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)

While growth of blood vessels is important in hypertension, relatively little is known about the contribution of catecholamines. Using isolated rat aorta and cultured smooth muscle cells, we examined adrenergic stimulation of gene expression. Phenylephrine, a selective alpha 1 adrenergic receptor agonist, caused a rapid and transient increase in c-fos mRNA accumulation which was inhibited by prazosin, an alpha 1 receptor antagonist. Similarly, phenylephrine stimulated c-jun and c-myc mRNA accumulation. Chloroethyl-clonidine, a compound which irreversibly blocks alpha 1B receptors, completely blocked the phenylephrine-induced increase in c-fos mRNA. RNase protection experiments demonstrated that rat aorta prominently expressed mRNA for alpha 1B and alpha 1A/D receptors. Phenylephrine-induced c-fos mRNA was partially inhibited by H-7, a protein kinase C inhibitor, and by nifedipine, a Ca2+ channel blocker; these two compounds together had additive effects. In situ hybridization showed that expression of c-fos mRNA induced by phenylephrine was localized to aorta's medial layer. These results suggest that alpha 1 receptor-induced increase in c-fos mRNA in aorta is mediated by a chloroethyl-clonidine-sensitive receptor subtype signaling via increasing intracellular Ca2+ concentrations and activating protein kinase C.
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PMID:Alpha 1 adrenergic receptor-induced c-fos gene expression in rat aorta and cultured vascular smooth muscle cells. 804 Feb 63

The effects of bryostatin 1 (Bryo 1), a protein kinase C (PKC) activator, on proliferation, differentiation and macromolecular synthesis were investigated in the two cell lines EHEB and JVM-2, established from patients with chronic B-cell leukemia. Treatment with Bryo 1 inhibited the proliferation, DNA and RNA synthesis in a time- and dose-dependent fashion. The cells differentiated along the B-cell pathway to plasmacytoid cells as judged by morphological examination and increased their production and secretion of immunoglobulins. c-myc mRNA expression was induced in both cell lines. The phorbol ester TPA, a pharmacological PKC activator, had similar differentiation-inducing effects. The biomodulators failed to induce significant alterations in the cell surface marker profile. Except for their surface markers, all parameters studied were more strongly altered in JVM-2 than in EHEB cells. JVM-2 was established from a patient with B-prolymphocytic leukemia (PLL), whereas EHEB originated from a case of B-chronic lymphocytic leukemia (CLL). These data support the notion that PLL cells appear to be activated B-cells, in contrast to the rather quiescent CLL cells. Since Bryo 1 lacks tumor-promoting activity, this naturally occurring compound, extracted from marine animals, has a potential role in the therapy of B-cell neoplasms as a differentiating agent.
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PMID:Induction of differentiation of B-cell leukemia cell lines JVM-2 and EHEB by bryostatin 1. 837 21

The effects of bryostatin-1 (Bryo) and 12-O-tetradecanoyl-phorbol 13-acetate (TPA), both activators of protein kinase C (PKC), on proliferation and differentiation of two monocytic leukemia cell lines, JOSK-I and JOSK-M, were investigated. Treatment with TPA or Bryo inhibited cellular proliferation in a dose-dependent manner. Both drugs induced distinct phenotypic changes associated with monocytic differentiation. Although c-myc mRNA is often found to be down-regulated during biomodulator-triggered in vitro myelomonocytic differentiation, however, here the modulation of c-myc expression was less pronounced. All parameters studied were more prominently altered in TPA- than in Bryo-treated cells, and, were more distinct in JOSK-I than in JOSK-M. Since Bryo was able to antagonize the TPA-mediated effects on proliferation and morphological alterations, an (at least partially) different mode of action of these PKC activators on monocytic cell lines may be suggested.
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PMID:Different effects of the two protein kinase C activators bryostatin-1 and TPA on growth and differentiation of human monocytic leukemia cell lines. 841 1

The effects of pulsatile and steady fluid flow on the mRNA levels of proto-oncogenes c-fos, c-jun, and c-myc in cultured human umbilical vein endothelial cells (HUVEC) were investigated. c-fos mRNA levels in stationary cultures were very low. A 1 Hz pulsatile flow with an average shear stress of 16 dynes/cm2 induced a dramatic increase of c-fos mRNA levels in HUVEC 0.5 h after the onset of flow, which declined rapidly to basal levels within 1 h. Steady flow with a similar shear stress also induced a transient increase of c-fos mRNA levels, but to a lesser extent. In addition, increased c-fos mRNA levels were observed when low shear (2-6 dynes/cm2) was replaced by high shear (16-33 dynes/cm2). Pulsatile and steady flow caused a slight increase of c-jun and c-myc mRNA levels. The role of pulsatility was also investigated in platelet-derived growth factor (PDGF) expression. Pulsatile flow induced a transient increase of PDGF A- and B-chain mRNA levels with peaks at 1.5-2 h. Pulsatile flow, which was more stimulatory in mediating c-fos expression, however, was less stimulatory than steady flow in mediating PDGF expression. By using various inhibitors, protein kinase C was found to be an important mediator in flow-induced c-fos expression, with the involvement of G proteins, phospholipase C, and intracellular calcium. Protein kinase C was previously shown as a possible major mediator in flow-induced PDGF expression which, at least partly, appeared to follow the induction mechanism of c-fos, suggesting a possible connection between c-fos and PDGF induction. However, the c-fos antisense treatment, which significantly inhibited c-fos transcription, failed to block the flow-induced PDGF expression, suggesting that flow-induced c-fos expression may not play an important role in the mechanism of flow-induced PDGF expression. The difference in the induction of c-fos and PDGF expression under pulsatile as compared to steady flow indicates that a complex, flow-mediated regulatory mechanism of gene expression exists in HUVEC. The increased expression of these proto-oncogenes mediated by flow may be important in regulating long-term cellular responses.
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PMID:Pulsatile and steady flow induces c-fos expression in human endothelial cells. 841

Stimulation of diglyceride production via phospholipase C (PLC) hydrolysis of phosphatidylcholine was an early event in the mitogenic action of colony-stimulating factor 1 (CSF-1) in the murine macrophage cell line BAC1.2F5 and was followed by a second phase of diglyceride production that persisted throughout the G1 phase of the cell cycle. Addition of phosphatidylcholine-specific PLC (PC-PLC) from Bacillus cereus to the medium of quiescent cells raised the intracellular diglyceride concentration and stimulated [3H]thymidine incorporation, although PC-PLC did not support continuous proliferation. PC-PLC treatment did not induce tyrosine phosphorylation or turnover of the CSF-1 receptor. The major protein kinase C (PKC) isotype in BAC1.2F5 cells was PKC-delta. Diglyceride production from PC-PLC did not target PKC-delta, since unlike phorbol esters, PC-PLC treatment neither decreased the electrophoretic mobility of PKC-delta nor increased the amount of GTP bound to Ras, and PC-PLC was mitogenically active in BAC1.2F5 cells in which PKC-delta was downregulated by prolonged treatment with phorbol ester. PC-PLC mimicked CSF-1 action by elevating c-fos and junB mRNAs to 40% of the level induced by CSF-1; however, PC-PLC induced c-myc mRNA to only 5% of the level in CSF-1-stimulated cells. PC-PLC addition to CSF-1-dependent BAC1.2F5 clones that constitutively express c-myc increased [3H]thymidine incorporation to 86% of the level evoked by CSF-1 and supported slow growth in the absence of CSF-1. Therefore, PC-PLC is a component of a signal transduction pathway leading to transcription of c-fos and junB that collaborates with c-myc and is independent of PKC-delta and Ras activation.
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PMID:Phosphatidylcholine hydrolysis and c-myc expression are in collaborating mitogenic pathways activated by colony-stimulating factor 1. 844 94

We found previously that stimulation of c-fos and c-myc mRNA expression are early events in hydrogen peroxide-induced growth in rat aortic smooth muscle (RASM) cells. In the present study, we investigated the role of phospholipase A2 (PLA2) and protein kinase C (PKC) in mediating hydrogen peroxide-induced c-fos mRNA expression in RASM cells. Mepacrine and p-bromophenacylbromide, potent inhibitors of PLA2 activity, blocked hydrogen peroxide-induced c-fos mRNA expression. Arachidonic acid, a product of PLA2 activity, stimulated the expression of c-fos mRNA with a time course similar to that of hydrogen peroxide. PKC down-regulation attenuated both hydrogen peroxide and arachidonic acid-induced c-fos mRNA expression by 50%. Nordihydroguaiaretic acid (a lipoxygenase-cytochrome P450 monooxygenase inhibitor) significantly inhibited both hydrogen peroxide and arachidonic acid-induced c-fos mRNA expression, whereas indomethacin (a cyclooxygenase inhibitor) had no effect. Together, these findings indicate that 1) hydrogen peroxide-induced c-fos mRNA expression is mediated by PLA2-dependent arachidonic acid release, 2) both PKC-dependent and independent mechanisms are involved in hydrogen peroxide-induced expression of c-fos mRNA and 3) arachidonic acid metabolism via the lipoxygenase-cytochrome P450 monooxygenase pathway appears to be required for hydrogen peroxide-induced expression of c-fos mRNA.
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PMID:Hydrogen peroxide-induced c-fos expression is mediated by arachidonic acid release: role of protein kinase C. 846 9

In human breast cancer cell lines, an inverse relationship exists between the basal levels of oestrogen receptor (ER) and epidermal growth factor receptor (EGF-R) gene expression. In addition, the tumour-promoting phorbol ester 12-O-tetradecanoyl-phorbol-13-acetate (TPA) inhibits ER and stimulates EGF-R expression in MCF-7 breast cancer cells. This study aimed to define further the potential mechanisms involved in the modulation of ER and EGF-R gene expression by TPA. ER mRNA levels were reduced after 3 h and declined to 30% of control between 12 and 72 h after exposure to 10 nM TPA. This decrease in mRNA levels was preceded by an apparent fall in ER transcription rate. There was no effect on the stability of ER mRNA following pretreatment for 3-24 h with TPA, supporting the conclusion that the fall in ER mRNA levels was predominantly due to a decrease in ER transcription rate. Levels of EGF-R mRNA increased 10-fold by 12 h due predominantly to an increased transcription rate. The TPA-induced decrease in ER mRNA was unaffected by the simultaneous administration of the protein synthesis inhibitor cycloheximide, whereas the increase in EGF-R mRNA was inhibited by co-incubation with cycloheximide. These data indicate a requirement for continuing protein synthesis for the TPA effect on EGF-R but not on ER mRNA levels. Because the modulation of ER and EGF-R gene expression by TPA is likely to involve the protein kinase C (PKC) signal transduction pathway, the effects of other known activators of PKC were investigated. The non-phorboid tumour promoter mezerein modulated ER (an 80% decrease) and EGF-R (a 20-fold increase) mRNA levels in a similar manner to TPA. In contrast, neither 1,2-dioctanoyl-sn-glycerol (DiC8) nor 1-oleoyl-2-acetyl-sn-glycerol (OAG), both permeant analogues of the endogenous physiological activators of PKC, affected ER and EGF-R mRNA levels. These latter results were not due to a lack of efficacy because a single administration of DiC8 was as effective as TPA in inducing c-fos mRNA at 30 min. However DiC8 was less active in the later induction of c-myc mRNA. These data demonstrate reciprocal regulation of ER and EGF-R gene expression by TPA, involving effects on transcriptional events, which appear to be mediated by sustained activation of PKC.
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PMID:Inverse regulation of oestrogen receptor and epidermal growth factor receptor gene expression in MCF-7 breast cancer cells treated with phorbol ester. 883 62

Quiescent Swiss 3T3 fibroblasts can be stimulated to reenter the cell cycle following stimulation with growth factors. Among these, bombesin is a potent mitogen for Swiss 3T3 cells and can act synergistically with insulin to stimulate DNA synthesis through protein kinase C-independent pathways. One of the earliest nuclear responses of quiescent cells treated with a combination of bombesin and insulin is a dramatic increase in c-Myc expression, and it has been suggested that this proto-oncogene plays a central role in the mitogenic response. In the present study, we have taken two approaches to study the relationship between c-Myc expression and the reinitiation of DNA synthesis. First, low concentrations of bombesin, in the presence of insulin, stimulated DNA synthesis in Swiss 3T3 fibroblasts in the absence of a large increase in c-myc mRNA or protein levels. Second, selective down-regulation of phorbol ester-inducible protein kinase C in Swiss 3T3 cells resulted in a 90% decrease in the induction of c-myc mRNA and an 80% reduction in Myc protein expression but did not affect the mitogenic response to bombesin and insulin. These observations were confirmed in detailed dose-response and time-course experiments. We conclude that the large induction of c-Myc is not an essential event for the entry of Swiss 3T3 fibroblasts into S phase. Quantitation of Myc protein levels using a sensitive ELISA indicated that quiescent cells could enter S phase with only 450 c-Myc molecules per cell. These results indicate that cells in the G0 phase of the cell cycle can be stimulated to reinitiate DNA synthesis with only marginal increases in Myc protein expression.
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PMID:Large induction of c-Myc is not essential for the mitogenic response of Swiss 3T3 fibroblasts. 904 Sep 40

Anti-HLA class I monoclonal antibody 01.65 inhibits the proliferative response of PHA-activated human T lymphocytes from peripheral blood mononuclear cells. The recruitment rate in the cell cycle is slack and the G1 and S phases are prolonged. Among the early events after PHA activation, only the calcium-dependent PKC activity appears to be modified: particulate PKC is completely depleted while cytosolic residual PKC is reduced by 80% after MAb 01.65 treatment. We have carried out in greater detail the study of c-myc gene regulation by MAb 01.65 and the results are as follows: (i) c-myc RNA transcription is normally initiated and finished, suggesting a post-transcriptional regulation of c-myc gene expression; (ii) no alteration in c-myc mRNA stability has been documented; (iii) steady-state levels of c-myc mRNA expression by Northern blot analysis and PCR amplification are decreased in the cytoplasmic compartment, while in the nuclear compartment they appear to be increased. Nuclear accumulation of mature mRNA after MAb 01.65 and PKC inhibitor (H7 and StSp) treatment appears to be the most probable mechanism involved. The possible implications of this are discussed.
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PMID:Nuclear accumulation of c-myc mRNA in phytohaemagglutinin-activated T lymphocytes treated with anti-HLA class I monoclonal antibody. 946 38

The protein kinase C (PKC) activator 12-O-tetradecanoyl-phorbol-13-acetate (TPA) activated cell death in androgen-sensitive LNCaP cells but not in androgen-independent DU-145 or PC-3 cells, whose growth was significantly decreased by PKC inhibitors staurosporine and H7. All cell lines had similar levels of total PKC activities which, however, differed on their dependency on Ca2+ ions and lipid and were regulated differently by TPA. Furthermore, expression of the immediate early genes c-fos and c-jun was up-regulated by TPA only in LNCaP and DU-145 cells, whereas PC-3 cells failed to express c-fos mRNA. The regulation of the c-myc mRNA by TPA correlated inversely with activation of cell death being down-regulated in LNCaP cells, and slightly increased in the androgen-independent cell lines. These results suggest that the PKC signal transduction pathway functions differently in androgen-sensitive and insensitive prostatic cells.
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PMID:The protein kinase C activator, phorbol ester, elicits disparate functional responses in androgen-sensitive and androgen-independent human prostatic cancer cells. 951 5


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