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)

Previous studies showed that the human monocytic leukemia cell line THP-1 can be induced to undergo monocytic differentiation by tumor promoting phorbol esters (TPA), suggesting that protein kinase C (PK-C), the primary binding site of TPA, may play a role in the control of monocytic differentiation: The effect of exogenous phospholipase C (PLC) on THP-1 cells was investigated. Within 24-48 hr, PLC induced over 40% of THP-1 cells to undergo monocytic differentiation as manifested by adherence, growth arrest, functional expression, morphological changes and expression of c-fms gene which encode for M-CSF receptors. Compared to TPA, however, the inducing activity of PLC was weaker, slower and not as effective. PLC treatment also induced a transient expression of c-fos proto-oncogene prior to c-fms expression. On the contrary, the level of c-myc RNA, which is constitutively expressed in THP-1 cells, was down-regulated 48 hr after PLC treatment. The PLC-induced monocytic differentiation in THP-1 cells was inhibited by staurosporine, a potent PK-C inhibitor, further suggesting that direct activation of the PK-C is one of the metabolic events essential for monocytic differentiation. It is postulated that in THP-1 cells the metabolic pathway transducing PK-C activation has been permanently blocked, thereby leading to uncontrolled proliferation without differentiation.
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PMID:Phospholipase C-induced monocytic differentiation in a human monocytic leukemia cell line THP-1. 149 32

Glucocorticoids stimulate the prostaglandin E2 production of confluent amnion cell cultures, but have no stimulatory effect on the PGE2 output of freshly isolated human amnion cells. Since protein phosphorylation may modify the responsiveness of target cells to steroids, and activators of protein kinase C (PKC), as well as corticosteroids, promote amnion cell PGE2 output by stimulating the synthesis of prostaglandin endoperoxide H synthase (PGHS), we investigated the possibility that PKC is involved in the glucocorticoid-induction of PGE2 synthesis in cultured amnion cells. The dexamethasone-induced PGE2 output of arachidonate-stimulated cells was blocked by the protein kinase inhibitors staurosporine, K-252a, H7, HA1004, and sphinganine, in a manner consistent with their effect on PKC. However, dexamethasone increased the PGE2 production of cultures treated with maximally effective concentrations of the PKC-activator compound TPA. Moreover, dexamethasone stimulated PGE2 synthesis in cultures which were desensitized to TPA-stimulation by prolonged phorbol ester treatment. Concentration-dependence studies showed that staurosporine completely (greater than 95%) blocked glucocorticoid-provoked PGE2 synthesis at concentrations which did not inhibit TPA-stimulated prostaglandin output, and that K-252a inhibited the effect of TPA by more than 95% at concentrations which decreased the effect of dexamethasone only moderately (approximately 40%). Dibutyryl cyclic AMP had no influence on the basal- or dexamethasone-stimulated PGE2 production, and on the staurosporine inhibition of the steroid effect. These results show that glucocorticoids and phorbol esters control amnion PGE2 production by separate regulatory mechanisms. It is suggested that the response of human amnion cells to glucocorticoids is modulated by protein kinase(s) other than phorbol ester-sensitive PKC and cyclic AMP-dependent protein kinase.
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PMID:Glucocorticoid stimulation of amnion cell prostaglandin synthesis: suppression by protein kinase C inhibitors and independence of phorbol ester-sensitive protein kinase C. 150 1

Thymocyte death is a complex phenomenon under the control of different signals and stimuli. We evaluated the effect of elevated temperature (heat shock, HS) on mouse thymocyte apoptosis. Incubation of thymocytes at 43 degrees C for 20 min induced DNA fragmentation and cell death, but it was also able to decrease the apoptosis induced by dexamethasone (DEX), TPA or Ca2+ ionophore. The anti-apoptotic effect was correlated with induction of heat shock proteins (HSPs) and abolished by protein synthesis inhibition. On the other hand, HS-induced unlike DEX-induced apoptosis was not inhibited by protein synthesis and mRNA transcription inhibitors, the PKC inhibitors H-7 and staurosporine, or interleukin-4 (IL-4), but only by Zn2+. These results suggest that HS interferes in thymocyte death by either inducing or inhibiting thymocyte apoptosis and that the induction process mechanisms are different from those of GCH.
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PMID:Heat shock induces apoptosis in mouse thymocytes and protects them from glucocorticoid-induced cell death. 151 81

Human immunodeficiency virus type 1 (HIV-1) spends a significant part of its life cycle as latent provirus in nonactivated cells. It induction requires mitogen stimulation. TPA treatment induces HIV-1 transcription by protein kinase C (PKC)-mediated activation of the cellular transcription factor NF-kB. PKC activation induces the dissociation of NF-kB from its inhibitor protein (IkB). The liberated NF-kB then binds to its proviral recognition sequence in the HIV-1 long terminal repeat (LTR) sequence. This step, however, is not sufficient to augment transcription. We demonstrate that NF-kB-mediated HIV-1 LTR activation is regulated by an additional event that is not dependent on IkB. A further phosphorylation event is proposed, since this step could be blocked by an inhibitor of a phospholipase C (PLC) type reaction. This inhibitor precludes the formation of diacylglycerols, which are required for activation of PKC isoenzymes. As an alternative pathway that is not dependent on PLC reactions, high-level transcription from the HIV-1 LTR is shown to require binding of both NF-kB and TAT.
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PMID:Binding of NF-kB to the HIV-1 LTR is not sufficient to induce HIV-1 LTR activity. 154 Apr 10

The calcium ionophore, A23187, can induce rat hepatic metallothionein (MT) when administered in vivo (5.8-fold, 5.0 microM, 11 h) and rat hepatocyte MT when administered in vitro (10.70-fold, 1.0 microM, 24 h). Several rat hepatoma cell lines (2M, 4.55-fold; JM2, 12.29-fold; EC3, 14.12-fold; HTC, 7.99-fold) and a normal rat liver cell line (Clone 9, 39.67-fold) were tested for their inducibility of MT mRNA by Cd2+ (10 microM, 8 h). Quantitatively, JM2 and 2M made the most MT mRNA, while HTC made the least. A23187 (0.1-7.0 microM) was studied as an inducer of MT mRNA in these cell lines (except for HTC) and in HeLa. A variety of responses and tolerances were seen with inductions ranging up to 32.11-fold. Quantitatively, the best responding cell lines were EC3 and 2M. A combination induction experiment, using TPA, a protein kinase C activator, and A23187 in EC3 cells revealed an additive effect of the two inducers on MT mRNA levels: TPA (10 nM), 11.71-fold; A23187 (3.0 microM), 6.71-fold; and TPA + A23187, 20.00-fold. These studies have implicated perturbations in cytosolic calcium ion concentrations, caused by the ionophore A23187, as being involved in the complicated signaling systems which can lead to induction of MT mRNA and protein.
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PMID:Induction of zinc metallothionein by calcium ionophore in vivo and in vitro. 154 93

Proteins of the ras family of oncogenes have been implicated in signal transduction pathways initiated by protein kinase C (PKC) and by tyrosine kinase oncogenes and receptors, but the role that ras plays in these diverse signalling systems is poorly defined. The activity of ras proteins has been shown to be controlled in part by a cellular protein, GAP (GTPase-activating protein), that negatively regulates p21c-ras by enhancing its intrinsic GTPase activity. Thus, overexpression of GAP provides a tool for determining the step(s) in signal transduction dependent on p21c-ras activity. In this paper, we report that overexpression of GAP blocks the phorbol ester (tetradecanoyl phorbol acetate [TPA])-induced activation of p42 mitogen-activated protein kinase (p42mapk), c-fos expression, and DNA synthesis. GAP overexpression did not block responses to serum or fluoroaluminate. Moreover, not all biochemical events elicited by TPA were affected by GAP overexpression, as increased glucose uptake and phosphorylation of MARCKS, a major PKC substrate, occurred normally. Reduction of GAP expression to near normal levels restored the ability of the cells to activate p42mapk in response to TPA. These findings suggest that ras and GAP together play a key role in a PKC-dependent signal transduction pathway which leads to p42mapk activation and cell proliferation.
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PMID:Regulation of tetradecanoyl phorbol acetate-induced responses in NIH 3T3 cells by GAP, the GTPase-activating protein associated with p21c-ras. 154 25

Certain biological actions of phorbol esters cannot be duplicated by diacylglycerol (DAG). Thus, the human neuroblastoma cell line SH-SY5Y differentiates when exposed to 12-tetradecanoyl-13-acetyl-beta-phorbol (TPA) and protein kinase C (PKC) inhibitors, but not when exposed to DAG. To investigate the specific features of the phorbol diester molecule that might be responsible for these effects, we examined the extension of neurites, expression of neuron-specific enolase, and appearance and localization of phosphorylated high molecular weight neurofilament subunits (NF-H). TPA, 12-deoxy-13-tetradecanoyl-beta-phorbol, and staurosporine, but not DAG or 4-O-methyl-TPA, caused neurite outgrowth. Neuron-specific enolase was expressed in cells treated with TPA and 12-deoxy-13-tetradecanoyl-beta-phorbol but not with DAG, staurosporine, or 4-O-methyl-TPA. NF-H increased in the perikarya of cells treated with DAG and 4-O-methyl-TPA, in processes and to varying degrees in perikarya of TPA- and 12-deoxy-13-tetradecanoyl-beta-phorbol-treated cells, but much more in the processes than in the perikarya of staurosporine-differentiated cells. These findings and additional differences between the differentiation induced by TPA (a PKC activator) and staurosporine (a PKC inhibitor), including distinct morphology of the cell body and processes and time of appearance of the morphological phenotype, suggest that activators and inhibitors of PKC induce differentiation of SH-SY5Y cells by different mechanisms, and that the five-membered/seven-membered terpene ring region present in TPA must be intact for the induction of morphological differentiation.
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PMID:Distinct mechanisms of differentiation of SH-SY5Y neuroblastoma cells by protein kinase C activators and inhibitors. 154 59

The role of protein kinase C in migration of tumor cells from spheroid cultures was investigated using parental rat glioma cells and their TPA resistant counterparts. These two lines differed in their PKC content as judged by the histone phosphorylation method. Also 4 days of treatment with IRA led to PKC down-regulation. Cells having a drastically decreased PKC level migrated better than those having a normal PKC content.
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PMID:The role of protein kinase C in migration of rat glioma cells from spheroid cultures. 156 92

Structure-activity studies of novel synthetic analogues of lyngbyatoxin A reveal that the lactam ring but not the 7-linalyl moiety of lyngbyatoxin A is essential for the in vitro stimulation of protein kinase C (PKC). (-)-Indolactam V (ILV), which contains no hydrophobic substituent at C-7, or analogues containing either a linalyl or n-hexyl group at C-7 were equally efficacious in stimulating HeLa cell PKC in vitro and in competing with phorbol 12,13-dibutyrate for binding to PKC in intact cells. The hydrophobicity of alkyl groups at C-7, however, influenced the potency of these compounds to bind to and activate PKC. In addition, these compounds exhibited differences in their ability to translocate PKC. Lyngbyatoxin A (0.1 microM) like TPA induced a rapid translocation of PKC from the cytosol to the membrane and subsequently led to a sustained decrease in both cytosolic and membrane PKC activity. In contrast, (-)-n-hexylILV (0.1 microM) and (-)-ILV (1 microM) produced a transient and attenuated decrease in cytosolic PKC activity. At concentrations that produced half-maximal PKC stimulation, (-)-ILV did not cause any downregulation of PKC whereas lyngbyatoxin A and (-)-n-hexylILV led to 60% and 40% PKC downregulation, respectively. Western blot analyses with monoclonal antibodies to PKC isoforms indicated that reduction in PKC activity by chronic exposure to TPA or lyngbyatoxin A analogues could be explained by downregulation of PKC alpha. Constitutive expression of PKC beta and PKC gamma isoforms was low in HeLa cells and was not affected significantly by TPA or lyngbyatoxin A analogues.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Structural requirements of lyngbyatoxin A for activation and downregulation of protein kinase C. 156 38

Phorbol esters, which activate protein kinase C, modulate vasoconstrictor-induced tension in vascular smooth muscle. We examined the effects of phorbol esters (phorbol 12,13-dibutyrate [PDBu] and 12-O-tetradecanoylphorbol 13-acetate [TPA]) on receptor agonist (serotonin [5-HT] and arginine vasopressin [AVP])-, high K(+)-, and caffeine-induced contractions in rings of rat aorta and a small (second-order) branch of the superior mesenteric artery (SMA). PDBu and TPA significantly augmented agonist-evoked contractions in aorta but diminished those in SMA. For example, 30 nM PDBu increased 5-HT- and AVP-evoked contractions 2.0-2.5-fold in aorta (p less than 0.01) but decreased 5-HT- and AVP-induced contractions by 40-60% in SMA (p less than 0.01). In contrast, PDBu and TPA amplified high K(+)- and 10 mM caffeine-induced contractions in both aorta and SMA. Augmentation of agonist-induced contractions by PDBu was greater in endothelium-denuded aorta than in intact aorta. Two protein kinase C antagonists, H-7 and staurosporine, inhibited 5-HT-evoked contractions in the absence as well as in the presence of PDBu in both types of arteries. The augmentation of contractile responses to caffeine and K+ by phorbol esters in both types of arteries suggests that the phorbols increase the sensitivity of the contractile apparatus to Ca2+, probably by activating protein kinase C. However, the inhibitory effects of phorbols on 5-HT- and AVP-evoked responses in SMA suggest that under these conditions the dominant effect of the phorbols is a marked reduction in the availability of Ca2+ in the SMA but not in the aorta.
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PMID:Contrasting effects of phorbol esters on serotonin- and vasopressin-evoked contractions in rat aorta and small mesenteric artery. 156 5


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