which PGE2 induced c-fos by a cAMP-dependent mechanism. Depletion of protein kinase C blocked induction of c-fos mRNA by PGE2, whereas a protein tyrosine kinase inhibitor had no effect. We further showed that PGE2 induces the c-fos gene by increasing the transactivating capacity of the serum-response element. Transient transfections with a CAT fusion gene driven by an AP-1 cis-element demonstrated that although PGE2 markedly induced c-fos, PGE2 did not increase AP-1-driven transcriptional responses. Electrophoretic gel mobility shift assays revealed that PGE2 failed to increase binding of AP-1 complexes to a consensus AP-1 DNA sequence. Taken together, these experiments provide evidence for a cAMP-independent, protein kinase C-dependent pathway linking a PGE2 receptor on the plasma membrane to transcriptional activation in the nucleus. Regulation of gene transcription by PGE2 probably involves c-fos induction without concomitant activation of AP-1.
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PMID:PGE2 induces c-fos expression by a cAMP-independent mechanism in glomerular mesangial cells. 752 23

In isolated rat hepatocytes angiotensin II and phorbol 12-myristate 13-acetate (PMA) induce the expression of c-fos. We studied the possible transduction pathway(s) involved in this effect using inhibitors of serine-threonine and tyrosine protein kinases. Calphostin and staurosporine, inhibitors of protein kinase C and other serine-threonine protein kinases, block in a dose-dependent manner the effect of angiotensin II and PMA. Interestingly, genistein also blocks the induction of this proto-oncogene, suggesting a role for tyrosine protein kinases. Inhibitors of serine-threonine protein phosphatases, such as okadaic acid, microcystin LR and calyculin also induce c-fos expression. These data suggest that protein phosphatases exert a tonic inhibitory control of c-fos expression. The effect of these phosphatase inhibitors were not blocked by staurosporine, calphostin or genistein. Our results suggest that the expression of c-fos in rat hepatocytes is regulated by complex phosphorylation-dephosphorylation cascade(s) probably involving serine/threonine and tyrosine protein kinase and protein phosphatase activities.
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PMID:Protein kinases and phosphatases modulate c-fos expression in rat hepatocytes. Effects of angiotensin II and phorbol myristate acetate. 753 72

Increased generation of active oxygen species such as H2O2 and O2- may be important in vascular smooth muscle cell growth associated with atherosclerosis and restenosis. In previous work, we showed that H2O2 stimulated vascular smooth muscle cell growth and proto-oncogene expression. In the present study, we compared the effects of H2O2 and O2- on cultured rat aortic vascular smooth muscle cell growth and signal transduction. O2- was generated in a concentration-dependent manner by the naphthoquinolinedione LY83583. Vascular smooth muscle cell growth, as measured by [3H]thymidine incorporation, was stimulated by 200 mumol/L H2O2 (110% increase versus 0.1% serum) and 1 mumol/L LY83583 (175% increase) to levels comparable to 10 ng/mL platelet-derived growth factor (210% increase). Since activation of mitogen-activated protein kinase (MAP kinase) is one of the earliest growth factor signal events, the activity of MAP kinase was measured by changes in mobility on Western blot and by phosphorylation of myelin basic protein. There was a concentration-dependent increase in MAP kinase activity by LY83583 (maximum, 10 mumol/L) but not by H2O2. The time course for activation of MAP kinase by LY83583 showed a maximum at 5 to 10 minutes with return to baseline by 20 minutes. Activation of MAP kinase by LY83583 was protein kinase C dependent. Expression of MAP kinase phosphatase-1 (MKP-1), a transcriptionally regulated redox-sensitive protein tyrosine/threonine phosphatase, was also measured. Although H2O2 induced MKP-1 mRNA to a greater extent than did LY83583, the increased MKP-1 expression could not explain the inability of H2O2 to stimulate MAP kinase, because mRNA levels were not detected until 60 minutes.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Differential activation of mitogen-activated protein kinases by H2O2 and O2- in vascular smooth muscle cells. 754 May 16


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