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)

Tetradecanoyl phorbol acetate (TPA) stimulates growth hormone (GH) and prolactin secretion from ovine anterior pituitary cells. Pretreatment of the cells with TPA abolishes this effect, presumably due to down-regulation of protein kinase C. Such pretreatment did not alter effects of thyrotropin-releasing hormone or dopamine on prolactin secretion, suggesting no involvement of protein kinase C. Pretreatment with TPA attenuated actions of GH-releasing hormone on GH release (but not actions on cyclic AMP levels), possibly due to depletion of cellular stores of GH. Such pretreatment also attenuated inhibition of GH release by somatostatin, possibly due to phosphorylation of receptors or associated proteins by protein kinase C.
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PMID:Effects of pretreatment with tetradecanoyl phorbol acetate on regulation of growth hormone and prolactin secretion from ovine anterior pituitary cells. 254 31

Specific aspects of the prolactin stimulation of RNA, DNA and protein synthesis in the Nb2 node lymphoma cell line were determined. In time sequence studies the onset of the prolactin stimulation of the incorporation of radiolabeled precursors into these macromolecules was found to be 0.5-1 h for [3H]uridine incorporation into RNA, 1-2 h for [3H]leucine incorporation into protein, and 4-8 h for [3H]thymidine incorporation into DNA. The total DNA content of the cell cultures was increased by 12-18 hours after addition of prolactin. Amiloride, an inhibitor of the plasma-membrane-bound Na+/H+ antiporter, was found to inhibit the mitogenic effects of prolactin. Amiloride was also found to inhibit the prolactin stimulation of DNA, RNA and protein synthesis, thus suggesting that the initial regulation of the Na+/H+ antiporter may initiate these responses as well as the mitogenic effect of prolactin. In contrast, H-7, a drug which inhibits protein kinase C, had no effect on the magnitude of the prolactin stimulation of DNA, RNA or protein synthesis at a drug concentration (100 muM) that abolished the mitogenic effect of prolactin. The early effects of prolactin on RNA, DNA and protein synthesis would therefore appear not to involve an activation of protein kinase C.
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PMID:Studies on the mechanism by which prolactin regulates protein, RNA, and DNA synthesis in Nb2 node lymphoma cells. 255 10

The phorbol ester 12-O-tetradecanoyl-phorbol 13-acetate (TPA) and thyroliberin exerted additive stimulatory effects on prolactin release and synthesis in rat adenoma GH4C1 pituicytes in culture. Both TPA and thyroliberin activated the adenylate cyclase in broken cell membranes. When combined, the secretagogues displayed additive effects. TPA did not alter the time course (time lag) of adenylate cyclase activation by hormones, guanosine 5'-[beta,gamma-imino]triphosphate or forskolin, nor did it affect the enzyme's apparent affinity (basal, 7.2 mM; thyroliberin-enhanced, 2.2 mM) for free Mg2+. The TPA-mediated adenylate cyclase activation was entirely dependent on exogenously added guanosine triphosphate. ED50 (dose yielding half-maximal activation) was 60 microM. Access to free Ca2+ was necessary to express TPA activation of the enzyme, however, the presence of calmodulin was not mandatory. TPA-stimulated adenylate cyclase activity was abolished by the biologically inactive phorbol ester, 4 alpha-phorbol didecanoate, by the protein kinase C inhibitor polymyxin B and by pertussis toxin, while thyroliberin-sensitive adenylate cyclase remained unaffected. Experimental conditions known to translocate protein kinase C to the plasma membrane and without inducing adenylate cyclase desensitization, increased both basal and thyroliberin-stimulated enzyme activities, while absolute TPA-enhanced adenylate cyclase was maintained. Association of extracted GTP-binding inhibitory protein, Gi, from S49 cyc- murine lymphoma cells with GH4C1 cell membranes yielded a reduction of basal and hormone-stimulated adenylate cyclase activities, while net inhibition of the cyclase of somatostatin was dramatically enhanced. However, TPA restored completely basal and hormone-elicited adenylate cyclase activities in the Gi-enriched membranes. Finally, TPA completely abolished the somatostatin-induced inhibition of adenylate cyclase in both hybrid and non-hybrid membranes. These data suggest that, in GH4C1 cells, protein kinase C stimulation by phorbol esters completely inactivates the n alpha i subunit of the inhibitory GTP-binding protein, leaving the n beta subunit functionally intact. It can also be inferred that thyroliberin conveys its main effect on the adenylate cyclase through activation of the stimulatory GTP-binding protein, Gs.
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PMID:Protein kinase C stimulates adenylate cyclase activity in prolactin-secreting rat adenoma (GH4C1) pituicytes by inactivating the inhibitory GTP-binding protein Gi. 256 96

Ca2+ is a major regulator of exocytosis in secretory cells, however, the biochemical mechanisms underlying regulation remain to be identified. To render the secretory apparatus accessible for biochemical studies, we have developed a cell permeabilization method (cell cracking) which utilizes mechanical shear. GH3 pituitary cells subjected to cracking were permeable to macromolecules but retained a normal cytoplasmic ultrastructure including secretory granules. Incubation of the permeable cells at 30-37 degrees C with 0.1-1.0 microM Ca2+ and millimolar MgATP resulted in the release of the secretory proteins, prolactin (PRL) and a proteoglycan, but not lysosomal enzymes. Extensively washed permeable cells were incapable of releasing PRL in response to Ca2+ and MgATP addition. However, addition of cytosol was found to restore Ca2+-activated, MgATP-dependent PRL release. The cytosolic factor responsible for activity was thermolabile and protease sensitive. The protein was partially purified, and its molecular mass was estimated to be equivalent to that of a globular protein of 200-350 kDa by molecular sieve chromatography. Inhibitors of calmodulin or protein kinase C (trifluroperazine, calmidazolium, H-7) failed to inhibit Ca2+-activated PRL release, and the required cytosolic protein could not be replaced by purified calmodulin, calmodulin-dependent protein kinase II, protein kinase C, or calpactin I. Further purification and characterization of the cytosolic protein should reveal the nature of biochemical events involved in regulated secretory exocytosis.
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PMID:A new method for cell permeabilization reveals a cytosolic protein requirement for Ca2+ -activated secretion in GH3 pituitary cells. 272 69

Recently, the protein kinase C (PKC) activator 12-O-tetradecanoylphorbol 13-acetate (TPA) was found to have prolactin (PRL)-like actions on specific metabolic processes in mouse mammary gland explants. Since TPA is known to stimulate PKC, these observations suggest that PKC may have a role in the PRL stimulation of lactogenic processes. The present studies provide further evidence for this by demonstrating a transient, time-dependent translocation of PKC to the particulate fraction in response to PRL. Particulate-associated PKC reached a maximum between 15-30 min and returned to control values within 1-2 h after PRL treatment. PRL treatment for 16 h also induced a down-regulation of total cellular PKC. Inhibition of PKC function, either by a 30 h pretreatment with TPA (PKC down-regulation) or 2 h with 1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride (H7), resulted in an attenuation of PRL-stimulated effects on ornithine decarboxylase activity and synthesis of RNA, caseins, and lipids.
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PMID:Role of protein kinase C in the prolactin-induced responses in mouse mammary gland explants. 275 24

These studies provide further support for the thesis that the activation of protein kinase C is likely involved in the prolactin (PRL) stimulation of mitogenesis in the Nb2 node lymphoma cell line. The diterpene mezerein is shown to potentiate the mitogenic effect of PRL at a hormone concentration which elicits a less than maximum response. A similar response was observed with two diglycerides, diolein and dicaprin. Neither mezerein nor the diglycerides affected the magnitude of response to a maximum stimulatory concentration of PRL.
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PMID:Effects of mezerein and diglycerides on the PRL stimulation of cell replication in Nb2 node lymphoma cells. 279 38

The results of several recent studies have indicated that protein kinase C (PKC) may be involved in the prolactin (PRL) stimulation of mitogenesis in the Nb2 node lymphoma cell line. The PKC activator 12-O-tetradeconylphorbol-13-acetate (TPA) at certain concentrations has been shown to potentiate the mitogenic effect of PRL, whereas at higher concentrations, TPA inhibits the PRL response. Several inhibitors of PKC have also been shown to impair the PRL stimulation of metabolic process in the Nb2 cells. These studies provide further evidence for the likely involvement of PKC in the PRL stimulation of mitogenesis in the Nb2 cells. A transient, time-dependent accumulation of PKC in the particulate fraction of the Nb2 cells is observed in response to PRL. TPA is also shown to elicit a similar effect, albeit at a much earlier time and with a greater magnitude. On long-term exposure (3 days), high concentrations of TPA down-regulate the PKC enzyme; this down-regulation likely accounts for the inhibitory effect of high concentrations of TPA on the PRL stimulation of cell division. In further studies, the PKC inhibitors H-7 and gossypol were shown to inhibit the PRL stimulation of cell division in a concentration-dependent fashion.
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PMID:Studies on the possible role of protein kinase C in the prolactin regulation of cell replication in Nb2 node lymphoma cells. 281 43

Phorbol myristate acetate (PMA) stimulates pituitary hormone release by activating protein kinase C (PKC). By doing so, PMA mimics the diacylglycerol (DAG) produced by the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2). The present study demonstrates that PMA and DAG augment prolactin release and attenuate the elevations of inositol phosphates (IPX) elicited by thyrotropin-releasing hormone (TRH), angiotensin II, neurotensin, bombesin and gonadotropin-releasing hormone (GnRH) in normal anterior pituitary and prolactin-secreting 7315a tumor cells. 4 alpha-Phorbol 12,13-didecanoate (PDD), an inactive analog of PMA, was found to have no effect on IPX levels; the PKC inhibitor H-7 attenuated the PMA-related inhibition of TRH-induced IPX. To examine whether PMA attenuates IPX generation or increases IPX metabolism, the effects of PMA on the levels of inositol phosphates and phosphoinositides were determined. TRH increased inositol trisphosphate, inositol bisphosphate and inositol monophosphate, and decreased PIP2 and phosphatidylinositol 4-phosphate levels. PMA had no effect on basal phosphoinositide or inositol phosphate levels, but attenuated the effects of TRH on these parameters. Thus PMA and DAG, by a mechanism involving PKC-mediated attenuation of secretagogue-induced hydrolysis of PIP2, decreases IPX production, and therefore PKC activation may exert negative feedback regulation on anterior pituitary secretory activity.
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PMID:Attenuation of pituitary polyphosphoinositide metabolism by protein kinase C activation. 282 75

Receptor-mediated regulation of prolactin synthesis by 1,25-dihydroxycholecalciferol (1,25(OH)2D3) in the pituitary cell strain GH4C1 is dependent on the concentration of extracellular calcium. We have now investigated the actions of 1,25(OH)2D3 on cytosolic free calcium concentrations [( Ca2+]i) in these cells using the fluorescent indicator quin2. Basal resting [Ca2+]i was unchanged in cells treated with 1 nM 1,25(OH)2D3 either acutely (from 0 to 15 min) or for periods of up to 48 h. However, the initial peak of the biphasic change in [Ca2+]i induced by thyrotropin-releasing hormone (TRH) was enhanced more than twofold in cells pretreated for 24 or 48 h with 1,25(OH)2D3. This 1,25(OH)2D3-enhanced calcium response was restricted to the initial phase of TRH action; the secondary plateau phase was unaffected. Neither the affinity nor number of TRH receptors nor the early time course of [3H]MeTRH binding to GH4C1 cells were affected by pretreatment with 1,25(OH)2D3. Because TRH binding was not altered, four sites along the intracellular signal transduction pathway of TRH action were examined. Neither protein kinase C activation nor inositol polyphosphate accumulation were enhanced in response to TRH, in 1,25(OH)2D3 pretreated cells, indicating that phosphatidylinositol hydrolysis was unchanged by pretreatment. A low concentration of ionomycin was used to probe the size of the nonmitochondrial intracellular calcium pool that is sensitive to TRH. Ionomycin was not able to mobilize more calcium from 1,25(OH)2D3 pretreated cells, indicating that TRH-responsive intracellular calcium stores were probably not enhanced by pretreatment. Chelation of extracellular calcium, however, did eliminate enhancement of the TRH response in 1,25(OH)2D3-pretreated cells. We conclude that 1,25(OH)2D3 modulates acute dynamic changes in [Ca2+]i induced by TRH without affecting basal [Ca2+]i. The mechanism of the enhanced response of 1,25(OH)2D3-pretreated cells to TRH appears to depend upon a postreceptor event independent of phosphatidylinositol hydrolysis that involves increased calcium conductance at the level of the plasma membrane. A less likely explanation involves enhancement of intracellular calcium stores in an ionomycin-resistant, EGTA-sensitive, TRH-mobilizable reservoir.
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PMID:Modulation by 1,25-dihydroxycholecalciferol of the acute change in cytosolic free calcium induced by thyrotropin-releasing hormone in GH4C1 pituitary cells. 283 Mar 13

Phorbol esters are tumor promotors that directly stimulate protein kinase C activity. We asked whether these agents affect basal or receptor initiated alterations in growth hormone (GH) and prolactin release. In 4 h incubations of anterior pituitary cells, phorbol esters enhanced basal and GH releasing factor (GRF)-induced GH release. Somatostatin reduced by 38% the 4-fold stimulation of GH release induced by phorbol ester. These tumor promoters also reversed the ability of bromocriptine, a dopamine agonist, to inhibit prolactin release, with no apparent effect on basal prolactin secretion. When these agents were applied for 24 h, an increase in the basal release of both GH and prolactin was apparent. These data lead us to suggest that an intact protein kinase C system may be necessary for the full expression of GRF-stimulated GH release and dopaminergic inhibition of prolactin release.
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PMID:Phorbol esters affect pituitary growth hormone (GH) and prolactin release: the interaction with GH releasing factor, somatostatin and bromocriptine. 286 49


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