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)

This study was undertaken to determine the involvement of arachidonic acid and protein kinase C in the actions of luteinizing hormone-releasing hormone on steroid and prostaglandin formation in the ovary. In primary culture of rat granulosa cells, treatment with 3 x 10(-7) mol/L melittin stimulates progesterone and prostaglandin E2 accumulation after a 5-hour culture period. Concomitant treatment of the cells with melittin and luteinizing hormone-releasing hormone or 12-0-tetradecanoylphorbol 13-acetate further enhances the stimulatory action of either luteinizing hormone-releasing hormone or 12-0-tetradecanoylphorbol 13-acetate by itself on prostaglandin E2 production. In contrast, no synergistic effects are observed on progesterone production by the same treatments. Treatment with luteinizing hormone-releasing hormone for 24 hours significantly decreases follicle-stimulating hormone-induced progesterone production by approximately 50%. Treatment of the cells with either follicle-stimulating hormone or luteinizing hormone-releasing hormone stimulates prostaglandin E2 production at least tenfold in the same cultures. When follicle-stimulating hormone and luteinizing hormone-releasing hormone are present concomitantly, they synergistically enhance prostaglandin E2 formation (p less than 0.01). Similar effects are observed with the phorbol ester, 12-0-tetradecanoylphorbol 13-acetate, which causes a dose-dependent inhibition of progesterone production by follicle-stimulating hormone whereas follicle-stimulating hormone-stimulated prostaglandin E2 formation is enhanced. Thus luteinizing hormone-releasing hormone-induced activation of protein kinase C may play multiple roles (stimulatory or inhibitory) in hormone production in the ovary.
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PMID:Differential role of protein kinase C in the action of luteinizing hormone-releasing hormone on hormone production in rat ovarian cells. 249 5

The effect of insulin and its interaction with intracellular messenger systems on in vitro inhibin production by adult rat isolated seminiferous tubules has been investigated using a recently developed inhibin radioimmunoassay (RIA). Seminiferous tubule segments (5 cm) from intact adult rats were exposed to insulin (0.05-5000 ng/ml) for 2 days of culture. Insulin caused a dose-dependent inhibition of basal inhibin secretion with reversal of this inhibition at very high doses (5000 ng/ml). The ability of follicle-stimulating hormone (FSH) to induce inhibin secretion was also inhibited by insulin (50 ng/ml). Insulin reduced the stimulation of inhibin production by dibutyryl cyclic AMP (dbcAMP) and this effect was prevented by the addition of theophylline (0.4 mM), while theophylline alone was unable to prevent the effect of insulin on basal inhibin secretion. Phorbol 12-myristate 13-acetate (PMA) mimicked the effect of insulin reducing basal and FSH-induced secretion of inhibin. No additive effects on basal inhibin secretion were observed with a combination of PMA and insulin. Ethylenediaminetetraacetic acid (EDTA, 2 mM) significantly reduced basal and FSH-induced inhibin production, while the combined effects of EDTA and insulin on basal and FSH-induced inhibin production were additive. These data demonstrate an inhibitory effect of insulin on inhibin production by isolated seminiferous tubules mediated via at least two mechanisms namely the inhibition of the cAMP-protein kinase A system and stimulation of protein kinase C activity.
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PMID:The effect of insulin on inhibin production in isolated seminiferous tubule segments from adult rats cultured in vitro. 253 42

Two major signal transduction systems operate within ovarian cells to control their function. Gonadotropins, such as follicle-stimulating hormone and luteinizing hormone, primarily utilize the cyclic adenosine 3',5'-monophosphate (cAMP) pathway to stimulate steroid hormone biosynthesis. On the other hand, an inositol lipid metabolism pathway is used by other effector molecules such as gonadotropin-releasing hormone or prostaglandin F2 alpha, as well as gonadotropins, to alter ovarian hormone production. Membrane polyphosphoinositides are hydrolyzed to inositol phosphates and diacylglycerol, resulting in alterations of intracellular free calcium concentration, activation of protein kinase C, and liberation of arachidonic acid. Some or all of these intracellular messengers may interact with the gonadotropin-induced cAMP pathway to control ovarian function.
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PMID:The role of inositol lipid metabolism in the ovary. 254 14

The initial step in the signal transduction of luteinizing hormone-releasing hormone (LHRH) in rat ovarian cells is the hydrolysis of membrane polyphosphoinositides into inositol phosphates and 1,2-diacylglycerol. The former compounds, especially inositol 1,4,5-triphosphate, are known to cause the release of calcium from intracellular stores, while diacylglycerol is a potent activator of protein kinase C. LHRH causes a rapid and transient increase in intracellular concentrations of free calcium ions, by approximately 4.5-fold, in the majority of granulosa cells as assessed by fura-2 microspectrofluorimetry. Like LHRH, a calcium ionophore (A23187) and activators of protein kinase C attenuate the steroidogenic response of the cells to follicle-stimulating hormone, but enhance the formation of gonadotropin-induced prostaglandin formation. These results support the concept that stimulation of polyphosphoinositide hydrolysis is intimately involved in the direct action of LHRH at the level of the ovary.
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PMID:Mechanism of action of luteinizing hormone-releasing hormone in rat ovarian cells. 268 58

In this study we examined the effects of A23187 (a calcium ionophore) and 12-O-tetradecanoyl phorbol-13-acetate, a known activator of protein kinase C, on progesterone production. Granulosa cells obtained from pregnant mare serum gonadotropin-primed rats were maintained in primary culture. Treatment with follicle-stimulating hormone (0.5 microgram/ml), 8-bromo-adenosine-3',5'-cyclic monophosphate (2 mmol/L), or cholera toxin (0.1 microgram/ml) for 5 hours or 24 hours markedly stimulated progesterone production. The concomitant presence of A23187 attenuated the elevated levels of progesterone induced by follicle-stimulating hormone, 8-bromo-adenosine-3',5'-cyclic monophosphate, or cholera toxin, with or without the presence of a phosphodiesterase inhibitor, 1-methyl-3-isobutylxanthine (0.2 mmol/L). Likewise, treatment of the cells with 12-O-tetradecanoyl phorbol-13-acetate suppressed follicle-stimulating hormone-induced progesterone production, whether or not 1-methyl-3-isobutylxanthine was present in the cultures. The effect of 12-O-tetradecanoyl phorbol-13-acetate was not mimicked by phorbol-13-monoacetate or 4 alpha-phorbol-12, 13-didecanoate. These results indicate that both A23187 and 12-O-tetradecanoyl phorbol-13-acetate inhibit follicle-stimulating hormone-induced progesterone production, in part at a step or steps beyond adenosine-3',5'-cyclic monophosphate generation and degradation. They further support a role of calcium and protein kinase C in the intraovarian action of luteinizing hormone-releasing hormone.
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PMID:Inhibition of follicle-stimulating hormone- and adenosine-3',5'-cyclic monophosphate-induced progesterone production by calcium and protein kinase C in the rat ovary. 282 29

Interactions between signal transducing systems may be important in the integrated control of cellular processes in basal and hormonally regulated cells. The swine granulosa cell provides a model to study the interactions between the cAMP and calcium-lipid-dependent signaling pathways. To this end, porcine granulosa cells were incubated in monolayer culture for 1-4 days in the presence of FSH (200 ng/ml), forskolin (85 microM), or cholera toxin (3 micrograms/ml) with or without an activator of protein kinase C, the phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA) (30 ng/ml). TPA had little effect on basal cAMP generation (1-4 days) or on follicle-stimulating hormone (FSH)-stimulated cAMP formation during the first 24 h. Phorbol ester did inhibit cAMP formation on day 2 (by approximately 25%), on day 3 (by approximately 70%) and on day 4 (by greater than 80%). Forskolin-mediated cAMP generation was inhibited (33-56%) on days 1-4, respectively. TPA suppressed dose-dependent FSH (3-300 ng/ml)-stimulated cAMP production on day 2, virtually abolished FSH-provoked cAMP formation on day 4 and inhibited dose-dependent forskolin-stimulated cAMP production on both days. TPA had no effect on the half-maximally effective dose, ED50, of FSH-stimulated cAMP production but did decrease the ED50 of forskolin and the maximal stimulatory effect of FSH and forskolin on days 2 and 4. Similar effects were observed with the synthetic diacylglycerols DOG (1,2-dioctanoylglycerol) and OAG (1-oleoyl-2-acetylglycerol). The TPA effect was limited to the mammalian adenylate cyclase as it had no effect on bacterially derived adenylate cyclase from Bordetella pertussis.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Interactions of protein kinase C with receptor- and non-receptor-mediated cyclic AMP generation in swine granulosa cells. 284 82

The effect of tetradecanoylphorbol acetate (TPA) on follicle-stimulating hormone (FSH)-induced synthesis of the cholesterol side-chain cleavage (SCC) enzyme complex was studied in rat ovarian granulosa cells cultured for 48 h in serum-free medium. Cell proteins were radiolabeled with [35S]methionine, followed by immunoprecipitation of cholesterol side-chain cleavage cytochrome P-450 (P-450SCC) as well as the iron-sulfur protein adrenodoxin. Polyacrylamide gel electrophoresis and fluorography of the immunoprecipitates showed that TPA, when added in combination with FSH (50 ng/ml) or dibutyryl cAMP (Bt2cAMP; 1 mM), suppressed the stimulatory effects of these compounds on the synthesis of the SCC components in a concentration-dependent fashion. The effect of TPA was accompanied by decreased progesterone formation and decreased cAMP accumulation. The structural analog of TPA, phorbol-4 alpha-didecanoate, which does not activate protein kinase C (Ca2+/phospholipid-dependent enzyme), had no effect on the FSH- or Bt2cAMP-stimulated synthesis of SCC and progesterone or on cAMP formation. In addition to inhibiting the synthesis of these proteins, TPA greatly reduced the FSH- and Bt2cAMP-induced increase in levels of mRNA encoding the precursor form of P-450SCC. It is concluded that the effect of the phorbol ester TPA to inhibit FSH-stimulated progesterone formation in cultured ovarian granulosa cells of the rat involves decreased synthesis of the components of the SCC enzyme complex due to reduced levels of mRNA encoding the precursor forms of these proteins. The results are indicative that TPA not only inhibits FSH-mediated stimulation of cAMP formation but also may block cAMP-mediated induction of SCC synthesis. It is postulated that the effects of TPA may reflect the physiological role of protein kinase C in the regulation of ovarian steroidogenesis.
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PMID:Tetradecanoyl phorbol acetate suppresses follicle-stimulating hormone-induced synthesis of the cholesterol side-chain cleavage enzyme complex in rat ovarian granulosa cells. 288 36

The induction of granulosa cell differentiation by follicle-stimulating hormone (FSH) is characterized by cellular aggregation, expression of luteinizing hormone (LH) receptors, and biosynthesis of steroidogenic enzymes. These actions of FSH are mediated by activation of adenylate cyclase and cAMP-dependent protein kinase and can be mimicked by choleragen, forskolin, and cAMP analogs. Gonadotropin releasing hormone (GnRH) agonists inhibit these maturation responses in a calcium-dependent manner and promote phosphoinositide turnover. The phorbol ester phorbol 12-myristate 13-acetate (PMA) also prevented FSH-induced cell aggregation and suppressed cAMP formation, LH receptor expression, and progesterone production, with an ID50 of 0.2 nM. In FSH-treated cells, PMA did not reduce the initial increase in cAMP formation during the first 24 hr of culture but prevented its secondary increase from 24 to 48 hr. PMA also inhibited LH receptor induction by cholera toxin, forskolin, and 8-bromo-cAMP, but it did not impair cAMP responses to the former two agents, indicating that the site of action of the phorbol ester is distal to adenylate cyclase. The early stimulation of cAMP-dependent protein kinase activity by FSH was also unaffected by PMA, consistent with its lack of effect on the initial cAMP response to FSH. However, PMA caused a marked decrease in cytosolic protein kinase C activity within 1 min of its addition to the cells. The permeant diacylglycerols, 1-oleoyl-2-acetoyl-sn-glycerol and sn-1,2-dioctanoyl glycerol, also inhibited LH receptor formation, while the nonpermeant diacylglycerol, diolein, was inactive. These results indicate that in situ activation of protein kinase C by PMA or permeant diacylglycerols inhibits cAMP-dependent granulosa cell differentiation, and suggest that the inhibitory actions of GnRH agonists on granulosa cell maturation are also mediated by protein kinase C.
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PMID:Inhibition of gonadotropin-induced granulosa cell differentiation by activation of protein kinase C. 300 7

Hormonal induction of granulosa cell maturation is inhibited by phorbol esters and permeant synthetic diacylglycerols, but these activators of protein kinase C differ in their effects on cAMP production and actions. Both agents prevented the induction of luteinizing hormone receptors and progesterone biosynthesis by follicle-stimulating hormone, choleragen, and forskolin, but only diacylglycerol abolished the cAMP responses to these stimuli. Granulosa cell aggregation and aromatase activity were inhibited by phorbol ester but not completely by diacylglycerol. In intact granulosa cells, cytosolic C kinase activity was rapidly decreased by phorbol ester but unaffected by diacylglycerol. Although diacylglycerol has a marked inhibitory action on cAMP production, the more prominent suppression of granulosa cell differentiation by phorbol ester may be related to its rapid and prolonged action on kinase C.
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PMID:Differential actions of phorbol ester and diacylglycerol on inhibition of granulosa cell maturation. 300 44

The link between the biochemical and morphological differentiation of granulosa cells was studied by investigating the organization and the expression of cytoskeletal proteins which determine cell shape and contacts. In cells treated with follicle-stimulating hormone (FSH), in a serum- and growth factor-free medium, or with other compounds which elevate cellular cAMP levels, the synthesis of the adherens junction proteins, vinculin, alpha-actinin, and actin was reduced significantly when compared to unstimulated cells (7-fold for vinculin, 5-fold for alpha-actinin, and 3-fold for actin). The in vitro translatability of the mRNAs coding for these proteins and the level of actin mRNA determined by RNA blot hybridization were generally reduced in differentiating cells. The synthesis and the organization of vimentin and tubulin was unaffected during this process, whereas the organization of actin and vinculin was dramatically affected, with FSH-treated cells displaying a diffuse pattern of actin and vinculin, with very little vinculin in adhesion plaques. Gonadotropin-releasing hormone agonist and the phorbol ester 12-O-tetradecanoylphorbol-13-acetate which are known to antagonize the cAMP-mediated biochemical differentiation of granulosa cells by reducing cAMP levels or by activating protein kinase C and phospholipid turnover, blocked to a large extent the FSH-induced effect on the adherens junction proteins. Epidermal growth factor, which blocked the FSH-induced cAMP increase, but not the FSH-induced progesterone production, failed to block the synthesis of vinculin, alpha-actinin, and actin. Cytochalasin B could induce steroidogenesis and similar changes in the synthesis of these cytoskeletal proteins, whereas fibronectin, which causes cell spreading, blocked in part the FSH-induced effect on the expression of cytoskeletal proteins. The modulation of cytoskeletal proteins may therefore be an essential feature of programmed differentiation events leading to the final phenotype of granulosa cells.
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PMID:In vitro regulation of granulosa cell differentiation. Involvement of cytoskeletal protein expression. 310 32


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