Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UNIPROT:P61278 (somatostatin)
22,083 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The second messengers and protein kinases involved in the induction of type I plasminogen activator inhibitor (PAI-1) synthesis by various agents were evaluated in cultured bovine aortic endothelial cells. Phorbol myristate acetate (PMA) induced PAI-1 in these cells implicating the protein kinase C (PK-C) pathway. However, bradykinin, which also activates PK-C in bovine aortic endothelial cells, did not induce PAI-1. Moreover, when PK-C was down-regulated by PMA pretreatment, subsequent induction of PAI-1 by transforming growth factor beta (TGF beta) and tumor necrosis factor alpha (TNF alpha) was unaltered, and induction by lipopolysaccharide (LPS) was decreased by only 50%. LPS increased phospholipid second messengers which can activate PK-C but TGF beta and TNF alpha did not. Agents which increase cAMP, (e.g., forskolin and isobutylmethylxanthine) blocked the induction of PAI-1 synthesis by PMA, LPS, TGF beta and TNF alpha suggesting that induction may occur by lowering cAMP. This possibility seems unlikely since cAMP levels did not change in response to any of these agents. Moreover, somatostatin lowered cAMP but did not induce PAI-1. PAI-1 was not induced by treating the cells with cGMP, Na+/H+ ionophore and calcium ionophore or arachidonic acid.
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PMID:Regulation of type I plasminogen activator inhibitor synthesis by protein kinase C and cAMP in bovine aortic endothelial cells. 165 42

Corticotropin (ACTH)-releasing factor, vasoactive intestinal peptide, and catecholamines--hormones that stimulate ACTH secretion and cAMP generation--increased cytosolic calcium in AtT-20 cells. The increase in intracellular calcium is presumably a consequence of the stimulated cAMP synthesis, since forskolin, an activator of the catalytic unit of adenylate cyclase, and the cAMP analog 8-bromoadenosine 3',5'-cyclic monophosphate (8Br-cAMP) also increased the cytosolic levels of this ion. Pretreatment with somatostatin, a neuropeptide that inhibits stimulation of the adenylate cyclase system and the secretion of ACTH blocked the increase of cytosolic calcium. The effect of 8Br-cAMP, which bypasses the cyclase, was not inhibited by somatostatin pretreatment. The source of the increased calcium appears to be mainly extracellular. This is indicated by the inability of the secretagogues to increase cytosolic calcium in a medium deprived of this ion or in the presence of blockers of voltage-gated calcium channels. The involvement of calcium channels in the calcium rise evoked by the secretagogues was supported by experiments using the whole-cell patch-clamp technique. In these experiments 8Br-cAMP increased voltage-dependent calcium currents. These results suggest the following chain of events in the receptor-mediated elevation of cytosolic calcium and the concomitant release of ACTH from AtT-20 cells: hormone-receptor binding----cAMP synthesis----protein kinase activation----calcium channel activation----increase in cytosolic calcium----many steps----ACTH release. Phorbol myristate acetate, a compound which does not stimulate cAMP generation but enhances the release of ACTH in AtT-20 cells, decreased the cytosolic calcium level.
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PMID:Hormone secretagogues increase cytosolic calcium by increasing cAMP in corticotropin-secreting cells. 241 78

When applied to the skin, phorbol esters (PEs) elicit signs of acute inflammation, suggesting they may induce the release of mediators from mast cells. Therefore, we have studied the effects of PEs on purified rat peritoneal and thoracic mast cells both alone and in conjunction with the calcium ionophore, A23187, and various other secretagogues that interact with immunoglobulin E (e.g., anti-IgE and Con A) or other cell surface receptors, e.g., somatostatin and compd 48/80. PEs alone caused little or no release of histamine. However, the PE 12-O-tetradecanoylphorbol-13-acetate (TPA, 10 ng/ml) tremendously potentiated release induced by the calcium ionophore A23187, reducing the EC50 for A23187 from 832 ng/ml to 56 ng/ml. In the presence of suboptimal A23187 (50 ng/ml), only active tumor promoting PEs elicited histamine release. The EC50 values of the various active PEs were: TPA 5 ng/ml; 4 beta-PDD, 83 ng/ml; and 4-O-methyl-TPA, 807 ng/ml, with maximal histamine release ranging from 54 to 80%. TPA synergistically enhanced stimulation of histamine release by anti-IgE and Con A over the entire concentration-response range. In contrast, this synergism was absent when cells were stimulated with somatostatin and compd 48/80. Phorbol esters may act by increasing the activity of a calcium/phospholipid-dependent protein kinase (Ca/PL-PK). Mast cells do have Ca/PL-PK activity, and TPA in the presence of suboptimal A23187 induces protein phosphorylation comparable with other secretagogues. These results suggest that in the purified mast cell, PE-induced mediator release increases the sensitivity of release mechanisms for calcium, acts syngergistically with secretagogues interacting with IgE, and as suggested from structure-activity relationships, occurs via a specific mechanism of action perhaps involving the Ca/PL-PK.
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PMID:Characterization of the effects of phorbol esters on rat mast cell secretion. 257 54

Phorbol esters alter cyclic AMP levels in a number of tissues, including the anterior pituitary. We report that membrane preparations from GH3 cells exposed to phorbol esters exhibit decreased vasoactive intestinal peptide (VIP)-stimulated and enhanced forskolin-stimulated adenylate cyclase activity. The responsiveness of adenylate cyclase activity to NaF, guanylyl-imidodiphosphate, and Mn2+ was also reduced by phorbol ester treatment. The ability of somatostatin to inhibit forskolin-stimulated adenylate cyclase activity was reduced while phorbol ester exposure had no apparent effect on somatostatin inhibition of VIP-stimulated adenylate cyclase activity. We suggest that protein kinase C alters at least two distinct components of the adenylate cyclase system. One modification disrupts hormone receptor-Gs interaction (lowering VIP efficacy) and the second perturbation augments the activity of the adenylate cyclase catalytic subunit.
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PMID:Phorbol esters induce two distinct changes in GH3 pituitary cell adenylate cyclase activity. 283 67

Addition of 12-O-tetradecanoylphorbol-13-acetate (TPA) to S49 lymphoma cells (wild type and a cyclic AMP-dependent protein kinase-lacking clone) has little effect alone but doubles accumulation of cyclic AMP in response to isoproterenol. The effect is immediate and has an apparent affinity and order of potency characteristic of the activation of protein kinase C by phorbol esters. Enhancement does not reflect an altered time course of the beta-adrenergic response, enhanced affinity of the cellular beta-receptor for agonist, or decreased degradation and export of cellular cyclic AMP. Reduction of the beta-adrenergic response by somatostatin does not remove the effect of TPA nor does TPA abolish the effect of somatostatin. Phorbol ester enhances cyclic AMP accumulation in response to cholera toxin in wild type and UNC clones but not in H21a or cyc-. TPA also enhances cAMP accumulation in response to forskolin in wild type cells. The effect of TPA is stable to rapid preparation of membranes. In adenylate cyclase assays on membranes from cells treated with TPA, the activation by guanosine 5'-(beta, gamma-imino)triphosphate is enhanced by 40% with no change in lag time; the effect of beta-agonist plus Gpp(NH)p is similarly enhanced; activation by Mn2+ is unchanged. We conclude that phorbol ester facilitates the productive interaction of the alpha subunit of the transducer protein Gs with the catalytic unit of adenylate cyclase, hypothetically via an action of protein kinase C.
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PMID:Enhancement of adenylate cyclase activity in S49 lymphoma cells by phorbol esters. Putative effect of C kinase on alpha s-GTP-catalytic subunit interaction. 285 14

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

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

Phorbol diester tumor promoters are potent cocarcinogens which also possess activity in a variety of biological assays. We have examined the effect of phorbol diesters on secretion of somatostatin-like immunoactivity (SRIF-LI) by dispersed cells of fetal rat brain maintained in long term culture. Phorbol-12-myristate-13-acetate (PMA) and phorbol 12, 13-dibutyrate stimulate SRIF-LI secretion in a dose-dependent fashion. 4-O-Methyl-PMA is approximately 100 times less potent than phorbol 12, 13-dibutyrate. 4-beta-Phorbol was inactive. Treatment with a nonphorbol irritant, teleocidin, also was associated with significantly augmented release of SRIF-LI. Significant stimulation is seen within 7.5 min of treatment and response is linear over 1 h. Administration of phorbol diesters in low calcium buffer (0.1 mM) with or without cobalt or pretreatment with verapamil are associated with significantly diminished secretion. Substitution for sodium ion by choline or pretreatment with tetrodotoxin (10(-7) M) also inhibits response to PMA. gamma-Aminobutyric acid (50 microM) or the gamma-aminobutyric acid agonist muscimol (5 microM) decrease response to PMA as does sodium pentobarbital (IC50 approximately 30 microM). Phenobarbital is less potent as an inhibitor; significant suppression is not seen until approximately 300 microM. The data are consistent with an action for phorbol diesters mediated at least in part by voltage dependent sodium channels and calcium influx into excitable cells. Inhibition by hyperpolarizing agents is compatible with this mechanism. Phorbol diesters may thus mimic endogenous modulator substances active at the nerve cell membrane.
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PMID:Phorbol diesters stimulate somatostatin secretion from cultured brain cells. 640 21

In this investigation we studied pancreastatin (PST) secretion from a human PST producing cell line (QGP-1N) in response to various secretagogues. Immunocytochemical study revealed the immunoreactivity of PST and somatostatin (SMT) in the same cells of a monolayer culture. Ki-ras DNA point mutation on codon 12 was found. Carbachol stimulated secretion of PST and SMT and intracellular Ca2+ mobilization in the range of 10(-6)-10(-4) M. The secretion and Ca2+ mobilization were inhibited by atropine, a muscarinic receptor antagonist. Phorbol ester and calcium ionophore (A23187) stimulated secretion of PST and SMT. The removal of extracellular calcium suppressed both secretions throughout stimulation with 10(-5) M carbachol. Fluoride, a well-known activator of guanine nucleotide binding (G) protein, stimulated intracellular Ca2+ mobilization and secretion of PST and SMT in a dose-dependent manner in the range of 5-40 mM. Also, 10(-5) M carbachol and 20 mM fluoride stimulated inositol 1,4,5-triphosphate production. However, cholecystokinin and gastrin-releasing peptide did not stimulate Ca2+ mobilization or secretion of the two peptides. These results suggest that secretion of PST and SMT from QGP-1N cells is regulated mainly by acetylcholine in a parallel fashion through muscarinic receptors coupled to the activation of polyphosphoinositide breakdown by a G-protein and that increases in intracellular Ca2+ and protein kinase C play an important role in stimulus-secretion coupling.
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PMID:Parallel secretion of pancreastatin and somatostatin from human pancreastatin producing cell line (QGP-1N). 809 76

The effects of various neuropeptides on human plasma cells were studied. Of the various neuropeptides tested, vasoactive intestinal peptide (VIP) enhanced Ig production and growth in human plasma cell lines, IM-9 and AF-10, and in plasma cells generated in vivo (four out of four patients with plasma cell leukemia) and in vitro. In contrast, other neuropeptides (neuropeptide Y, somatostatin, substance P, peptide YY, neurokinin A, calcitonin gene-related peptide, chole-cystokinin octapeptide, and beta-endorphin) were ineffective. Moreover, VIP-induced enhancement was specifically blocked by VIP receptor antagonist. Among the various cytokines, IL-6, GH, and insulin-like growth factor I (IGF-I) also enhanced Ig production and thymidine uptake in plasma cells. However, VIP-induced enhancement was not mediated by IL-6, GH, or IGF-I because antibodies to these cytokines failed to block VIP-induced enhancement. Phorbol 12,13 dibutyrate enhanced Ig production and thymidine uptake in plasma cells, and the Phorbol 12,13 dibutyrate-induced enhancement was blocked by H7 (a protein kinase C inhibitor) but not by H8 (a protein kinase A inhibitor). Similarly, VIP-induced enhancement was blocked by H7 but not by H8. Collectively, VIP enhances plasma cell responses via mechanisms that may involve protein kinase C.
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PMID:Vasoactive intestinal peptide enhances immunoglobulin production and growth in human plasma cells via mechanisms that may involve protein kinase C. 876 69


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