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)

Expression of protein kinase C-epsilon was examined in the human monoblastoid U937 cell. This cell type contained the alpha, beta, and epsilon isoforms of protein kinase C (PKC). While PKC-epsilon content was slightly higher in the cytosolic than in the particulate fraction, the amount contained in the particulate fraction was higher than the alpha and beta isoforms which were predominantly localized to the cytosol. After an acute exposure to tetradecanoyl-13-phorbol acetate (TPA), PKC-epsilon translocated to the particulate fraction. Acute or chronic exposure to ionomycin did not alter content of the epsilon isoform. Longer exposures to TPA decreased PKC-epsilon in both cellular fractions. PKC-epsilon displayed a similar sensitivity to TPA-induced down-regulation as did PKC-beta while PKC-alpha was more resistant to this effect. After a 72-h exposure to 0.1 nM TPA, increases in the alpha and beta isoforms but not in PKC-epsilon were observed. However, 1,25-dihydroxy vitamin D3 and dibutyryl cyclic AMP which induce U937 differentiation enhanced PKC-epsilon expression.
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PMID:Modulation of protein kinase C-epsilon by phorbol esters in the monoblastoid U937 cell. 139 83

1. Glomerular epithelial cells (GEC) were cultured from human kidneys and immunologically characterized. 2. The effect of extracellular nucleotides on the cytosolic free calcium activity [Ca2+]i was investigated with the fura-2 microfluorescence method. Extracellular UTP, UDP, UMP, ATP, adenosine 5'-O-(3-thio)-trisphosphate (ATP-gamma-S), inosine-triphosphate (ITP), guanyltriphosphate (GTP), 2-methylthio-ATP, AMP, alpha,beta-methylene-ATP and adenosine led to a rapid, transient, concentration-dependent increase of [Ca2+]i, followed by a plateau above the baseline level. 3. In a calcium-free extracellular solution, the rapid increase of [Ca2+]i was still present, whereas the plateau level was abolished. 4. ATP and UTP (ED50 both: 10(-5) M) stimulated inositol trisphosphate (InsP3) formation in GEC. 5. The order of potency for the purine nucleotides in stimulating InsP3 formation was ATP = ATP-gamma-S greater than ADP greater than 2-methylthio-ATP greater than AMP = a,beta methylene-ATP = adenosine. 6. The increase of InsP3 induced by ATP (10(-5) M) could be inhibited by the P2 receptor blocker suramin (greater than 10(-4) M). Reactive blue 2 exhibited a weak stimulating effect on the InsP3 formation and only a weak inhibitory effect at a concentration of 10(-3) M was observed. 7. Protein kinase C activation by preincubation of GEC with phorbol 12-myristate 13-acetate (PMA, 100 ng ml-1, 15 min) abolished the effect of ATP (10(-5) M) on InsP3 formation. Downregulation of protein kinase C by long term incubation (18 h) with PMA had no significant effect on the phosphoinositol turnover induced by ATP.8. The results indicate that an increase of [Ca2+]i and inositol phosphate breakdown can be mediated via activation of a P2 receptor in human GEC.
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PMID:Effect of nucleotides on the cytosolic free calcium activity and inositol phosphate formation in human glomerular epithelial cells. 142 72

Relatively little is known about the regulation of secretion of hypothalamic beta-endorphin, the potent opioid that is believed to play a variety of physiological roles in brain. Previous work has shown that arginine vasopressin (AVP), which acts in brain primarily via activation of the phosphoinositol (PI) second messenger system, stimulates secretion of hypothalamic beta-endorphin. To test the hypothesis that activators of protein kinase C (PKC), which is activated following PI hydrolysis, stimulates secretion of beta-endorphins from hypothalamus, we studied the separate effects of stimulators of PKC including phorbol ester 12-myristate-13-acetate (PMA) and 1-oleolyl-2-acetyl glycerol (OAG- a diacyl glycerol analogue) on secretion of immunoreactive (IR-) beta-endorphin (measured by RIA) from dissociated fetal rat hypothalamic cell cultures. We also studied AVP and angiotensin II (Ang II), hypothalamic peptides which activate the PI second messenger pathway, and interactions of PMA and forskolin (FSK), an activator of the cyclic AMP/protein kinase A (PKA) pathway. PMA, OAG, AVP, and Ang II stimulated IR-beta-endorphin secretion. The stimulatory effect of both PMA and FSK on IR-beta-endorphin secretion was greater than that of PMA or FSK alone and was essentially additive.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Protein kinase C activators stimulate beta-endorphin secretion from hypothalamic cells. 142 53

CRE-BP1 is a transcriptional activator binding to the cyclic AMP response element, which has a putative metal finger structure and the leucine zipper motif linked to a cluster of basic amino acids in the amino and carboxyl-terminal regions, respectively. The activities of a number of transcription factors are known to be controlled through phosphorylation and dephosphorylation. At the first step for understanding of the regulation of CRE-BP1, phosphorylation of CRE-BP1 was studied in vitro. The human recombinant CRE-BP1 was phosphorylated by protein kinase C and cyclic AMP-dependent protein kinase. These two protein kinases recognized distinct seryl residues of CRE-BP1. Amino acid sequence analysis after phosphopeptide map indicated that two seryl residues, Ser-340 and Ser-367, located in the basic region of CRE-BP1 were identified as the major protein kinase C phosphorylation sites, whereas Ser-62 downstream of the metal finger structure was determined as the phosphorylation site by cyclic AMP-dependent protein kinase. The phosphorylation of CRE-BP1 by these two protein kinases may regulate the function of this transcriptional activator protein.
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PMID:Phosphorylation of CRE-BP1, a cyclic AMP response element binding protein, by protein kinase C and cyclic AMP-dependent protein kinase. 145 87

1. Sodium absorption is the dominant ion transport process in conducting airways and is a major factor regulating the composition of airway surface liquid. However, little is known about the control of airway sodium transport by intracellular regulatory pathways. 2. In sheep tracheae and human bronchi mounted in Ussing chambers under short circuit conditions, the sodium current can be isolated by pretreating tissues with acetazolamide (100 microM) to inhibit bicarbonate secretion, bumetanide (100 microM) to inhibit chloride secretion and phloridzin (200 microM) to inhibit sodium-glucose cotransport. This sodium current consists of amiloride-sensitive (57%) and amiloride-insensitive (43%) components. 3. The regulation of the isolated sodium current by three second messenger pathways was studied using the calcium ionophore A23187 to elevate intracellular calcium, a combination of forskolin and the phosphodiesterase inhibitor zardaverine to elevate intracellular cyclic AMP, and the phorbol ester 12,13-phorbol dibutyrate (PDB) to stimulate protein kinase C. 4. In sheep trachea, A23187 produces a dose-related inhibition of the sodium current with maximal effect (38% of ISC) at 10 microM and IC50 1 microM. This response affects both the amiloride-sensitive and insensitive components of the sodium current and is not altered by prior stimulation of protein kinase C or elevation of intracellular cyclic AMP. In human bronchi, A23187 (10 microM) produced a significantly greater inhibition of ISC (68%), a response which was unaffected by prior treatment with PDB or forskolin-zardaverine. 5. In sheep trachea, stimulation of protein kinase C with PDB produced a dose-related inhibition of ISC maximal (56% of ISC) at 50 nM (IC50 7 nM). This response was abolished by amiloride (100 microM) pretreatment suggesting a selective effect on the amiloride-sensitive component of the sodium current. The response was not altered by prior elevation of intracellular calcium or cyclic AMP. PDB (10 nM) caused a similar inhibition of ISC in human bronchi (43%). The effect of PKC stimulation following pretreatment with A23187 was diminished in human bronchi. Elevating intracellular cyclic AMP did not alter this response. 6. Addition of forskolin (1 microM) together with the phosphodiesterase inhibitor zardaverine (100 microM) produced a mean 35-fold increase in intracellular cyclic AMP in sheep trachea. This was associated with a small, but significant, 6% transient increase in ISC followed by a significant 4% fall. Neither effect could be abolished by amiloride pretreatment. In human bronchi, a small decrease in ISC which could not be distinguished from that occurring in controls was observed.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Second-messenger regulation of sodium transport in mammalian airway epithelia. 146 41

The toxicity of polycyclic aromatic hydrocarbons such as benzo(a)pyrene, 7,12-dimethylbenz(a)anthracene, and 3-methylcholanthrene has been associated with alterations in the proliferation of vascular smooth muscle cells and the development of lesions of mesenchymal origin. Because phosphorylation of endogenous substrates plays a central role in the regulation of smooth muscle cell growth, the present studies were conducted to evaluate the phosphorylation pattern of medial aortic protein upon repeated in vivo exposure of Japanese quail to benzo(a)pyrene (BaP). Medial aortic homogenates from quail treated for 10 weeks with 10 mg/kg benzo(a)pyrene or vehicle were processed for in vitro measurements of protein phosphorylation. In vitro phosphorylation of endogenous or exogenous proteins stimulated in vitro by phorbol myristate acetate/phosphatidylserine or cyclic AMP, known activators of protein kinase C and cyclic AMP-dependent protein kinase, respectively, was examined in the cytosolic and particulate fractions of homogenates from control and treated animals. Benzo(a)pyrene treatment significantly enhanced the basal phosphorylation of M(r) 113, 35, and 23 kDa proteins in the cytosolic fraction. Modest increases in the phosphorylation of M(r) 71, 52, and 38 kDa were also observed under basal conditions. No changes in the basal phosphorylation of particulate proteins were observed. Phosphorylation of endogenous protein substrates by protein kinase C in the cytosolic fraction was not altered by benzo(a)pyrene treatment. In contrast, inhibition of C-kinase-mediated phosphorylation of endogenous M(r) 272, 72, and 45 kDa proteins was observed in the particulate fraction of aortic homogenates from benzo(a)pyrene-treated quail relative to controls. Exogenous histone phosphorylation by PKC in the particulate, but not cytosolic fraction, was decreased by benzo(a)pyrene treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Modulation of aortic protein phosphorylation by benzo(a)pyrene: implications in PAH-induced atherogenesis. 147 92

The protein kinase inhibitor 1-(5'-isoquinolinesulfonyl)-2-methylpiperazine (H7) has been widely used because of its ability to inhibit cyclic AMP- and cyclic GMP-dependent protein kinases (PKA and PKG) and protein kinase C (PKC) at roughly equal concentrations; it is much less potent on other kinases. Previous studies in other laboratories have found that H7 samples from different commercial sources have different properties in cellular studies and protein kinase C inhibition assays. We now report the results of chemical and biological tests which show that H7 samples also differ in chemical structure, again depending on their commercial source. Chemical synthesis and NMR spectroscopy indicate that H7 from most suppliers has the structure originally proposed for H7, while "H7" from another supplier is in fact its 3-methylpiperazine positional isomer.
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PMID:The structure and biological activities of the widely used protein kinase inhibitor, H7, differ depending on the commercial source. 153 Jun 23

A number of lines of evidence indicate that the Ca2+ and cyclic AMP signalling systems interact in NCB-20 cells. However, to date, the regulation of [Ca2+]i homeostasis has not been studied in this cell line. The present study aimed to clarify our understanding of [Ca2+]i homeostasis in these cells and to evaluate tools that manipulate [Ca2+]i, independently of protein kinase C effects. Bradykinin, by a B2-receptor, elevated [Ca2+]i by a pertussis-toxin-insensitive mechanism. The BK-stimulated [Ca2+]i rise originated from intracellular sources, without a contribution from Ca2+ entry mechanisms. The effect of BK was precluded by pretreatment with thapsigargin and ionomycin--compounds that elevated [Ca2+]i independent of phospholipase C activation. Both compounds, however, exerted effects in addition to stimulating release of Ca2+ from BK-sensitive stores; the BK-sensitive Ca2+ pool was a subset of the thapsigargin-sensitive pool; ionomycin strongly stimulates Ca2+ entry. Activation of protein kinases A and C attenuated the duration of the BK-induced rise in [Ca2+]i, without affecting the peak [Ca2+]i, suggesting interference with the BK response at a step downstream of the activation of phospholipase C. Application of these approaches should enhance the delineation of the consequences of Ca2+ mobilization on cyclic AMP accumulation.
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PMID:Manipulation of intracellular calcium in NCB-20 cells. 153 72

Activators of protein kinase C, such as 12-O-tetradecanoylphorbol 13-acetate (TPA), are known to regulate the expression of many genes, including the tumor necrosis factor alpha (TNF) gene, by affecting the level or activity of upstream transcription factors. To investigate the mechanism whereby TPA activates the TNF promoter, a series of 5'-deletion mutants of the human TNF promoter linked to chloramphenicol acetyltransferase was transfected into U937 human promonocytic cells. TPA produced a 7- to 11-fold activation of all TNF promoters tested, even those promoters truncated to contain only the core promoter with no upstream enhancer elements. The proximal TNF promoter containing only 28 nucleotides upstream and 10 nucleotides downstream of the RNA start site confers TPA activation to a variety of unrelated upstream enhancer elements and transcription factors, including Sp1, CTF/NF1, cyclic AMP-response element, GAL-E1a, and GAL-VP16. The level of activation by TPA depends on the TATA box structure, since the TPA response is greater in promoters containing the sequence TATAAA than in those containing TATTAA or TATTTA. These findings suggest that the core promoter region is a target for gene regulation by second-messenger pathways.
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PMID:The core promoter region of the tumor necrosis factor alpha gene confers phorbol ester responsiveness to upstream transcriptional activators. 154 16

smg p21A and -B (smg p21s) are ras p21-like small GTP-binding proteins (G proteins) with the same putative effector domain as ras p21s. Both smg p21A mRNA and smg p21B mRNA were detected in CMK, a human megakaryocytic leukemia cell line, and their levels were markedly elevated by treatment with 12-O-tetradecanoyl-phorbol-13-acetate (TPA), which caused the differentiation of this cell line into more mature megakaryocytes. The smg p21 protein molecules also increased during the TPA-induced differentiation of CMK cells. The mRNA level of glycoprotein IIb (GPIIb), a typical marker of the megakaryocytes, was increased by this treatment, but the time course of the increase in the smg p21 mRNA levels as more rapid than that of the increase in the GPIIb mRNA level. Ha-ras p21 mRNA was undetectable, but both Ki- and N-ras p21 mRNAs were detected in CMK cells and their levels were also increased during TPA-induced differentiation of CMK cells, although to a lesser extent than those of smg p21 mRNAs. Protein kinase C inhibitors inhibited the basal and TPA-induced smg p21A mRNA level, but cyclic AMP-elevating prostaglandin E1 or Ca(2+)-mobilizing ionomycin did not inhibit them. Cycloheximide enhanced the basal and TPA-induced smg p21A mRNA levels. Actinomycin D blocked the TPA-induced smg p21A mRNA levels, but showed no detectable effect on the elevated smg p21A mRNA level which was induced by pretreatment with TPA. A dramatic increase in the smg p21 mRNA levels was also observed in other leukemia cell lines during TPA-induced differentiation. These results suggest that TPA stimulated expression of the smg p21A gene, presumably through the action of protein kinase C at the transcriptional level rather than at the post-transcriptional level, in hematopoietic leukemia cells.
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PMID:Induction of smg p21/rap1A p21/krev-1 p21 gene expression during phorbol ester-induced differentiation of a human megakaryocytic leukemia cell line. 154 53


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