Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P61278 (somatostatin)
 22,083 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

We and others have suggested previously that the binding of somatostatin to its receptors in the pancreas is regulated by not only somatostatin analogs but also cholecystokinin analogs in proportion to their known biological potencies. To clarify the precise mechanism by which unrelated peptides modulate somatostatin binding, the effect of a phorbol ester, 12-O-tetradecanoylphorbol 13-acetate (TPA), or a synthetic diacylglycerol analog, 1-oleyl-2-acetylglycerol (OAG), on [125I-Tyr1]somatostatin binding to pancreatic acinar cell membranes was examined. Pretreatment of pancreatic acini for 120 min at 37 degrees C with 100 ng/ml TPA maximally reduced subsequent labeled somatostatin binding to acinar membranes. The inhibitory effect of TPA on the somatostatin binding was dependent on the dose used or the time and temperature of pretreatment. These effects of TPA were almost mimicked by the treatment of acini with OAG. Scatchard analysis of [125I-Tyr1]somatostatin binding demonstrated that the decrease in the labeled somatostatin binding induced by TPA or OAG pretreatment was due to the decrease in the maximum binding capacity without a significant change in the binding affinity. A specifically labeled single band of Mr = 90,000 obtained with a photoaffinity cross-linking study indicates that the somatostatin-binding sites are the same somatostatin receptor as previously described. Moreover, the intensity of the Mr = 90,000 band was dramatically decreased when acini were treated with increasing concentrations of TPA, a finding consistent with TPA-induced decrease in binding capacity. Such an inhibitory effect of TPA was abolished when pretreatment of acini with TPA was performed in the presence of Ca2+-chelating compounds such as EDTA and EGTA or phospholipid-interacting drugs such as chlorpromazine and tetracaine. Interestingly, the combined treatment of TPA and Ca2+ ionophore A23187 caused synergistic inhibition of the subsequent labeled somatostatin binding to acinar membranes, although Ca2+ ionophore itself almost failed to affect the somatostatin binding. These results suggest, therefore, that TPA or OAG can modulate somatostatin binding to its receptors on rat pancreatic acinar cell membranes, presumably through activation of Ca2+-activated, phospholipid-dependent protein kinase (protein kinase C); and the activated protein kinase C and intracellular Ca2+ mobilization presumably act to modulate the pancreatic acinar somatostatin receptors synergistically.
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PMID:Phorbol ester or diacylglycerol modulates somatostatin binding to its receptors on rat pancreatic acinar cell membranes. 286

Recent studies suggest that 12-O-tetradecanoylphorbol 13-acetate (TPA), one of a family of phorbol esters that are known tumor promoters, can activate intracellular Ca2+, phospholipid-dependent protein kinase (protein kinase C) directly. To examine the possible involvement of protein kinase C-mediated mechanisms in regulating gastric somatostatin release, we studied the effects of TPA on isolated enriched canine gastric somatostatin cells in short-term culture. TPA markedly stimulated somatostatin release such that nearly 10% of total cellular content of somatostatin was released into media within 2 h of incubation. Among the phorbol compounds tested, TPA was the most potent, with half-maximum effective dose (ED50) obtained at a dose of 5 X 10(-9) M. Phorbol 12,13-dibutyrate (PDBu) also stimulated somatostatin release but with only 5% of the potency of TPA, whereas phorbol compounds with no biological activity in other systems failed to stimulate somatostatin release. In the absence of extracellular Ca2+, the effects of TPA were significantly attenuated. In contrast, stimulation of somatostatin release by forskolin (10(-4) M) was not affected by Ca2+ deprivation but was potentiated by TPA. No such potentiation was observed when TPA was combined with the Ca2+ ionophore A23187. Carbamylcholine (10(-5) M), which inhibits the stimulatory actions of beta-adrenergic agonists or dibutyryl cyclic adenosine monophosphate on somatostatin cells, also inhibited TPA-induced somatostatin release. These data suggest the presence of dual stimulatory mechanisms for gut somatostatin release, both of which are susceptible to inhibition by muscarinic agonists.
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PMID:Phorbol esters stimulate somatostatin release from cultured cells. 287 64

The brain peptide human growth hormone releasing factor (1-40) (GRF), which stimulates adenylate cyclase activity in the anterior pituitary, is the predominant hormone signal for pituitary growth hormone (GH) release. Activators of protein kinase C such as teleocidin and 4 beta-phorbol 12-myristate 13-acetate (PMA) double the cyclic AMP accumulation induced by GRF, with no apparent effect on GRF potency; an inactive 4-alpha-PMA has no such action in cultured anterior pituitary cells. This PMA potentiation can be measured as early as 60 s, is maximal by 15 min, and wanes such that by 3-4 h there is no such amplifying effect of PMA. PMA, phorbol 12,13-dibutyrate, and teleocidin ED50 values for potentiating GRF activity are similar to those obtained for direct protein kinase C activation. The major inhibitory peptide somatostatin reduced both GRF- and GRF + PMA-stimulated cyclic AMP accumulation. Pertussis toxin totally blocked this somatostatin action without affecting the degree of maximal GRF potentiation achieved with PMA. Thus, the pertussis toxin target(s) are required for somatostatin inhibition of the cyclic AMP generating system, but may not be involved in the PMA potentiation of GRF-stimulated cyclic AMP accumulation.
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PMID:Protein kinase C enhances growth hormone releasing factor (1-40)-stimulated cyclic AMP levels in anterior pituitary. Actions of somatostatin and pertussis toxin. 287 83

To clarify the precise mechanism by which unrelated peptides, cholecystokinin or carbamylcholine, modulate the somatostatin binding, the effect of a phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA) or a synthetic diacylglycerol analog, 1-oleyl-2-acetylglycerol (OAG) on [125I-Tyr1]somatostatin binding to pancreatic acinar cell membranes was examined. Pretreatment of pancreatic acini for 120 min at 37 degrees C with 100 ng/ml TPA maximally reduced subsequent labeled somatostatin binding to acinar membranes. The inhibitory effect of TPA on the somatostatin binding was dependent on the dose used, or the time and temperature of pretreatment. These effects of TPA were almost mimicked by the treatment of acini with OAG. Scatchard analysis of [125I-Tyr1]somatostatin binding demonstrated that the decrease in the labeled somatostatin binding induced by TPA or OAG pretreatment was due to the decrease in the maximum binding capacity without a significant change in the binding affinity. A specifically labeled single band of the Mr = 90 K obtained with a photoaffinity cross-linking study indicates that the somatostatin binding sites are the same somatostatin receptor as previously described. Moreover, the intensity of the Mr = 90 K band was dramatically decreased when acini were treated with increasing concentrations of TPA, a finding consistent with TPA-induced decrease in binding capacity. Such an inhibitory effect of TPA was abolished when pretreatment of acini with TPA was performed in the presence of Ca2+ chelating compounds such as EDTA and EGTA. Interestingly, the combined treatment of TPA and Ca2+ ionophore A23187 caused synergistic inhibition of the subsequent labeled somatostatin binding to acinar membranes, although Ca2+ ionophore itself almost failed to affect the somatostatin binding. These results suggest, therefore, that TPA or OAG can modulate somatostatin binding to its receptors on rat pancreatic acinar cell membranes, presumably through activation of Ca2+-activated, phospholipid-dependent protein kinase (protein kinase C) and the activated protein kinase C and intracellular Ca2+ mobilization presumably act to modulate pancreatic acinar somatostatin receptors synergistically.
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PMID:[Phorbol ester or diacylglycerol modulates somatostatin binding to its receptors on rat pancreatic acinar cell membranes]. 287 6

Proglucagon is a polyprotein precursor containing not only glucagon and glicentin, but glucagon-like peptides-I and -II and an intervening peptide (IP-II). The glucagon gene is expressed in both pancreatic islets and neuroendocrine L-cells of the gastrointestinal tract. We have recently cloned an islet cell line from a rat pancreatic islet cell tumour that simultaneously expresses the glucagon, insulin, somatostatin, and angiotensinogen genes. We investigated the potential role of "second messenger" pathways in the regulation of glucagon gene expression. Both the tumor promoter agent phorbol myristate acetate (PMA) and a diacylglycerol analog, 1,2-dioctanoylglycerol, induced a 2.7- and 2.5-fold increase in steady-state glucagon mRNA levels at 24 h, respectively. The increase was progressive up to 24 h and was specific for glucagon mRNA; the insulin and somatostatin mRNA levels remained unchanged. An inactive phorbol ester, 4 beta-phorbol 12,13,20-triacetate, was without effect. The glucagon mRNA increase induced by PMA was mediated through an increase in glucagon gene transcription reaching maximal stimulation at 30-60 min. Glucagon mRNA half-life was similar in both control and PMA-treated cells, approximating 12 h. The stimulation of glucagon gene transcription was accompanied by a corresponding 3-fold increase in proglucagon biosynthesis. Neither dibutyryl cAMP nor glucocorticoids affected glucagon mRNA levels, while inducing a 5-fold increase in somatostatin mRNA levels and 4.8-fold stimulation in angiotensinogen mRNA at 24 h, respectively. We conclude that expression of the glucagon gene in this islet cell line is regulated at the level of transcription through a protein kinase C (Ca2+/phospholipid-dependent enzyme)-activated pathway.
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PMID:Glucagon gene transcription in an islet cell line is regulated via a protein kinase C-activated pathway. 287 43

To clarify the role of the breakdown of phosphatidylinositol 4,5-bisphosphate (PIP2) in GH secretion in human somatotrophs and the effects of inhibitors of GH secretion on this mechanism, we studied the effects of 12-tetradecanoylphorbol-13-acetate (TPA) and phospholipase C (Plase C) on GH secretion and the interactions of somatostatin (SRIH), bromocriptine, and pertussis toxin (IAP) with TPA or Plase C, using human GH-secreting pituitary adenoma cells in culture. SRIH (10(-9)-10(-7) M) inhibited and TPA (10(-10)-10(-8) M) and Plase C (0.125-1.0 U/mL) stimulated GH secretion. SRIH (10(-9)-10(-7) M) inhibited GH release induced by TPA (10(-8) M) or Plase C (1.0 U/mL). Bromocriptine (10(-8) M) also inhibited 10(-8) M TPA-induced GH secretion. When adenoma cells were treated with 100 ng/mL IAP for 24 h, basal and TPA-induced GH secretion rates did not change. However, the inhibitory effects of SRIH (10(-8) M) or bromocriptine (10(-8) M) on basal and 10(-8) M TPA-stimulated GH secretion were attenuated. In addition, IAP reduced GH secretion induced by 0.5 U/mL Plase C, while SRIH inhibition of Plase C-evoked GH release was diminished by IAP. We conclude that the hydrolysis of PIP2 by Plase C, which causes activation of protein kinase C by 1,2-diacylglycerol and Ca2+ mobilization by inositol 1,4,5-triphosphate, is a physiological intracellular mechanism leading to GH secretion in human somatotrophs; SRIH inhibits GH secretion mediated by this mechanism, and bromocriptine blocks at least protein kinase C-mediated GH release; the inhibitory guanine nucleotide-binding protein (Ni) is involved in these inhibitory effects of SRIH and bromocriptine; and Ni modulates the breakdown of PIP2 by Plase C.
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PMID:Phorbol ester and phospholipase C-induced growth hormone secretion from pituitary somatotroph adenoma cells in culture: effects of somatostatin, bromocriptine, and pertussis toxin. 288 Aug 63

To examine the potential mechanisms by which somatostatin inhibits gastric acid secretion we studied its effects on isolated canine gastric parietal cells. Using 125I-[Leu8-D-Trp22-Tyr25]somatostatin-28 as ligand, we identified somatostatin-binding sites in parietal cell-enriched fractions of fundic mucosa. Two binding sites with respective dissociation constants of 3.2 X 10(-9) and 2.1 X 10(-7) M were identified. Somatostatin-14 and -28 were equally potent both in displacing bound ligand and in inhibiting parietal cell activity as measured by [14C]aminopyrine uptake. Pertussis toxin reversed the ability of somatostatin to inhibit the uptake of [14C]aminopyrine and production of cAMP by parietal cells stimulated with histamine and forskolin but not with dibutyryl cAMP or pentagastrin. Furthermore, somatostatin had no effect on parietal cell membrane inositol phospholipid turnover or changes in protein kinase C (Ca2+/phospholipid-dependent enzyme) activity induced by carbachol or pentagastrin. These data indicate that somatostatin directly inhibits parietal cell activity via mechanisms both dependent on and independent of the pertussis toxin-sensitive inhibitory guanine nucleotide-binding protein.
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PMID:Mechanisms for direct inhibition of canine gastric parietal cells by somatostatin. 288 65

In experiments using a synaptosomal preparation from the striatum and nucleus accumbens, somatostatin caused a dose-dependent increase in dopamine synthesis. This increase was additive with that produced by 8-BrcAMP but not with that produced by the phorbol ester 12-O-tetradecanoyl-phorbol-13-acetate (TPA), and was blocked by the protein kinase C inhibitor polymyxin B (PMB). These findings suggest that stimulation of dopamine synthesis by somatostatin is mediated by activation of protein kinase C.
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PMID:Protein kinase C mediates the stimulation by somatostatin of dopamine synthesis in the rat striatum and nucleus accumbens. 289 60

Functional gastrin-containing tumor cells (GT cells) have been maintained in short-term culture on microporous membranes, and their response to selected agents has been determined. After dispersion of gastrinoma by collagenase-DNAase digestion coupled with mechanical disruption, dispersed cells were depleted in stromal material by selective attachment to a plastic substrate, then cultured for 72 hours on porous cellulose membranes. Cultures contained 68 +/- 5% GT cells with a viability of 92 +/- 2%. Secretin stimulated the rate of gastrin release from cultured GT cells in both a time- and a dose-dependent fashion. To examine the possible involvement of adenylate cyclase- and protein kinase C-mediated mechanisms in regulating gastrin release from the neoplastic GT cells, we evaluated the effects of 8-bromoadenosine 3':5'-cyclic monophosphate (8-BrcAMP; 10(-4) - 10(-2) mol/L), the diterpene forskolin (10(-5) mol/L), 12-0-tetradencanoylphorobol 13-acetate (TPA; 10(-8) - 10(-6) mol/L), and 4 alpha-phorbol 12,13-didecanoate (4 alpha PDD; 10(-8) - 10(-6) mol/L) on gastrin release. Among all compounds tested, 8-BrcAMP (10(-2) mol/L) was the most potent, stimulating the rate of gastrin release 263% above basal. Both 8-BrcAMP and TPA stimulated gastrin release in a dose-dependent fashion. The biologically inactive phorbol ester, 4 alpha PDD, was without effect at all concentrations. Somatostatin (10(-8) - 10(-6) mol/L) inhibited 8-BrcAMP-stimulated gastrin release in a dose-dependent fashion to a maximum of 75%.
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PMID:Control of gastrin release in cultured gastrinoma-derived G cells. 289 16


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