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)

[Met5]-Enkephalin (ME) secretion and the expression of proenkephalin A (proENK) mRNA were studied following long-term exposure of bovine adrenal medullary chromaffin (BAMC) cells to pertussis toxin. Treatment with pertussis toxin for 24 h increased the secretion of ME in a concentration- and time-dependent manner. The magnitude of ME secretion continued to increase with time in the presence of pertussis toxin. The intracellular concentration of ME in the pertussis toxin-treated group was not significantly different from controls, suggesting that elevated levels of ME secretion result from increased biosynthesis of ME rather than from release of stored ME. Prolonged (24 h) stimulation of BAMC cells with pertussis toxin also increased proENK gene expression. Pretreatment with nimodipine (a calcium channel blocker) and calmidazolium (a calmodulin antagonist) inhibited both the secretion of ME and the increase in proENK mRNA levels induced by pertussis toxin, while the intracellular calcium antagonist dantrolene and the protein kinase C inhibitors sphingosine and H7 [1-(5-isoquinolinylsulfonyl)-2-methylpiperazine] were ineffective in blocking pertussis toxin-induced responses. Forskolin (an adenyl cyclase activator) and isobutyl methyl xanthine (a phosphodiesterase inhibitor) increased both ME secretion and proENK mRNA levels; pertussis toxin synergistically increased the secretion of ME with these cyclic AMP-elevating agents but had only an additive effect with these agents on the level of proENK mRNA. Our results suggest that a pertussis toxin-sensitive G protein may tonically regulate the secretion of ME as well as the level of proENK mRNA.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pertussis toxin stimulates the secretion of [Met5]-enkephalin and the expression of proenkephalin A mRNA in bovine adrenal medullary chromaffin cells. 128 24

When incubated with N6-2'-O-dibutyryladenosine 3',5'-cyclic monophosphate (dbcAMP), HL-60 cells expressed formyl peptide receptor (FPR) (as assessed by ligand binding) and FPR transcripts in a time- and concentration-dependent fashion. Experiments using dbcAMP analogs modified at either the C-6 or C-8 position indicated that the process was mediated by a protein kinase A type I, and protein kinase A type I activity was isolated from undifferentiated HL-60 cells by DEAE-Sephacel chromatography. Forskolin mimicked the effects of dbcAMP. Forskolin and dbcAMP-dependent expression of FPR and FPR transcript was inhibited by staurosporine. Retinoic acid (but not retinal or retinol) was capable of inhibiting dbcAMP-dependent expression of FPR mRNA half-life. Dexamethasone enhanced the effects of dbcAMP and blocked the inhibitory effect of retinoic acid on expression of FPR and FPR transcripts. Phorbol 12-myristate 13-acetate (PMA) alone (1.5-15 nM) failed to induce HL-60 to express FPR and FPR transcripts. Low concentrations (1.5 nM) of PMA enhanced the ability of dbcAMP to induce HL-60 cells to express FPR and FPR transcript, whereas high (15 nM) concentrations of PMA inhibited dbcAMP effects. These results indicate that expression of FPR and FPR transcripts by HL-60 cells can be up- and down-regulated by agents that induce HL-60 cells to differentiate and that a "cross-talk" effect exists between protein kinase A and protein kinase C that modulates FPR gene transcription (and receptor expression) by these cells.
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PMID:Regulation of formyl peptide receptor expression and its mRNA levels during differentiation of HL-60 cells. 130 42

The effect of dopamine (DA) on the binding of [3H]phorbol 12,13-dibutyrate ([3H]PdBu) in cultured rat striatal cells was examined. DA maximally increased specific [3H]PdBu binding by 70 +/- 10%, an increase comparable to that observed with norepinephrine (NE). This finding suggests that DA activates protein kinase C in cultured striatal cells, because increases in [3H]PdBu binding reflect translocation of protein kinase C. Half-maximal stimulation was observed with 10(-6) M DA. The peak response was observed at 2-3 min after addition of 10(-4) M DA, but [3H]PdBu binding was still increased above basal at 30 min. DA was not acting via an adrenergic receptor. Prazosin (10(-6) M) blocked the response to NE, suggesting mediation by an alpha 1-adrenergic receptor, but had little effect on the response to DA. Conversely, the D1 receptor antagonist SCH-23390 (10(-6) M) blocked the response to DA, but only partially inhibited the response to NE. Morphine (10(-6) M) inhibited the response to DA by 46 +/- 14%, but did not affect significantly the response to NE. The DA effect on [3H]PdBu binding is apparently independent of the increase in cyclic AMP seen on D1 receptor activation. Forskolin, apomorphine, and the D1 agonist SKF-38393 all increased cyclic AMP in striatal cells, but were less effective than DA in stimulating [3H]PdBu binding. The D2 agonist quinpirole was ineffective in stimulating either cyclic AMP or [3H]PdBu binding.
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PMID:Dopamine stimulates [3H]phorbol 12,13-dibutyrate binding in cultured striatal cells. 131 74

In vitro luteinization of bovine granulosa (LGC) and theca (LTC) cells was achieved by culturing cells with forskolin (10 microM) and insulin (2 micrograms/ml) for 9 days. This treatment induced the presence of cytochrome P450scc and adrenodoxin in both cell types, but to substantially higher levels in LGC than in LTC. Forskolin dose-dependently stimulated the secretion of progesterone and cAMP after 3 h of incubation in both cell types although LGC were less sensitive to this stimulation than were LTC. Only LTC were responsive to LH, in accordance with their higher LH/hCG binding capacity. Both prostaglandin F2 alpha (PGF2 alpha) and phorbol 12-myristate 13-acetate (TPA) increased progesterone production during 3 h incubation of LGC and LTC, and treatment with staurosporine (a protein kinase C inhibitor) reversed this effect. Neither TPA nor PGF2 alpha alone affected cAMP levels but each acted synergistically with forskolin to increase cAMP accumulation. These results indicate that 1) elevated progesterone output from LGC is related to steroidogenic enzyme level; 2) bovine LH (up to 100 ng/ml) does not provoke a response in LGC due to their low LH/hCG binding capacity; 3) cAMP-protein kinase A and protein kinase C pathways are both involved in progesterone production by LGC and LTC, possibly by enhancing cholesterol transport.
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PMID:Steroidogenic enzyme content and progesterone induction by cyclic adenosine 3',5'-monophosphate-generating agents and prostaglandin F2 alpha in bovine theca and granulosa cells luteinized in vitro. 131 23

The bovine 17 alpha-hydroxylase cytochrome P450 gene (CYP17) contains at least two cAMP-responsive sequences (CRS) within its 5'-flanking region. In this study it is demonstrated that one of the sequences, CRS1, is also a target for protein kinase C (PKC)-mediated regulation. Forskolin-induced, CRS1-dependent transcription of a heterologous minimal promoter/structural gene which had been transfected into the mouse adrenocortical tumor cell line Y1 was suppressed by activation of PKC by phorbol esters such as 12-O-tetradecanoyl phorbol-14-acetate and phorbol 12,13-didecanoate-beta (PDD beta). Use of the active and inactive forms of PDD (PDD alpha and PDD beta) as well as down-regulation of PKC by prolonged treatment of the cells with 12-O-tetradecanoyl phorbol-14-acetate demonstrated that the effect of phorbol esters on transcription conferred by CRS1 was mediated through the PKC pathway and not a consequence of general toxicity to the cells. Analysis of the different steps in the signal transduction pathway between the adenylate cyclase and the CRS1 element suggests that phrobol esters do not exert their effect by altering the forskolin-induced cAMP production, activation of PKA, or the binding of nuclear proteins to CRS1. These results establish the CRS1 element as a target not only for PKA, but also for the PKC-mediated signal transduction pathway. They further suggest that PKC interferes with the transcriptional activation competence of factors bound to CRS1 and the minimal promoter.
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PMID:A novel 3',5'-cyclic adenosine monophosphate-responsive sequence in the bovine CYP17 gene is a target of negative regulation by protein kinase C. 132 75

Phorbol-myristate-acetate (PMA) induced in lymphocytes the production or reactive oxygen intermediates in a process which was stimulated by the presence of vasoactive intestinal peptide (VIP) in a dose-dependent response at VIP concentrations in the range 10(-11)-10(-8) M. The dissociation constant for the high-affinity receptors of VIP agreed with the ID50 of the activation of adenylate cyclase, and the ID50 for the stimulation by VIP of PMA-induced chemiluminescence, which were close to 0.2 nM VIP. Forskolin produced in lymphocytes an effect quite similar to VIP. A comparison of the response to VIP and forskolin of lymphocytes and monocytes showed that, in contrast to forskolin, VIP failed to induce the above described effect in monocytes. A possible mechanism involving protein kinase C, which is activated by PMA, and an intracellular signal linked to VIP receptors is pointed out. This study further supports a role for VIP as a mediator in the neuroimmune system.
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PMID:Vasoactive intestinal peptide enhances phorbol myristate acetate-induced chemiluminescence in human lymphocytes. 133 43

The respective roles of cAMP-dependent protein kinase (protein kinase A [PKA]) and protein kinase C (PKC) in the early stages of neurite outgrowth were examined in SH-SY-5Y human neuroblastoma cells. Forskolin or dbcAMP, agents that increase intracellular cAMP levels, and intracellular delivery of PKA catalytic subunit induced neurite outgrowth. The PKA inhibitor, N-(2-guanidinoethyl)-5-isoquinolinesulfonamide (HA 1004), prevented the increases, and decreased further the percentage of cells possessing short, filopodia-like neurites in the absence of inducers. In contrast to effects on PKA activation, PKC activation by 12-0-tetradecanoylphorbol-13-acetate (TPA) reduced the percentage of filopodia-like neurites elaborated by otherwise untreated cells, and prevented neurite outgrowth induced by PKA activators. PKC inhibitors 1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride (H7), staurosporine, and sphingosine induced neurite outgrowth. Neurites induced by PKA activation contained higher levels of tubulin immunoreactivity than those induced by PKC inhibition. Furthermore, PKA-induced neurites rapidly retracted in the presence of colchicine, while those elaborated following PKC inhibition were more resistant. These data suggest that neurites elaborated in response to PKA activation are dependent upon microtubule polymerization, and that neurite induction following PKC inhibition is mediated by a different mechanism. PKA activators and PKC inhibitors exerted additive effects on neurite outgrowth, suggesting that the distinct pathways regulated by these two kinases function cooperatively during neuritogenesis.
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PMID:Opposing influences of protein kinase activities on neurite outgrowth in human neuroblastoma cells: initiation by kinase A and restriction by kinase C. 133 89

Using dispersed cultures of fetal rat hypothalami, we studied the effects of forskolin and the phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA), activators of protein kinase A and C, respectively, upon vasopressin (VP) secretion, VP mRNA expression and VP mRNA poly(A) tail length. Forskolin stimulated the VP mRNA content and peptide secretion 2.6-fold and induced an increase in the poly(A) tail length of approximately 90 nucleotides. TPA induced an increase in VP mRNA size and stimulated 1.9-fold the secretion of VP without an increase in VP mRNA content. Depolarization with potassium induced an increase in the VP peptide secreted of 2.2-fold, with no effect on the VP mRNA content or size. Increased osmolality had no effect on either VP peptide or VP mRNA. We conclude that VP expression in cultured fetal rat hypothalamic cells is regulated via both protein kinase A and protein kinase C pathways.
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PMID:Regulated expression of vasopressin gene by cAMP and phorbol ester in primary rat fetal hypothalamic cultures. 135 50

Using fetal brain cells in culture, we have previously shown that activation of the cAMP pathway by forskolin induces the production and secretion of neuropeptide Y (NPY). In this study we wished to ascertain 1) if activation of the protein kinase C pathway induces NPY production and/or secretion and if there is synergism between the pathways, and 2) the role of protein/RNA synthesis and influx of extracellular calcium. Aggregates, formed from dissociated cells obtained from the hypothalamus-olfactory tubercle area of 17-day-old rat fetuses, were cultured in serum-free medium for 12 days. The NPY content of aggregates incubated for 24 h with solvent (control) was 4.4 ng/flask, and the medium content was 7.6 ng. Forskolin (10 microM) or phorbol 12-myristate 13-acetate (PMA; 20 nM) marginally affected aggregate content, but each increased medium content 2- to 3-fold; forskolin and PMA were additive. When cycloheximide (75 microM) was included along with forskolin, PMA, or forskolin plus PMA for a period of 10 h, the increase in NPY medium content was abolished. Actinomycin D (Act-D; 5 micrograms/ml) inhibited the response to each secretagogue in a time-dependent manner. When Act-D was included along with forskolin, PMA, or forskolin plus PMA for a total period of 12 or 24 h, the 12 h increase in content was not affected, whereas the 24 h increase was abolished. When the presence of Act-D was limited to 0-24, 6-24, or 12-24 h, and forskolin plus PMA were included for the entire 24-h period, the increase in NPY content was inhibited by 94%, 57%, and 12%, respectively. Verapamil (100 microM) totally inhibited the 24 h response to forskolin and partially (40-50%) inhibited the response to PMA or forskolin plus PMA. In none of these conditions was the inhibition of the increase in medium NPY content accompanied by an increase in aggregate content, nor was the NPY content of aggregate/medium of control cultures affected.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Forskolin and phorbol ester stimulation of neuropeptide Y (NPY) production and secretion by aggregating fetal brain cells in culture: evidence for regulation of NPY biosynthesis at transcriptional and posttranscriptional levels. 137 Jul 98

In A-431 cells, platelet-activating factor (PAF) induces the expression of c-fos and TIS-1 genes in both the absence and the presence of cycloheximide in a structurally specific and receptor-coupled manner. We have now investigated the molecular mechanisms of this response, particularly in relation to the role of protein kinases. Pretreatment of cells with genistein or methyl-2,5-dihydroxycinnamate (tyrosine kinase inhibitors) or staurosporine (a protein kinase C inhibitor) for 20 min abolished the c-fos expression induced by PAF. Interestingly, when genistein was added 90 s after addition of PAF, no inhibition was observed. Similarly, staurosporine did not inhibit c-fos expression when added 8 min after PAF addition to the cells. These inhibitions were dose-dependent (IC50 for staurosporine was 180 nM, and for genistein 50 microM). Simultaneous addition of PAF and phorbol 12-myristate 13-acetate (PMA) did not give a synergistic effect on c-fos expression. Pretreatment of cells with PMA had no effect on [3H]PAF binding, but abolished the PAF-induced gene expression. PAF-stimulated gene expression was desensitized if cells were pretreated with PAF. Interestingly, epidermal growth factor was able to stimulate c-fos expression in PAF-desensitized cells, and thus indicated involvement of distinct mechanisms for the two stimuli. Forskolin, an activator of adenylate cyclase, did not induce c-fos expression and had no effect on the PAF response. Exposure of cells to PAF for as little as 1 min, followed by its removal, was sufficient to activate the gene expression and demonstrated the rapidity and the exquisite nature of the signalling involved in this process. It is concluded that activation of PAF receptor (a proposed G-protein-coupled receptor) causes rapid production of signals which induce the expression of c-fos gene and that this is mediated via tyrosine kinase and protein kinase C.
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PMID:Involvement of tyrosine kinase and protein kinase C in platelet-activating-factor-induced c-fos gene expression in A-431 cells. 138 9


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