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)

Cells of the immune system produce biologically active adrenocorticotropic hormone (ACTH). Many laboratories, however, have been unable to replicate experiments which demonstrate ACTH in immune cells. Sensitive immunohistochemical staining and digital scanning, confocal microscopy were used to study regulation of ACTH-like immunoreactivity (ACTH-IR) in human mononuclear cells. Cytoplasmic ACTH-IR was induced by corticotrophin releasing factor (CRF)/arginine vasopressin (AVP), and also by protein kinase C (PKC) activation and by the interferon (IFN-alpha beta inducer, Na-polyinosinic-polycytidylic acid (polyIC). Induction of cytoplasmic ACTH-IR was maximal within 6 hr of stimulation with CRF/AVP or phorbol myristate acetate (PMA). Recombinant human interleukin-1 beta (rhIL-1 beta) was also stimulatory, but rhIL-1 alpha had minimal effect. Regulation of ACTH-IR production in immune cells parallels the regulation of ACTH in the anterior pituitary, and ACTH-like material may affect immune responses.
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PMID:Regulation of production of adrenocorticotropin-like proteins in human mononuclear cells. 133 62

The effect of several chemically related chloride channel blocking drugs was investigated on the adrenocorticotropic hormone (ACTH) secretory process in mouse clonal AtT-20 corticotrophs. When cells were simultaneously exposed to diphenylamine-2-carboxylate (DPC) or related substances (Hoechst compounds 131, 143, and 144) and the adenylate cyclase activator forskolin, ACTH secretion was inhibited by 76-95% [half-maximal inhibitory concentration (IC50) 450, 15, 84, and 32 microM, respectively]. All four compounds also blocked forskolin-stimulated adenosine 3',5'-cyclic monophosphate (cAMP) synthesis in AtT-20 cells by 51-87% (IC50 190, 29, 100, and 130 microM for DPC and compounds 131, 143, and 144, respectively). Pertussis toxin pretreatment of cells caused a partial reversal of DPC-inhibited forskolin-stimulated cAMP formation. The toxin had no effect on inhibition of forskolin-stimulated ACTH secretion by DPC. Secretion of ACTH in response to cAMP-independent stimulants such as the protein kinase C activator 12-O-tetradecanoylphorbol-13-acetate or the calcium channel agonist BAY K 8644 were blocked by compound 131 as was the secretory response to 8-bromoadenosine 3',5'-cyclic monophosphate. These results suggest that phenylanthranilic acids have adenylate cyclase inhibiting action but that the postcyclase activity is more relevant to the ability of these compounds to block ACTH secretion. DPC also blocked 125I efflux (an index of Cl- secretion) from AtT-20 cells. Because an increase in osmotic strength of the culture media reduced forskolin-stimulated ACTH secretion, these data suggest that DPC and related compounds may negatively modulate chloride-dependent osmotically driven ACTH secretion from AtT-20 cells.
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PMID:Chloride channel blockers inhibit ACTH secretion from mouse pituitary tumor cells. 170 5

In AtT-20 cells somatostatin inhibits the secretion of adrenocorticotropic hormone (ACTH) through the activation of GTP binding proteins (G proteins) linked to second messengers such as calcium and cyclic AMP (cAMP). Recently, it has been proposed that there may be G proteins that regulate directly the exocytotic machinery. We have investigated whether somatostatin could inhibit secretion at a step distal to second messengers through a GTP binding protein. For these studies two experimental paradigms were used: (1) intact cells stimulated by calcium ionophores and (2) digitonin-permeabilized cells exposed to buffers of increasing Ca2+ concentrations. Somatostatin inhibited by 70% the ACTH release caused by the calcium ionophore ionomycin without modifying the ionophore-induced elevation in cytosolic [Ca2+]. This effect was cAMP independent because (1) it was observed in the presence of high concentrations of membrane-permeant cAMP analogues, and (2) it was not accompanied by a change in cAMP levels. The effect was also independent of the levels of activators of protein kinase C because it could be produced in the presence of high concentrations of phorbol esters. The action of somatostatin was prevented by pertussis toxin. In digitonin-permeabilized AtT-20 cells somatostatin inhibited release induced by calcium buffers in a GTP-dependent manner. These two observations indicate the involvement of a G protein. It is proposed that a G protein coupled to somatostatin receptors inhibits the intracellular machinery of secretion at a step distal to second messengers, perhaps at the exocytotic site.
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PMID:Evidence that receptor-linked G protein inhibits exocytosis by a post-second-messenger mechanism in AtT-20 cells. 196 44

Cells of the Y-1 corticoadrenal line are: (a) functional, (b) cell cycle-arrested by adrenocorticotropic hormone (ACTH), (c) tumorigenic, and (d) c-Ki-ras overexpressing. We here report that the phorbol ester phorbol 12-myristate 13-acetate (PMA) mimics all ACTH-specific effects in Y-1 cells, namely: (a) steroid-ogenesis stimulation, (b) cell cycle block, and (c) cell shape change. In addition, both ACTH and PMA caused a rapid and transient induction of the c-fos proto-oncogene while having no effect on c-Ki-ras mRNA steady state levels. Dibutyryl cAMP, known to elicit ACTH effects in Y-1 cells, was a poor inducer of the c-fos gene. PMA pretreatment rendered Y-1 cells unresponsive to ACTH. These results suggest that protein kinase C is likely to be involved in the mechanisms of action of ACTH.
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PMID:Phorbol ester mimics ACTH action in corticoadrenal cells stimulating steroidogenesis, blocking cell cycle, changing cell shape, and inducing c-fos proto-oncogene expression. 215 81

Previous work has shown that corticotropin releasing factor, vasoactive intestinal peptide, phorbol ester, and forskolin cause the secretion of adrenocorticotropic hormone and beta-endorphin from the AtT-20 mouse pituitary cell line. Human recombinant interleukin 1 alpha and 1 beta also stimulated adrenocorticotropic hormone and beta-endorphin secretion from AtT-20 cells in a time- and dose-related manner. The effect appeared only after pretreatment with interleukin 1 (IL-1) for at least 18 hr and was maximum at 24 hr. After pretreatment of the cells over a period of time with IL-1, the secretion induced by corticotropin releasing factor and vasoactive intestinal peptide was increased in more than an additive manner. The enhancement of corticotropin releasing factor-induced beta-endorphin release produced by IL-1 was apparent after 12 hr and reached a maximum at 24 hr. IL-1 did not affect forskolin-induced cAMP generation but enhanced the effect of forskolin on beta-endorphin secretion. This suggests that IL-1 does not induce adenylate cyclase and that forskolin causes the secretion of beta-endorphin by a mechanism independent of cAMP. IL-1 enhanced phorbol ester-induced beta-endorphin secretion. After prolonged treatment with phorbol ester (an activator of protein kinase C), the secretion induced by phorbol ester was abolished as well as the enhancement induced by IL-1. However, prolonged treatment with phorbol ester had no effect on IL-1-induced beta-endorphin secretion. These observations suggest that IL-1 enhances peptide-generated secretion of beta-endorphin by inducing protein kinase C.
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PMID:Interleukin 1 potentiates the secretion of beta-endorphin induced by secretagogues in a mouse pituitary cell line (AtT-20). 253 29

Proteins in lacrimal gland fluid are secreted primarily by the acinar cells. Secretory proteins are synthesized in the endoplasmic reticulum, modified in the Golgi apparatus, stored in secretory granules, and released upon a change in the cellular level of second messenger. The second messenger level is controlled by a process termed signal transduction. Agonists, primarily neurotransmitters in the lacrimal gland, bind to receptors in the basolateral membrane of secretory cells. This interaction activates enzymes in the membrane that cause production of second messengers. It has been hypothesized that second messengers stimulate secretion by activating specific protein kinases to phosphorylate proteins important for secretion. In the lacrimal gland, cholinergic agonists stimulate protein secretion. They act by activating phospholipase C to break down phosphatidylinositol bisphosphate into 1,4,5-inositol trisphosphate (1,4,5-IP3) and diacylglycerol (DAG). 1,4,5-IP3 causes release of Ca2+ from intracellular stores. This Ca2+, perhaps in conjunction with calmodulin, activates specific protein kinases that may be involved in secretion. DAG activates protein kinase C which stimulates protein secretion. alpha 1-Adrenergic agonists also stimulate lacrimal gland protein secretion. These agonists use a pathway that is separate from that utilized by cholinergic agonists and vasoactive intestinal peptide (VIP). The specific pathway has not been identified but may be DAG and protein kinase C. VIP, beta-adrenergic agonists, alpha-melanocyte stimulating hormone, and adrenocorticotropic hormone are lacrimal gland secretagogues. They activate adenylate cyclase to produce cAMP. cAMP stimulates protein kinase A, which perhaps causes protein secretion. Thus, three separate cellular pathways stimulate lacrimal gland protein secretion. Cholinergic agonists and VIP also stimulate lacrimal gland fluid secretion, and the same signal transduction pathways utilized by these agonists to stimulate protein secretion are most likely used for electrolyte and water secretion.
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PMID:Signal transduction and control of lacrimal gland protein secretion: a review. 254 11

1,2-Dioleoyl-rac-glycerol, a potent activator of protein kinase C, was found to enhance the growth-inhibitory effect of triamcinolone acetonide on L5178Y lymphoblasts in adrenalectomized, male DBA/2 mice. On the other hand, in mice without adrenalectomy, it markedly inhibited tumor growth without increasing the plasma level of corticosterone or adrenocorticotropic hormone or reducing the body weight. These results suggest that diacylglycerol enhances the action of endogenous glucocorticoid to a sufficient level to inhibit the growth of lymphoblasts. Of various diacylglycerols with different carbon chain lengths tested, 1,2-dioleoyl-rac-glycerol was the most potent growth inhibitor and was maximally effective at a dose of above 30 micrograms/100 g body weight. This finding suggests that diacylglycerols may be useful for enhancing the antitumor effect of a low dose of glucocorticoid or endogenous glucocorticoid on lymphoblasts without any significant side effect.
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PMID:Diacylglycerols enhance the anti-tumor effect of glucocorticoid on L5178Y lymphoblasts in vivo. 255 70

In this paper we provide evidence to show that the pathways by which adrenocorticotropic hormone (ACTH) and angiotensin II (AII) stimulate steroidogenesis in bovine fasciculata cells are only partially independent. Both hormones have the same intrinsic activity but a 500-fold higher dose of AII is required to achieve 50% stimulation of steroidogenesis. Whereas ACTH acts by way of cAMP, AII appears to operate through protein kinase C. The phorbol ester, 12-O-tetradecanoylphorbol-13 acetate (TPA), and the calcium ionophore, A23187, each stimulate steroidogenesis and, when added together, act synergistically. To test the relationship between the ACTH and AII pathways, we added the two hormones simultaneously and measured steroid production. When the hormones were present at submaximal concentrations, their effects were additive. At maximal doses, steroid production was 40% above that elicited by either hormone alone. In contrast to the action of AII in the glomerulosa cell where it inhibits ACTH-stimulated cAMP formation, AII causes no inhibition in the fasciculata. Cycloheximide inhibits steroidogenesis stimulated by AII or a mixture of TPA and A23187. Scatchard analysis of the binding of 125I-AII to particulates from adrenal cortical fasciculata indicates the presence of a single class of binding sites (Kd = 0.6 X 10(-8) M). Binding is not inhibited by ACTH. Biotin-containing AII analogs that bind specifically to the particulates have been evaluated as potential tools for avidin-biotin affinity chromatography of the receptor. One of these, [N epsilon-6-(biotinylamido)hexyllys1, Val5] AII, is a promising candidate for receptor isolation.
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PMID:Angiotensin stimulation of adrenal fasciculata cells. 284 22

Previous studies have shown that phorbol esters and lithium each stimulate the secretion of adrenocorticotropic hormone (ACTH) by the anterior pituitary tumor cell line AtT20/D16-16. Pretreatment with either lithium or phorbol ester desensitizes the cells to subsequent stimulation by phorbol ester. An early consequence of phorbol ester action in other systems is the translocation of protein kinase C from cytosol to membranes. We have assayed protein kinase C activity in cytosol and membranes of AtT20 cells after treatment with phorbol dibutyrate, lithium, or other agents that stimulate secretion of ACTH in these cells. Phorbol dibutyrate clearly induced translocation of protein kinase C, but lithium treatment did not cause translocation itself, nor did pretreatment with lithium affect the translocation induced by phorbol dibutyrate. These results are consistent with a role for translocation of protein kinase C in the stimulatory and desensitizing effects of phorbol esters but fail to implicate translocation in the actions of lithium on AtT20 cells.
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PMID:Translocation of protein kinase C in anterior pituitary tumor cells. 302 60

Human melanocytes, maintained on bovine corneal endothelium-derived extracellular matrix for at least 4 days in the absence of phorbol 12-myristate 13-acetate (PMA) and cholera toxin (CT), displayed increased tyrosinase activity when exposed to several pro-opiomelanocortin-derived (POMC) peptides. Melanocytes from 9 of 14 donors showed significantly increased tyrosinase activity after treatment with adrenocorticotropic hormone (ACTH; mean increase 320 +/- 107 (S.E.M.)% of control, P < 0.005), while melanocytes from 8 of 13 donors increased tyrosinase in the presence of diacetyl-melanocyte stimulating hormone (di-MSH; mean increase 223 +/- 31 (S.E.M.)% of control, P < 0.005). Maximal increases in tyrosinase were seen after treatment with 10(-10) M ACTH and with 10(-6) M di-MSH. In two cell cultures which showed tyrosinase stimulation, melanin synthesis was similarly increased in the presence of added POMC peptides. PMA but not CT increased tyrosinase activity in melanocytes cultured under these conditions. In the presence of staurosporine, an inhibitor of protein kinase C (PKC), the magnitude of the increase in tyrosinase due to PMA, ACTH and di-MSH was significantly reduced. These results indicate that tyrosinase activity in melanocytes from most human donors, under appropriate conditions, is susceptible to the stimulatory effects of POMC peptides, that ACTH is considerably more potent than di-MSH in this test system and that in human cells the PKC pathway may be important in modulating melanogenesis.
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PMID:Stimulation of tyrosinase in human melanocytes by pro-opiomelanocortin-derived peptides. 759 39


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