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)

Genes for five somatostatin receptor subtypes, designated sst1-5, have been cloned and shown to belong to the seven transmembrane domain receptor family. The sst2 mRNA transcript is alternatively spliced to generate two related receptor products (sst2A and sst2B) which differ in their carboxylterminal sequence whereas each of the other genes is transcribed to give a single unique receptor protein. The six sst receptor subtypes all bind SRIF14, SRIF28 and the cortistatins with high affinity but vary in their affinity for analogs, such as octreotide. Although the tissue distribution of sst mRNAs has been extensively examined, much less is known about the cellular distribution of the individual receptor proteins. Recent studies with sst subtype specific antibodies have localized individual sst receptors to specific cell types within the rat gastrointestinal tract, pancreas, pituitary and brain. Furthermore, sst receptors have recently been identified in human tumors by immunocytochemistry, providing a significantly improved method for sst receptor detection. All six sst receptor subtypes are linked to guanine nucleotide binding proteins (G proteins) and lead to inhibition of adenylyl cyclase following hormone binding. The sst receptors also regulate a variety of different effectors via G proteins, including calcium and potassium channels and serine and tyrosine phosphatases. In addition to signalling, two other processes are activated by hormone binding: receptor desensitization and receptor internalization. The extent to which these occur seems to vary for the different receptor subtypes. Recent studies have shown that the sst2A receptor is rapidly phosphorylated upon hormone binding, suggesting that this phosphorylation may be responsible for the desensitization and/or internalization of this receptor. The importance of receptor regulation in cellular responsiveness to somatostatin and for receptor detection as well as the molecular mechanisms by which these processes occur provide important areas for future investigations.
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PMID:Somatostatin receptors present knowledge and future directions. 1039 28

Phosphorylation of transcription factors fos/jun dimer activator protein (AP)-1 and nuclear factor-kappaB (NF-kappaB) plays a cardinal role in vascular smooth muscle cell (SMC) response to growth stimuli. Activity of protein tyrosine (PTP) and serine/threonine phosphatases (PP2A, B, and C) regulates in balance with the activity of protein kinases the level of transcription factor phosphorylation. Somatostatin analog octreotide stimulates phosphatase activity and inhibits cell growth. We examined in rats the activity of tissue phosphatases after arterial wall injury and treatment with octreotide and its effect on AP-1 and NF-kappaB phosphorylation and arterial response to injury. The activity of PTP did not change after balloon injury. Treatment of rats with PTP stimulator octreotide increased the PTP activity by 20% +/- 18% in uninjured arteries (p = 0.04 compared with control) and by 49% +/- 44% compared with injured untreated rats (p = 0.017). Treatment of rats with okadaic acid, a specific phosphatase inhibitor, prevented the octreotide-induced increase in PTP activity. PP2A activity of uninjured arteries was not affected significantly with treatment with octreotide (105% +/- 21%, p = 0.57 compared with control). After balloon injury PP2A activity was significantly reduced, 54% +/- 24% of control (p = 0.001). This reduction was prevented with treatment with octreotide, activity 88% +/- 25% of control. When rats were treated with octreotide and okadaic acid, the activity of PP2A in uninjured arteries was decreased to 65% +/- 12% of control (p = 0.03) and the injury-induced reduction was preserved, activity 54% +/- 8% of control (p = 0.001). There was no change in PP2B and C activity after balloon injury. Increased phosphatase activity with octreotide was associated with stabilization of the unphosphorylated form and reduction in nuclear binding of AP-1 and NF-kappaB and was associated with reduced SMC proliferation after balloon injury. Inhibition of increased phosphatase activity with okadaic acid was associated with increased nuclear binding of AP-1 and NF-kappaB. Increased nuclear binding of AP-1 and NF-kappaB after injury was associated with increased expression of fos, jun, and p105 subunit mRNA and restored the proliferative response of SMC after balloon injury. We conclude that the activity of PP2A is decreased after arterial balloon injury which leads to increased AP-1 and NF-kappaB phosphorylation and nuclear binding and is involved in regulation of SMC proliferation. Treatment with octreotide prevented the injury-induced reduction in PP2A activity and decreased transcription factor phosphorylation and SMC proliferation. Modification of phosphatase activity is a potential regulatory mechanism of arterial wall response to injury.
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PMID:Phosphatase activity in the arterial wall after balloon injury: effect of somatostatin analog octreotide. 1046 31

These studies were conducted to determine the effect of route of gluconeogenic amino acid delivery on the hepatic uptake of the amino acids. After a sampling period with no experimental intervention (basal period), conscious dogs deprived of food for 42 h received somatostatin, intraportal infusions of insulin (3-fold basal) and glucagon (basal), and a peripheral infusion of glucose to increase the hepatic glucose load 1.5-fold basal for 240 min. A mixture of alanine, glutamate, glutamine, glycine, serine and threonine was infused intraportally at 7.6 micromol. kg(-1). min(-1) (PorAA group, n = 6) or peripherally at 8.1 micromol. kg(-1). min(-1) (PerAA, n = 6), to match the hepatic load of gluconeogenic amino acids in PorAA. During the infusion period, there were no differences in PerAA and PorAA, respectively, with regard to arterial plasma insulin (144 +/- 18 and 162 +/- 18 pmol/L), glucagon (51 +/- 8 and 47 +/- 11 ng/L), hepatic glucose load (199.8 +/- 22.2 and 210.9 +/- 16.6 micromol. kg(-1). min(-1)), net hepatic glucose uptake (2.8 +/- 2.2 and 2.2 +/- 1.7 micromol. kg(-1). min(-1)), hepatic load of amino acids (68 +/- 14 and 62 +/- 7 micromol. kg(-1). min(-1)), or net hepatic glycogen synthesis (11.1 +/- 2.2 and 8.9 +/- 2.2 micromol. kg(-1). min(-1)). The net hepatic uptake of glutamine (2.1 +/- 0.4 vs. 0.8 +/- 0.3 micromol. kg(-1). min(-1)) and the net hepatic fractional extractions of glutamine (0.11 +/- 0.02 vs. 0.05 +/- 0.02) and serine (0.41 +/- 0.03 vs. 0.34 +/- 0.02) were greater in PorAA than in PerAA (P < 0.05). We speculate that one or more of the amino acids in the mixture causes enhancement of the net hepatic uptake and fractional extraction of glutamine, and perhaps other gluconeogenic amino acids, during intraportal amino acid delivery.
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PMID:Net hepatic gluconeogenic amino acid uptake in response to peripheral versus portal amino acid infusion in conscious dogs. 1057 53

The sst1 somatostatin (SRIF) receptor subtype is widely expressed in the endocrine, gastrointestinal, and neuronal systems as well as in hormone-sensitive tumors, yet little is known about its regulation. Here we investigated the desensitization, internalization, and phosphorylation of sst1 expressed in CHO-K1 cells. Treatment of cells with 100 nm SRIF for 30 min reduced maximal SRIF inhibition of adenylyl cyclase from 40 to 10%. This desensitization was rapid (t(12) < 2 min) and dependent on agonist concentration (EC(50) = 2 nm). However, internalization of receptor-bound ligand occurred slowly (t(12) > 180 min). Incubation of cells with SRIF also caused a rapid (t(12) < 2 min) increase in sst1 receptor phosphorylation in a dose-dependent manner (EC(50) = 1.3 nm), as determined in a mobility shift phosphorylation assay. Receptor phosphorylation was not affected by pertussis toxin, indicating a requirement for receptor occupancy rather than signaling. The protein kinase C activator, phorbol 12-myristate 13-acetate also stimulated sst1 receptor phosphorylation whereas forskolin did not. Both agonist- and phorbol 12-myristate 13-acetate-stimulated receptor phosphorylation occurred mainly on serine. These studies are the first to demonstrate phosphorylation of the sst1 receptor and suggest that phosphorylation mediated uncoupling, rather than sequestration, leads to its desensitization.
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PMID:Agonist-induced phosphorylation of somatostatin receptor subtype 1 (sst1). Relationship to desensitization and internalization. 1107 61

Oral cancer which comprises about 40% of total cancers in India, has one of the lowest relative survival rates of all cancers. Epidermal growth factor (EGF) has been known to play a role in the proliferation/malignant transformation of oral neoplasms. Since, the somatostatin analog RC-160 is reported to be a potent inhibitor of EGF stimulated cell proliferation, its anti-proliferative activity in the human oral carcinoma cell line KB was investigated, in this study. RC-160 was found to potently inhibit EGF-induced proliferation in KB cells in vitro, suggesting a therapeutic potential of the same in oral carcinoma. However, the therapeutic potential of RC-160 is limited by its short serum half life. To overcome this limitation, fatty acids namely butanoic acid and myristic acid individually were coupled to RC-160. The lipophilized derivatives of RC-160 were synthesized, purified and characterized. The anti-proliferative activity of lipophilized derivatives of RC-160 on KB cells was evaluated in vitro. Myristoyl-RC-160 (0.75 nM) inhibited the growth of KB cells at a 10-fold lower concentration relative to RC-160 (8.8 nM) and at a 100-fold lower concentration relative to butanoyl-RC-160 (0.83 microM) (p<0.001). The affinity of RC-160 towards somatostatin receptors remains unaltered by lipophilization. The signaling pathways underlying the antineoplastic activity of these lipopeptides are similar to RC-160, and do not involve the stimulation of a protein tyrosine phosphatase or a serine threonine phosphatase 1A and 2A. The anti-proliferative activity of the lipopeptides was found to be mediated by somatostatin receptors and correlates with the inhibition of protein tyrosine kinase activity and decrease in intracellular cAMP levels. Myristoyl-RC-160 displayed significantly greater resistance towards trypsin and serum degradation than RC-160 (p<0.01). These findings demonstrate that RC-160 can inhibit the growth of oral cancer cells in vitro. Lipophilization of RC-160 with long chain fatty acids like myristic acid improves its stability and anti-proliferative activity, in human oral carcinoma cells in vitro, thereby enhancing the scope of improving its therapeutic index.
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PMID:Lipophilization of somatostatin analog RC-160 with long chain fatty acid improves its anti-proliferative activity on human oral carcinoma cells in vitro. 1126 86

Over the past decade, antiproliferative effects of somatostatin and analogs have been reported in many somatostatin receptor-positive normal and tumor cell types. Regarding the molecular mechanisms involved, somatostatin or analogs mediate their action through both indirect and direct effects. Somatostatin acts through five somatostatin receptors (SSTR1-5) which are variably expressed in normal and tumor cells. These receptors regulate a variety of signal transduction pathways including inhibition of adenylate cyclase, regulation of ion channels, regulation of serine/threonine and tyrosine kinases and phosphatases. This review focuses on recent advances in biological mechanisms involved in the antineoplastic activity of somatostatin and analogs.
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PMID:Antiproliferative effect of somatostatin and analogs. 1127

1. Measurements of cell capacitance were used to investigate the molecular mechanisms by which somatostatin inhibits Ca(2+)-induced exocytosis in single rat glucagon-secreting pancreatic alpha-cells. 2. Somatostatin decreased the exocytotic responses elicited by voltage-clamp depolarisations by 80 % in the presence of cyclic AMP-elevating agents such as isoprenaline and forskolin. Inhibition was time dependent and half-maximal within 22 s. 3. The inhibitory action of somatostatin was concentration dependent with an IC(50) of 68 nM and prevented by pretreatment of the cells with pertussis toxin. The latter effect was mimicked by intracellular dialysis with specific antibodies to G(i1/2) and by antisense oligonucleotides against G proteins of the subtype G(i2). 4. Somatostatin lacked inhibitory action when applied in the absence of forskolin or in the presence of the L-type Ca(2+) channel blocker nifedipine. The size of the omega-conotoxin-sensitive and forskolin-independent component of exocytosis was limited to 60 fF. By contrast, somatostatin abolished L-type Ca(2+) channel-dependent exocytosis in alpha-cells exposed to forskolin. The magnitude of the latter pool amounted to 230 fF. 5. The inhibitory effect of somatostatin on exocytosis was mediated by activation of the serine/threonine protein phosphatase calcineurin and was prevented by pretreatment with cyclosporin A and deltamethrin or intracellularly applied calcineurin autoinhibitory peptide. Experiments using the stable ATP analogue AMP-PCP indicate that somatostatin acts by depriming of granules. 6. We propose that somatostatin receptors associate with L-type Ca(2+) channels and couple to G(i2) proteins leading to a localised activation of calcineurin and depriming of secretory granules situated close to the L-type Ca(2+) channels.
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PMID:Somatostatin inhibits exocytosis in rat pancreatic alpha-cells by G(i2)-dependent activation of calcineurin and depriming of secretory granules. 1153 41

To test the hypothesis that fetal hepatic glutamate output diverts the products of hepatic amino acid metabolism from hepatic gluconeogenesis, ovine fetal hepatic and umbilical uptakes of glucose and glucogenic substrates were measured before and during fetal glucagon-somatostatin (GS) infusion and during the combined infusion of GS, alanine, glutamine, and arginine. Before the infusions, hepatic uptake of lactate, alanine, glutamine, arginine, and other substrates was accompanied by hepatic output of pyruvate, aspartate, serine, glutamate, and ornithine. The GS infusion induced hepatic output of 1.00 +/- 0.07 mol glucose carbon/mol O(2) uptake, an equivalent reduction in hepatic output of pyruvate and glutamate carbon, a decrease in umbilical glucose uptake and placental uptake of fetal glutamate, an increase in hepatic alanine and arginine clearances, and a decrease in umbilical alanine, glutamine, and arginine uptakes. The latter result suggests that glucagon inhibits umbilical amino acid uptake. We conclude that fetal hepatic pyruvate and glutamate output is part of an adaptation to placental function that requires the fetal liver to maintain both a high rate of catabolism of glucogenic substrates and a low rate of gluconeogenesis.
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PMID:Fetal hepatic and umbilical uptakes of glucogenic substrates during a glucagon-somatostatin infusion. 1183 55

Molecular imaging can reveal in vivo analysis and quantification of biochemical reactions. To enable cell-surface imaging of receptors, novel ligands have been developed which can be radiolabeled or imaged by bioluminescence. Specific examples include somatostatin receptors, estrogen and progesterone receptors, receptors involved in adhesion and externalization of phosphatidyl serine as an indicator of apoptosis. Central nervous system imaging can be carried out using ligands for receptors including dopamine, serotonin and Gamma amino butyric acid (GABA). In addition, tumor and metabolic imaging can be carried out with the Na-K ATPase pump using the tracer thallium-201 for SPECT or F-18 FDG for PET imaging. Finally, novel receptors or endogenous metabolic pathways can be analyzed combining cell-gene therapy to create specific tracer targets in cells that can be studied by molecular imaging. The challenge of molecular imaging is to first identify key pathways that are unique for a specific disease processes, such as atherosclerosis, cancer, CNS disorders, immunologic and arthritis disorders and next to devise a high-affinity specific small molecular ligand that can be adapted to be a radiolabeled tracer to study this pathway. Advances in genomics and proteomics combine with new peptide-chemistry approaches should provide a large number of targets and tracers in the near future to achieve these imaging objectives.
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PMID:Molecular imaging: new applications for biochemistry. 1255 16

Ca(2+)/calmodulin-dependent protein kinase II is a member of a broad family of ubiquitously expressed Ca(2+) sensing serine/threonine-kinases. Ca(2+)/calmodulin-dependent protein kinase II is highly expressed in insulin secreting cells and is associated with insulin secretory granules and has been proposed to play an important role in exocytosis or in insulin granule transport to release sites. To elucidate its function the antisense sequence of the major beta-cell subtype, Ca(2+)/calmodulin-dependent protein kinase II delta(2), was stably expressed in INS-1 rat insulinoma cells. This caused a loss of Ca(2+)/calmodulin-dependent protein kinase II delta(2) expression at the mRNA and protein level, while the expression of the 95% homologous Ca(2+)/calmodulin-dependent protein kinase II gamma and of beta-cell specific proteins such as the homeodomain factor pancreatic-duodenal homeobox factor-1 (PDX-1, also referred to as islet/duodenum homeobox-1, IDX-1, insulin promoter factor-1, IPF-1 and somatostatin transactivating factor-1, STF-1), the glucagon-like peptide-1 (GLP-1) receptor and K(ATP)-channels K(IR)6.2/SUR-1 (sulfonylurea receptor-1) was not altered. Unexpectedly, the cells showed a large reduction of insulin gene expression, which was due to reduced insulin gene transcription. Electrophoretic mobility shift assays of PDX-1 binding to the insulin promoter A1 and E2/A3A4 elements showed additional bands indicating alterations of PDX-1 complex formation. Stable over expression of Ca(2+)/calmodulin-dependent protein kinase II delta(2), by contrast, was associated with elevated expression of insulin mRNA. Therefore, we conclude that Ca(2+)/calmodulin-dependent protein kinase II delta(2) links fuel-dependent increases in intracellular Ca(2+) concentrations to transcriptional regulation of genes related to the metabolic control of insulin secretion.
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PMID:Ca2+/calmodulin-dependent protein kinase II delta2 regulates gene expression of insulin in INS-1 rat insulinoma cells. 1260 Aug 4


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