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)

The adenylate cyclase activator, forskolin, was found to induce expression of class I and class II major histocompatibility complex antigens in a B precursor cell line, Reh, as well as in a B lymphoid cell line, Raji. No such effect was, however, observed when the promyelocytic cells line HL-60 was treated with either forskolin or the cAMP analogue 8-bromoadenosine cyclic monophosphate. As expected, all three cell lines showed reduced proliferation upon forskolin treatment. Forskolin induced expression of class I and class II major histocompatibility complex antigens in cell lines not affected by interferon-gamma and vice versa, indicating that cAMP is not involved in the regulation of histocompatibility antigens by interferon-gamma. We also compared the effect of interferon-gamma and 12-O-tetradecanoylphorbol 13-acetate on major histocompatibility complex class I and class II expression, and despite differences in the response on the tested cell lines, we can not at this point exclude the possibility that protein kinase C is involved in the action of interferon-gamma.
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PMID:Distinct effect of forskolin and interferon-gamma on cell proliferation and regulation of histocompatibility antigen expression in hematopoietic cells. 308 31

Phospholipases (PL) A-2 and C stimulated the outputs of prostaglandin (PG) F-2 alpha, PGE-2 and 6-keto-PGF-1 alpha from the Day-7 and Day-15 guinea-pig uterus superfused in vitro. PLC had a more pronounced effect than PLA-2, particularly on the output of PGE-2. The ratios of the outputs of PGF-2 alpha and PGE-2 were similar after stimulation by A23187 and PLA-2, but this ratio was lower after stimulation by PLC. It appears that the stimulation of endometrial PGF-2 alpha synthesis by Ca2+ is via activation of PLA-2 rather than via activation of PLC, although the PLC used was of bacterial origin (which uses phosphatidylcholine as substrate) rather than of mammalian origin (which uses phosphatidylcholine as substrate). Forskolin (which increased endometrial and myometrial cyclic AMP levels) and phorbol 12-myristate-13-acetate had no effect on uterine PG output, indicating that cyclic AMP and protein kinase C are not involved in the stimulation of endometrial PGF-2 alpha synthesis in the guinea-pig. Uterine PG output was not stimulated by 54 mM-KCl, which shows that the pulsatile nature of endometrial PGF-2 alpha synthesis and release is not due to an intermittent, synchronous depolarization of the endometrial cells.
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PMID:Effects of various factors on prostaglandin synthesis by the guinea-pig uterus. 311 14

The biochemical mechanisms responsible for regulating cellular platelet-derived growth factor expression are incompletely understood. Our previous studies have shown that platelet-derived growth factor B/c-sis mRNA levels are induced in human renal microvascular endothelial cells by either thrombin or transforming growth factor (TGF-beta), while exposure to agents which elevate cAMP levels blocks the induction responses. The current studies use combined transcription run-off and message decay rate experiments to show greater than 3-fold increases in rate of transcription after stimulation with either thrombin or TGF-beta. c-sis message has a 70-90-min half-life under basal conditions that is effectively unaltered by thrombin or TGF-beta. Forskolin does not decrease the stability of c-sis mRNA, although it attenuates transcription increases seen with inducing agents. TGF-beta induction of c-sis transcription is mediated independent of the protein kinase C (Ca2+- and phospholipid-dependent enzyme)-mediated responses to phorbol ester, as it remains intact following down-regulation of protein kinase C response; TGF-beta and phorbol elicit additive induction. Inhibitory effects of cAMP upon transcription act distal to early thrombin-receptor-coupled increases in phosphatidylinositol turnover and are capable of turning off TGF-beta-activated transcription after activation has been established. Both inducing and suppressing agents alter endothelial platelet-derived growth factor B/c-sis mRNA expression dominantly through effects upon rates of transcription, cAMP suppression of transcription is dominant, and TGF-beta and phorbol esters mediate induction of transcription through distinct pathways.
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PMID:Distinct pathways mediate transcriptional regulation of platelet-derived growth factor B/c-sis expression. 319 52

Quantitative in-vitro autoradiographic study was performed to localize two prominent second-messenger systems (the adenylate cyclase and phosphoinositide systems) in the normal gerbil brain. [3H] Forskolin and [3H] phorbol 12, 13-dibutyrate (PDBu) were used to identify the regional distribution of adenylate cyclase and protein kinase C, respectively. The localization of the forskolin binding was not uniform, being particularly concentrated in the striatum, the accumbens nucleus, the olfactory tubercle, the substantia nigra, the CA3 region of the hippocampus and the molecular layer of the cerebellum. On the other hand, the PDBu binding was rather uniform, although the superficial layer of the cerebral neocortices, the strata oriens of the CA1 region of the hippocampus and the molecular layer of the cerebellum showed relatively dense binding. Quantitative autoradiography of the second-messenger systems in the brain is expected to provide important information concerning the role of neurotransmitters in the pathophysiology of various conditions.
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PMID:Autoradiographic analysis of second-messenger systems in the gerbil brain. 320 56

1. The major purpose of this study was to investigate cellular regulation of the ductal transport processes in salivary glands which act to modify the electrolyte composition of primary saliva and cause it to become hypotonic. This was achieved using an isolated mandibular gland preparation by observing the effect of different stimuli on the electrolyte composition of saliva secreted at the same flow rate, on the assumption that these stimuli do not influence primary saliva composition. The effects of the same stimuli on the volume of primary fluid secretion and on protein secretion were also observed. Proteins were measured in total and as individual components after their separation by high-performance liquid chromatography. 2. Acetylcholine was used as a 'Ca2+-mobilizing' agonist (i.e. one which both elevates intracellular Ca2+ concentration and activates protein kinase C). Isoprenaline was initially used to elevate intracellular cyclic AMP concentration but was subsequently abandoned in favour of forskolin. 3. Acetylcholine was a very potent stimulus of primary fluid secretion. By contrast, isoprenaline and forskolin were essentially without effect, even when superimposed on acetylcholine stimulation. 4. As judged by saliva electrolyte composition, increasing the concentration of acetylcholine enhanced ductal absorption of Na+ and Cl- and secretion of K+ (and presumably HCO3-). Forskolin had the opposite effect: when superimposed on submaximal acetylcholine stimulation it caused saliva concentrations of Na+ and Cl- to remain high and K+ low (i.e. it inhibited ductal transport processes). The inhibitory effect of forskolin on ductal transport could be overcome by increasing the concentration of acetylcholine, and vice versa. 5. Acetylcholine, isoprenaline and forskolin each increased salivary protein secretion, although the kinetics of secretion differed. The spectrum of proteins secreted in response to the three stimuli was the same. The relative proportions of the individual proteins was influenced by the strength of stimulation (i.e. the proportions at high total protein output differed from those at low total protein output) but not apparently by the nature of the stimulus. 6. Thus, the three major secretory processes in the rabbit mandibular salivary gland respond differently to the two major signal transduction mechanisms. For primary fluid secretion, Ca2+ is stimulatory and cyclic AMP almost without effect; for ductal transport, Ca2+ is stimulatory and cyclic AMP inhibitory; and for protein secretion both Ca2+ and cyclic AMP are stimulatory.
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PMID:Effects of acetylcholine, isoprenaline and forskolin on electrolyte and protein composition of rabbit mandibular saliva. 325 19

Granulosa cells obtained from immature estradiol-treated SD rats (10 rats/experiment) were employed in elucidating the control mechanism of steroid secretion. Phorbol 12-myristate 13-acetate (PMA) inhibited estradiol production by cultured rat granulosa cells with IC50 less than 1 nM. PMA, however, stimulated small but significant increases in progesterone production in a dose-dependent manner with ED50 of 14 nM to 3.5-fold above the basal control level. These effects could not be induced by calcium ionophore A23187. Forskolin-stimulated progesterone production was inhibited by the concomitant addition of PMA with IC50 less than 1 nM. The phosphorylation of proteins by [32P] orthophosphate-labelled cells was examined by two-dimensional polyacrylamide gel electrophoresis and autoradiography. Treatment of cells with forskolin altered the intensity of 40 kDa acidic phosphoprotein compared to that of the control. On the other hand, treatment of cells with PMA altered the intensity of 78 and 32 kDa acidic phosphoproteins. These results suggest, therefore, that PMA can modulate steroidogenesis in rat granulosa cells, presumably through activation of Ca2+-activated, phospholipid-dependent protein kinase (protein kinase C).
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PMID:[Effects of phorbol ester and forskolin on steroidogenesis and protein phosphorylation in cultured rat granulosa cells]. 342 89

We have previously shown that insulin-like growth factor (IGF-I) suppresses basal and GHRH-induced GH gene transcription. cAMP is a putative intracellular mediator of GHRH action. We, therefore, studied the mechanism of IGF-I action on the somatotroph with or without cAMP activators. Primary rat pituitary cells growing in serum-free medium were treated with IGF-I. GH secretion was measured by RIA, and mRNA levels were measured by hybridization to [32P]GH cDNA. 8-Bromo-cAMP (8-Br-cAMP; 0.625 mM) stimulated GH mRNA levels after 72 h by 238%. IGF-I (6.5 nM) caused a 64% inhibition of 8-Br-cAMP-stimulated GH mRNA levels and a similar inhibition of GH secretion. This inhibition was time and dose dependent, with maximal (71%) suppression of cAMP-induced GH achieved with 13 nM IGF-I after 72 h. Forskolin (1 microM), a stimulator of adenylate cyclase, stimulated GH secretion (198%) which was inhibited by IGF-I by 42%. 12-O-Tetradecanoylphorbol 13-acetate, (a phorbol ester; 50 nM), a potent activator of protein kinase C, strongly stimulated GH secretion (347%), which was similarly suppressed by IGF-I by 51%. The suppressive action of IGF-I on somatotroph gene expression is unimpaired by direct activation of both cAMP and protein kinase C, suggesting that IGF-I acts upon the GH gene by a mechanism that is not altered by these second messengers. The negative feedback inhibition of physiological concentrations of IGF-I on GH, therefore, appears to override the potent stimulation of GH by these intracellular messengers.
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PMID:Insulin-like growth factor I action on rat anterior pituitary cells: effects of intracellular messengers on growth hormone secretion and messenger ribonucleic acid levels. 367 37

The uptake and release of catecholamines was investigated in the isolated perfused adrenal gland of the rat after preloading the preparation with [3H]norepinephrine, and the effects of various agents were examined on the stimulation-evoked secretion of catecholamines and total tritium. Large quantities of tritium were found in the adrenal medulla after either intravenous injection of [3H]norepinephrine to the rat, or perfusion of the isolated adrenal gland with Krebs-bicarbonate solution containing [3H]norepinephrine. The retention of the tritium was inhibited 90% by desipramine. Acute treatment with guanethidine and chronic treatment with 6-hydroxydopamine abolished the secretion of tritium without affecting the secretion of catecholamines evoked at 1 Hz. Nicotine, muscarine and acetylcholine enhanced the secretion of catecholamines but not tritium, whereas tyramine and ephedrine enhanced the secretion of tritium but not catecholamines. It is concluded that chromaffin cells do not possess the norepinephrine uptake mechanism and that the uptake of [3H]norepinephrine occurs mainly in sympathetic nerve terminals present in the adrenal gland and the surrounding blood vessels (adrenal and renal veins). The differential localization of [3H]norepinephrine and catecholamines allowed us to test the effects of a variety of pharmacological agents that alter neurotransmitter release by acting on receptors on the neuronal membrane, acting on sodium and potassium channels, or acting to alter the intracellular concentrations of adenosine 3',5'-cyclic monophosphate and protein kinase C. Transmural stimulation (1 Hz for a total of 300 pulses) markedly enhanced the release of catecholamines and tritium which was blocked by tetrodotoxin (sodium channel-blocker) and potentiated by tetraethylammonium and gallamine (potassium channel-blockers). Phentolamine, an alpha adrenergic blocking agent which acts on both alpha-1 and alpha-2 receptors, caused a 3- to 4-fold facilitation of the tritium secretion while inhibiting catecholamine secretion by 45%. [Met]enkephalin almost completely inhibited the evoked-secretion of tritium but had very little effect on the secretion of catecholamines. Forskolin inhibited the tritium secretion by 80% but produced more than a 2-fold facilitation of catecholamine secretion. Phorbol 12,13-dibutyrate caused facilitation of evoked secretion of both catecholamines and tritium. A combination of phorbol ester and forskolin had a synergistic effect on stimulation-evoked secretion of catecholamines, whereas phorbol ester partially reversed the inhibitory effects of forskolin on the tritium secretion.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Simultaneous secretion of catecholamines from the adrenal medulla and of [3H]norepinephrine from sympathetic nerves from a single test preparation: different effects of agents on the secretion. 376 30

The effect of phorbol myristate acetate (PMA) was compared with that of histamine on the guinea-pig lung parenchymal strip. PMA, 10(-5) M, caused a slowly developing sustained contraction which had approximately the same magnitude as the maximal histamine contraction. Isoprenaline, at 10(-5) M, caused 86% relaxation of the histamine contraction but only 22% relaxation of the PMA contraction. Forskolin, at 10(-5) M had a similar action to isoprenaline on the effects of both spasmogens while aminophylline, 5 X 10(-4) M, was considerably less effective. Sodium nitroprusside had little effect on the histamine contraction and actually increased the PMA spasm. It is suggested that protein kinase C may have a role in the tonic phase of the contraction of bronchiolar smooth muscle. These findings could have relevance for the delayed phase of asthma, which is known to be insensitive to beta-agonists.
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PMID:Phorbol myristate acetate causes in guinea-pig lung parenchymal strip a maintained spasm which is relatively resistant to isoprenaline. 404 98

We have identified and studied a posttranscriptional mechanism of lactate dehydrogenase A (LDH) subunit gene expression at the level of mRNA stability. Using the well differentiated rat C6 glioma cell line as a model system, the effects of activators of the protein kinase A and C pathways on the half-life of LDH A mRNA were measured by two independent methods: 1) by the RNA synthesis inhibitor-chase method using actinomycin D, and 2) by analysis of decay of LDH A [3H]mRNA in [3H]uridine-labeled cells. By each method, the half-life of relatively short-lived LDH A mRNA was increased 5- to 7-fold in 8- (4-chloro-phenylthio) cAMP or forskolin-treated and about 3-fold in 12-0-tetradecanoylphorbol-13- acetate (TPA) or dioctanoylglycerol-treated cells. Forskolin acted synergistically with TPA to prolong LDH A mRNA half-life from 55 min to more than 20 h. The relatively rapid basal decay rate of LDH A mRNA was also considerably slowed in the presence of the protein phosphatase inhibitor okadaic acid, suggesting a functional role for protein phosphorylation in the stabilization process. In glioma cells stably transformed with a protein kinase A catalytic subunit expression vector, overexpression of the catalytic subunit stabilized LDH mRNA to the degree seen in forskolin-treated cells. In cells transfected with a protein kinase A inhibitor-expression vector, cAMP-mediated stabilization of LDH A mRNA half-life was prevented. Furthermore, both staurosporin and 3- [1-(3-dimethylaminopropyl)-indol-3-yl]-3-(indol- 3-yl)- maleimide, inhibitors of protein kinase C, prevented the TPA-induced stabilization of LDH A mRNA. We conclude from the experimental data that the protein kinase A and C signal pathways play an active functional role in regulating LDH A mRNA stability and act cooperatively to achieve LDH A mRNA stability regulation.
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PMID:Lactate dehydrogenase A subunit messenger RNA stability is synergistically regulated via the protein kinase A and C signal transduction pathways. 747 96


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