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 neuropeptide somatostatin inhibits secretion from electrically excitable cells in the pituitary, pancreas, gut and brain. In mammalian pituitary tumour cells somatostatin inhibits secretion through two distinct pertussis toxin-sensitive mechanisms. One involves inhibition of adenylyl cyclase, the other an unidentified cyclic AMP-independent mechanism that reduces Ca2+ influx by increasing membrane conductance to potassium. Here we demonstrate that the predominant electrophysiological effect of somatostatin on metabolically intact pituitary tumour cells is a large, sustained increase in the activity of the large-conductance Ca(2+)- and voltage-activated K+ channels (BK). This action of somatostatin does not involve direct effects of Ca2+, cAMP or G proteins on the channels. Our results indicate instead that somatostatin stimulates BK channel activity through protein dephosphorylation.
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PMID:Somatostatin stimulates Ca(2+)-activated K+ channels through protein dephosphorylation. 171 Jul 83

Somatostatin (SS-14) is known as an antigrowth factor for a variety of cell types, including gastrointestinal mucosa, exocrine pancreas, lymphocytes, and some tumors. We have recently identified and biochemically characterized SS-14-binding protein on rat liver plasma membranes (S. E. Raper, P. C. Kothary, and J. DelValle, Gastroenterology 96: A408, 1989; P. C. Kothary et al., Digestion 46 (Suppl 1): 58, 1990). We hypothesized that SS-14 may affect liver growth as well and investigated cellular mechanisms of this phenomenon focusing on the second messenger cAMP. Freshly isolated rat hepatocytes were plated on tissue culture dishes coated with Matrigel (laminin, heparan sulfate, and type IV collagen). The medium was not supplemented with serum or hormones. Either dibutyryl-cAMP (1 mM) or isobutylmethylxanthine (IBMX, 0.1 mM) was added in the presence or absence of SS-14 (10 nM). DNA synthesis was estimated by the rate of [3H]thymidine incorporation into DNA and by the labeling index (an autoradiographic measurement of the number of labeled nuclei). SS-14 significantly inhibited both [3H]thymidine incorporation and labeling index of rat hepatocytes stimulated by dibutyryl-cAMP or IBMX. SS-14 also inhibited intracellular cAMP accumulation stimulated by IBMX. We conclude that SS-14 exerts at least part of its antiproliferative effects via the adenylate cyclase system. Further study using other signal transduction systems may yield more information about mechanisms of hepatocyte growth.
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PMID:Inhibitory effects of somatostatin on rat hepatocyte proliferation are mediated by cyclic AMP. 171 80

Altered osmotic pressure and somatostatin (SRIF) rapidly alter prolactin (PRL) release from the pituitary gland of the euryhaline teleost, the tilapia. The present studies were undertaken to determine whether altered osmotic pressure and SRIF influence cAMP metabolism in a manner that is correlated with the pattern of PRL release observed previously. Although PRL release is stimulated within 10-20 min when medium osmotic pressure is reduced, cAMP metabolism was not altered. However, following 1 hr of incubation in the presence of IBMX, cAMP accumulation was higher in PRL tissue exposed to medium of reduced osmotic pressure. This suggests that cAMP does not initiate an increase in PRL release in response to reduced osmotic pressure. By contrast, SRIF reduced the forskolin-stimulated increase in cAMP levels in a manner consistent with its rapid effects on PRL release. Moreover, the ability of SRIF to suppress the forskolin-stimulated increase in cAMP levels suggests that SRIF may act to render adenylate cyclase less responsive to direct stimulation by forskolin.
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PMID:Effects of osmotic pressure and somatostatin on the cAMP messenger system of the osmosensitive prolactin cell of a teleost fish, the tilapia (Oreochromis mossambicus). 171 2

We examined the induction, by heat shock, of heat shock transcription factor (HSTF) DNA-binding and hsp 70 gene promoter activities during aging of the IMR-90 human diploid fibroblasts. Cells with population doubling level (PDL) ranging from 15-48 were heat shocked at temperatures of 39, 42, and 45 degrees C for various time periods; the binding of HSTF to its consensus DNA was determined by gel retardation assay and the promoter activity of the human hsp 70 gene was analyzed by transient expression of reporter gene activity. We observed that the induction of HSE-binding activity was inversely related to the PDL of the cells used. Importantly, as cells progress through their life span, a higher temperature and a longer period of heat shock were needed to evoke an optimal increase in HSE-binding activity. A substantial and rapid (within 30 min) increase in HSE-binding activity was observed when PDL 20 cells were heat shocked at 39, 42, or 45 degrees C. However, PDL 35 cells did not respond to 39 degrees C, and PDL 48 cells responded slowly to heat shock at 45 degrees C, but not 39 or 42 degrees C. Experiments on the heat induced increase in hsp 70 promoter driven reporter gene expression provided similar information on the age-dependent decrease in transcriptional activation of hsps. These results were further corroborated by quantitation of the abundance of mRNA of hsp 70. Analysis of the cAMP induced expression of the rat somatostatin promoter driven CAT gene provided evidence that the decrease in transcriptional activation of hsps in aging diploid cells was not a reflection of a generalized dysfunction of signal transduction. We conclude that functional changes in the heat shock response occur before cells lose their capacity to replicate, and we suggest that these changes are likely to have a central role in the expression of the aging phenotype.
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PMID:Molecular events involved in transcriptional activation of heat shock genes become progressively refractory to heat stimulation during aging of human diploid fibroblasts. 172 Jul 88

The gel retardation assay with a single-stranded oligo-DNA of cAMP-response element (CRE) in a somatostatin promoter region was selected to examine the possibility of transcriptional regulation of cAMP-inducible genes by chronic morphine or ethanol treatment of NG108-15 cells. When the nuclear extracts from the cells treated with morphine (50 microM) or ethanol (100 mM) for several days were assayed, the amount of DNA-protein complex was decreased about 30-40% compared to that of the control. The decreased complex was recovered by 1-2 days after withdrawal of the drugs. Treatment of the cells with these drugs for 1 h did not change the amount of the DNA-protein complex. Thus, changes in CRE-binding proteins from the cells treated chronically with morphine or ethanol suggest that these drugs can modulate the expression of cAMP-inducible genes through which tolerance and dependence may develop.
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PMID:Effects of chronic exposure of NG108-15 cells to morphine or ethanol on binding of nuclear factors to cAMP-response element. 182 20

A cAMP regulatory element (CRE) at nucleotide position -170 of the fibronectin gene was characterized previously (Dean, D. C., Blakeley, M. S., Newby, R. F., Ghazal, P., Hennighausen, L., and Bourgeois, S. (1989) Mol. Cell. Biol. 9, 1498-1506). Here we identify two additional low affinity CREs at nucleotide positions -260 and -415 which differ in sequence by 1 base pair. Interestingly, these CREs did not compete for binding of nuclear proteins in gel retardation assays and partial tryptic digestion of protein-DNA complexes produced a different pattern with each CRE, indicating that they bind different proteins. CRE (-170) competed for binding of proteins to both CREs, suggesting that it may represent a composite of the two elements. CRE (-415) competed effectively for binding of nuclear proteins to the somatostatin gene CRE, suggesting that, like the somatostatin CRE, it binds the nuclear protein CREB. On the other hand, CRE (-260) appears to bind the nuclear protein PEA-2, which also binds a site in the polyoma virus enhancer. In summary, disruption of dyad symmetry in the 3' region of the CRE, as occurs with CRE (-260) and CRE (-415), results in a lower affinity site and may also change the specificity for different nuclear proteins.
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PMID:Characterization of three different elements in the 5'-flanking region of the fibronectin gene which mediate a transcriptional response to cAMP. 184 87

Galanin, an ubiquitous neuropeptide, was recently shown to inhibit somatostatin release by the rat islet tumor cell line, Rin-m. By using the clonal pancreatic delta cell line Rin14B, originating from Rin-m cells, we were able to identify the presence of one type of specific galanin-binding site of high affinity (Kd = 1.6 nM; maximal binding capacity = 270 fmol/mg protein) and high specificity for the peptide. Binding of 125I-galanin to these receptors was time-dependent and highly sensitive to guanine nucleotides. Using the cross-linker disuccinimidyl tartrate, covalent linking of the galanin receptor to 125I-galanin in membranes from Rin14B cells, followed by SDS/PAGE analysis of membrane proteins, indicated that the galanin receptor is a protein of 54 kDa. 0.1-100 nM galanin also exerted a marked inhibitory effect on the cAMP-production system under basal conditions, as well as in the presence of the pancreatic peptide glucagon. At a maximal dose, galanin induces a 90-100% decrease of basal and glucagon-stimulated cAMP production levels, with a median inhibition concentration (IC50) of 3 nM galanin. The direct inhibitory effect of galanin on the adenylate cyclase activity in Rin14B cell membranes was also demonstrated (IC50 = 3 nM galanin). The inhibitory effect of galanin on the basal and glucagon-stimulated cAMP production in Rin14B cells was reversed by pertussis toxin. The toxin was also shown to specifically ADP-ribosylate a protein of 41 kDa in membranes from Rin14B cells. Taken together, these data show that the pancreatic delta cell line Rin14B expresses high affinity galanin receptors negatively coupled to a pertussis-toxin-sensitive cAMP-production system.
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PMID:A clonal rat pancreatic delta cell line (Rin14B) expresses a high number of galanin receptors negatively coupled to a pertussis-toxin-sensitive cAMP-production pathway. 184 83

The mechanism of regulatory expression of human cytochrome P-450scc gene by cAMP was investigated in a transient expression system using Y-1 cells (mouse adrenal tumor cell line) and a chimeric DNA composed of the structural gene for bacterial chloramphenicol acetyltransferase and the 5' flanking upstream sequence of the cytochrome P-450scc (cholesterol desmolase) gene which was revealed to contain a DNA element(s) responsive to cAMP [Inoue, H. et al. (1988) Eur. J. Biochem. 171, 435-440]. Introduction of deletions and point mutations in the upstream regulatory sequence demonstrated that three regions were mainly required for response to cAMP. These regions contained a short similar sequence. All of them have a 5-bp motif GTCAT (or ATGAC) in common, and have at least two motifs which conserve four out of five base pairs of the consensus sequence of the cAMP-responsive element (CRE), CGTCA (or TGACG). They are all apparently necessary for regulation by cAMP. Gel mobility shift assays suggested that a binding factor(s) to these regions was present in the nuclear extracts of Y-1 cells and adrenal cortex tissues and appeared to be different from the somatostatin CRE-binding protein. Deletion analysis also suggested that the region around -44 was essential to the basal transcriptional activity. This region shows some similarity to the CTF NF-1 binding site [Johnson and McKnight (1989) Annu. Rev. Biochem. 58, 799-839].
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PMID:Structures of regulatory regions in the human cytochrome P-450scc (desmolase) gene. 184 89

Guanine nucleotide-binding proteins (G proteins) are critically important mediators of many signal-transduction systems. Several important sites regulating stimulus-secretion coupling and release of insulin from pancreatic beta-cells are modulated by G proteins. Gs mediates increases in intracellular cAMP associated with hormone-induced stimulation of insulin secretin. Gi mediates decreases in intracellular cAMP caused by inhibitors of insulin secretion, e.g., epinephrine, somatostatin, prostaglandin E2, and galanin. G proteins also regulate ion channels, phospholipases, and distal sites in exocytosis. Cholera and pertussis toxins irreversibly ADP ribosylate G proteins and are important tools that can be used both to manipulate G-protein-dependent modulators of insulin secretion and detect and quantify G proteins by electrophoretic techniques. The stage is set to pursue these initial observations in greater depth and ascertain whether G-protein research will provide important new insights into normal and abnormal regulation of insulin secretion.
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PMID:G proteins and modulation of insulin secretion. 190 7

CGRP exerts a potent central action to inhibit gastric acid secretion in rats and dogs and gastric emptying, contractility and ulcer formation in rats. The site of action to inhibit acid secretion has been localized in the dorsal vagal complex. The inhibition of acid secretion is related primarily to the decrease in vagal efferent activity whereas the inhibition of gastric motor functions involves increases in sympathetic outflow. The central action of CGRP to prevent ethanol-induced lesions is unique to this peptide and not shared by other centrally acting inhibitors of gastric function. It may be related to the increase in gastric mucosal blood induced by central CGRP. The presence of CGRP-like immunoreactivity and receptors in medullary nuclei receiving visceral information and influencing vagal outflow suggests a possible role of the peptide in the vagal regulation of gastric secretion. Peripheral injection of CGRP also inhibits acid secretion when administered peripherally in rats, dogs, rabbits and humans. Its antisecretory effect is unlikely to be related to a direct action on the parietal cells. It involves specific and marked release of gastric somatostatin through an interaction with CGRP receptors characterized on D cells and coupled with cAMP. In addition, CGRP induces a decrease in acetylcholine transmission in the enteric nervous system which may contribute to the inhibition of acid. Peripheral CGRP inhibits gastric emptying and motility by a direct action on smooth muscles through receptors linked with cAMP. The release of CGRP from spinal afferents innervating the stomach in response to stimulation of capsaicin-sensitive fibers suggests a role of the peptide in the regulation of gastric function.
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PMID:Central and peripheral actions of calcitonin gene-related peptide on gastric secretory and motor function. 195 Jul 84


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