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 data presented concern the chemistry and biology of cardiotrop peptides and proteins isolated by us from the hypothalamus. The molecular mechanisms of the effect of neurohormone "C" (NC) as well as of a new cardiotrop hexapeptide from cattle hypothalamus are discussed. In in vitro studies on homogenates NC has been found to inhibit greatly not only 3'--5'-cyclo-AMP phosphodiesterase activity of brain and heart but also 3'--5'-cyclo-GMP phosphodiesterase activity. NC has been shown to be bound to specific proteins and to the regulatory unit of cyclo-AMP-dependent histone kinase of brain. It seems to compete with cyclo-AMP for the same proteins and is considered to be a regulator of intracellular cyclic nucleotides. NC has been shown to be combined to specific proteins in brain with non covalent bonds. A new cardiotrop hexapeptide has been shown to be present in bovine hypothalamus and its chemical structure has been found to be Tyr-Leu-Gly-Arg-Pro-Gly-amide. The acetylated form of this hexapeptide, which may be also present in brain, is much more active. The radioimmunochemical experiments carried out with antiserum 744 (from prof. Schally) by us have confirmed the existence of this hexapeptide and other fragments of LH-RH in the bovine hypothalamus. The effect of this hexapeptide on cardiac function and metabolism has been compared with a number of polypeptides (luliberin fragments). The hexapeptide has been shown to have not only cardiotropic but also a hypoglycaemic effect. It enhances the secretion of insulin and counteracts the inhibitory action of somatostatin on the insular apparatus. The hexapeptide produces significant changes in the activities of phosphorylase a and b as well as in that of phosphoprotein phosphatases. It reduces the amount of kinines in blood. Certain fractions of substance P, have been shown to have cardiotrop actitivty--they increase the rate of blood leaving the heart. The organotrop effects of a number of peptide neurohormones are discussed in connection with the hexapeptide. The results obtained have shown that the mechanisms underlying the effects of the cardioactive substances found by us are quite different. The data presented show that in brain a number of chemical factors (mainly peptides) are formed, which are involved in the regulation of heart function.
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PMID:[Chemistry and biology of hypothalamic cardioactive proteins and peptides]. 22 93

It has been assumed that the histamine release from mast cells induced by various neuropeptides or basic protein plays some important roles in the development of the hyperreactivity of airways. In the present study, the mechanisms of the histamine release induced by neuropeptides and histone were investigated. Substance P, somatostatin, neurotensin or histone induced histamine release from isolated rat peritoneal mast cells even in the Ca free medium; Ca2+ release from intracellular Ca store was detected very significantly. In order to study the interaction between neuropeptides and phospholipid bilayer of cell membrane, model membrane systems were used. It was indicated that the interaction between basic amino acid residues of neuropeptides and acidic portion in the lipid bilayer caused the conformational changes of neuropeptides from the random coil in the water to the beta-form in the lipids. At the same time, hydrophobic amino acid residues may interact with the hydrophobic region in the lipid bilayer of cell membrane and induce the membrane perturbation, which may cause an increase of the permeability of the membrane. Subsequently, it became evident that after an increase in intracellular Ca2+ concentration, the cytoskeletons inside the mast cell were activated so as to extrude the granules out of the cell.
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PMID:[Mast cell]. 170 50

Using 32P-labeled histone as exogenous substrate, we showed a potent stimulatory effect of somatostatin on cytosolic phosphoprotein phosphatases (PPPases; phosphoprotein phosphohydrolase, EC 3.1.3.16) in rat gastric mucosal cells. Partial purification of cytosolic fraction in DEAE-Sephadex ion-exchange chromatography and further gel filtration on Sephadex C-75 and Sephadex G-100 separated somatostatin-dependent PPPases into three distinct molecular species. One corresponding to Mr 130,000 was devoid of any PPPase activity but specifically bound [Tyr1]somatostatin 125I-labeled on the Tyr ([125I-Tyr1]somatostatin) with an apparent equilibrium dissociation constant of 3 x 10(-10) M. The two other molecular species corresponded to Mrs 64,000 and 13,000. They produced catalytic dephosphorylation of 32P-labeled histone, but they were not sensitive to somatostatin and did not show any specific binding to radiolabeled hormone. Mixing of the larger with either of the two smaller molecular species resulted in concentration -dependent inhibition of PPPase activity. However this inhibition was reversed by increased concentrations of somatostatin, with the concentration for half-maximal reactivation on being close to 0.1 nM. Furthermore somatostatin stimulation in reconstituted materials developed according to a rapid time course (t1/2, less than 5 sec), consistent with that observed for binding of [125I-Tyr1]somatostatin. These results strongly argue for the presence of an intracellular somatostatin receptor in gastric mucosal cells and characterize this receptor as a PPPase regulatory subunit. Thus, substrate dephosphorylation could be the primary event triggering physiological effects of somatostatin in stomach and perhaps other organs of the digestive tract [Reyl, F. & Lewin, M. J.l M. (1981) Biochim. Biophys. Acta 675, 297-300].
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PMID:Intracellular receptor for somatostatin in gastric mucosal cells: decomposition and reconstitution of somatostatin-stimulated phosphoprotein phosphatases. 612 13

In this report we describe a novel in vitro phenomenon involving the interaction of insulin with purified protein phosphatases. Evidence is presented that porcine insulin is capable of activating and binding to rabbit skeletal muscle protein phosphatases in vitro. Its effects were examined on four rabbit skeletal muscle protein phosphatases. Two of these, phosphatases C-I and C-II, are of Mr approximately 35,000 and are the dissociated forms of protein phosphatase. The two other phosphatases, H-I and H-II, have Mr approximately 250,000 by gel filtration and represent nondissociated forms of phosphatase. Insulin reproducibly activated homogeneous preparations of protein phosphatase C-II and H-II approximately 3-5-fold in vitro. The activation was dependent on temperature, time, and insulin concentration. The activities of the phosphatases toward both phosphorylase alpha and histone were affected, indicating that this was not a substrate-directed effect. The activation phenomenon was not mimicked by insulin A or B chains, somatostatin, glucagon, or bovine serum albumin, and could be prevented by insulin antiserum. 125I-Insulin was shown to bind to the protein phosphatases by solid phase binding assays. Phosphatases C-I, C-II, and H-II, but not phosphatase H-I, were found to bind insulin reversibly. Half-maximal binding to the protein phosphatases was observed at approximately 5 X 10(-10) M insulin. Labeled insulin was found to coelute with protein phosphatase H-II on gel filtration when a mixture of the two was chromatographed, providing evidence for the formation of an enzyme-insulin complex. These findings suggest that certain protein phosphatases may have a specific binding site(s) for insulin and that these insulin-phosphatase complexes may also exhibit enhanced catalytic activity.
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PMID:A novel in vitro interaction of insulin with rabbit skeletal muscle protein phosphatases. 632 53

Isolated sheep thyroid follicles release insulin-like growth factors (IGF)-I and -II together with IGF-binding proteins (IGFBPs). We previously showed that TSH suppresses the biosynthesis and release of IGFBPs in vitro which may increase the tissue availability of IGFs, allowing a synergy with TSH which potentiates both thyroid growth and function. Many of the actions of TSH on thyroid cell function are dependent upon activation of adenylate cyclase, although increased synthesis of inositol trisphosphate and activation of protein kinase C (PKC) have also been implicated. We have now examined whether probable changes in intracellular cyclic adenosine monophosphate (cAMP) or PKC are involved in TSH-mediated suppression of IGFBP release. Confluent primary cultures of ovine thyroid cells were maintained in serum-free Ham's modified F-12M medium containing transferrin, somatostatin and glycyl-histidyl-lysine (designated 3H), and further supplemented with sodium iodide (10(-8)-10(-3) mol/l), dibutyryl cAMP (0.25-1 mmol/l), forskolin (5-20 mumol/l) or 12-O-tetradecanoylphorbol-13-acetate (TPA; 10(-11)-10(-6) mol/l), with or without exposure to TSH (200 microU/ml). The uptake and organification of Na [125I] by cells was examined after test incubations of up to 48 h, and IGFBPs in conditioned media were analysed by ligand blot using 125I-labelled IGF-II. The PKC activity in the cytosol and plasma membrane fractions of cells was measured by phosphorylation of histone using [gamma-32P]ATP, and PKC immunoreactivity was visualized by Western immunoblot analysis. While dibutyryl cAMP or forskolin largely reproduced the stimulatory effect of TSH on iodine organification, they did not mimic the inhibitory effect of TSH on the secretion of IGFBPs of 43, 34, 28 and 19 kDa. Incubation with physiological or pharmacological concentrations of iodide (10(-6)-10(-3) mol/l) for up to 48 h significantly decreased TSH action on iodide uptake and organification but did not alter the inhibitory action of TSH on IGFBP release. Incubation of cells with 10(-11)-10(-6) mol TPA/l for 24 h inhibited the subsequent ability of TSH both to potentiate iodine organification and to suppress IGFBP release. In 3H medium, PKC activity was predominantly recovered from the membrane fraction but, following incubation for 48 h with TSH, the enzyme was no longer translocated to the membrane and was recovered predominantly from the cytosol.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Role of 3', 5' cyclic adenosine monophosphate and protein kinase C in the regulation of insulin-like growth factor-binding protein secretion by thyroid-stimulating hormone in isolated ovine thyroid cells. 751 34

Studies were undertaken to elucidate further the mechanism whereby the pancreatic peptide amylin induces insulin resistance. Sixteen male Sprague-Dawley rats underwent hyperinsulinemic (14 pmol/kg/min, 0 to 120 minutes) euglycemic clamps in the presence or absence of amylin (500 pmol/kg/min, 60 to 120 minutes). Amylin induced insulin resistance at both the hepatic level (mean +/- SE: hepatic glucose output [HGO] with amylin 1.4 +/- 0.2 v without amylin -1.9 +/- 0.3 mmol/kg/h, P < .001) and peripheral level (glucose disposal [Rd] with amylin 5.0 +/- 0.2 v without amylin 8.5 +/- 0.6 mmol/kg/h, P < .001). Serum insulin levels were similar in the presence or absence of amylin alone (661 +/- 89 v 636 +/- 50 pmol/L, respectively, P = NS), but were significantly less when somatostatin (SRIF) was simultaneously infused (408 +/- 15 pmol/L, P < .02 v the other two groups). This suggests that endogenous insulin production was not suppressed by amylin under these study conditions. Similar findings were obtained in 18 animals in the absence of exogenous insulin infusion. In vitro kinase activity toward histone of skeletal muscle insulin receptors (IRs) activated by insulin in vivo was reduced in the presence of amylin to 6.0 +/- 0.8 versus 9.1 +/- 1.2 fmol phosphate into histone (insulin-infused) and 3.9 +/- 0.7 versus 6.9 +/- 1.4 (non-insulin-infused; P < .03 by ANOVA). Serum calcium was significantly decreased in amylin-treated animals (1.93 +/- 0.04 v 2.30 +/- 0.05 mmol/L, P < .001).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Amylin-mediated reduction in insulin sensitivity corresponds to reduced insulin receptor kinase activity in the rat in vivo. 778 53

We previously introduced the concept that intrahepatic bile duct epithelial cells, or cholangiocytes, are functionally heterogeneous. This concept is based on the observation that secretin receptor (SR) gene expression and secretin-induced cAMP synthesis are present in cholangiocytes derived from large (> 15 microns in diameter) but not small (< 15 microns in diameter) bile ducts. In work reported here, we tested the hypothesis that cholangiocytes are heterogeneous with regard to proliferative capacity. We assessed cholangiocyte proliferation in vivo by measurement of [3H]thymidine incorporation and in vitro by both [3H]thymidine incorporation and H3 histone gene expression in small (fraction 1) and large (fraction 2) cholangiocytes isolated from rats after bile duct ligation (BDL). In the two cholangiocyte subpopulations, we also studied basal somatostatin receptor (SSTR2) gene expression as well as the effects of somatostatin on 1) SR gene expression and secretin-induced cAMP synthesis and 2) [3H]thymidine incorporation and H3 histone gene expression. In normal rat liver, cholangiocytes, unlike hepatocytes, were mitotically dormant; after BDL, incorporation of [3H]thymidine markedly increased in cholangiocytes but not hepatocytes. When subpopulations of cholangiocytes were isolated after BDL, DNA synthesis assessed by both techniques was limited to large cholangiocytes, as was SSTR2 steady-state gene expression. In vitro, somatostatin inhibited SR gene expression and secretin-induced cAMP synthesis only in large cholangiocytes. Moreover, compared with no hormone, somatostatin inhibited DNA synthesis solely in large cholangiocytes. These results support the concept of the heterogeneity of cholangiocytes along the biliary tree, extend this concept to cholangiocyte proliferative activity, and imply that the proliferative compartment of cholangiocytes after BDL is located principally in the cholangiocytes lining large (> 15 microns) bile ducts.
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PMID:Heterogeneity of the proliferative capacity of rat cholangiocytes after bile duct ligation. 957 60

The thymus provides an optimal humoral microenvironment for the development of immunocompetent T cells. Although yolk sac derived pre-T, committed hematopoietic stem cells enter the thymus using a homing receptor, the immigration process also requires secretion of a peptide called thymotaxin by the cells of the reticulo-epithelial (RE) network of the thymic cellular microenvironment. The majority of RE cells have a round or irregular pale nucleus, which contains few, scattered, chromatin granules with a defined, spherical nucleolus, rich in basic histones. Their cytoplasm occasionally displays RNP granules, and is rich in non-histone proteins, fine phospholipid, lipid or cholesterin granules, and vacuoles filled with secreted substances. The cells of the subcapsular, endocrine RE cell layer (giant or nurse cells), characterized by PAS positive granules, express A2B5/TE4 cell surface antigens and MHC Class I (HLA A, B, C) molecules. In contrast to medullar RE cells, these subcapsular nurse cells also produce thymosins beta 3 beta 4. Thymic nurse cells (TNCs) display a neuroendocrine cell specific immunophenotype (IP): Thy-1+, A2B5+, TT+, TE4+, UJ13/A+, UJ127.11+, UJ167.11+, UJ181.4+, and presence of common leukocyte antigen (CLA+). Medullar RE cells display MHC Class II (HLA-DP, HLA-DQ, HLA-DR) molecule restriction. These cells also contain transforming growth factor-beta (TGF-beta) type II receptors and participate in the positive selection of T cells. Transmission electron-microscopic (TEM) observations have defined four functional subtypes of medullar RE cells: undifferentiated, squamous, villous, and cystic. All subtypes are connected by desmosomes. Immunocytochemical observations have shown that the secreted thymic hormones, thymosin alpha 1 and thymopoietin (and its short form, thymopentin or TP5), are produced by the same RE cells. Thymic RE cells also produce numerous cytokines including IL1, IL6, G-CSF, M-CSF, and GM-CSF that likely are important in various stages of thymocyte activation and differentiation. The co-existence of pituitary hormone and neuropeptide secretion, such as growth hormone, prolactin, adrenocorticotropic hormone, thyroid stimulating hormone, triiodothyronine, somatostatin, oxytocin, follicle stimulating hormone, luteinizing hormone, arginine vasopressin, growth hormone releasing hormone, corticotropin releasing hormone, nerve growth factor, vasoactive intestinal peptide, (pro) enkephalin, and beta-endorphin, production of a number of interleukins and growth factors, as well as the expression of receptors for all, by the same RE cell is an unique molecular biological phenomenon. These data illustrate the immensely important and diverse immuno-neuroendocrine functions of the thymic RE cellular network. Based on our systematic observations of the thymus in humans and other mammalian species, we suggest that the thymic RE cell network represents an extremely important cellular and humoral microenvironment in homeopathic regulatory mechanisms of the multicellular organism. Intrathymic T lymphocyte selection is a complex, multistep process, influenced by several functionally specialized RE cell subtypes and under constant immuno-neuroendocrine regulation, reflecting the dynamic changes of the organism.
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PMID:Molecular biological ontogenesis of the thymic reticulo-epithelial cell network during the organization of the cellular microenvironment. 1045 6

Type 1 diabetes is caused by the destruction of pancreatic beta-cells by T cells of the immune system. Islet transplantation is a promising therapy for diabetes mellitus. Bone marrow stem cells (BMSC) have the capacity to differentiate into various cell lineages including endocrine cells of the pancreas. To investigate the conditions that allow BMSC to differentiate into insulin-producing cells, a novel in vitro method was developed by using the histone deacetylase inhibitor, trichostatin A (TSA). BMSC, cultured in presence of TSA, differentiated into islet-like clusters under appropriate culture conditions. These islet-like clusters were similar to the cells of the islets of the pancreas. The islet-like clusters showed endocrine gene expression typical for pancreatic beta-cell development and function, such as insulin (I and II), glucagon, somatostatin, GLUT-2, pancreatic duodenal homeobox-1 (PDX-1), and Pax 4. Immunocytochemistry confirmed islet-like clusters contained pancreatic hormones. The colocalization of insulin and C-peptide was also observed. Enzyme-linked immunosorbent assay analysis demonstrated that insulin secretion was regulated by glucose. Western blot analysis demonstrated the presence of stored insulin. Electron microscopy of the islet-like cells revealed an ultrastructure similar to that of pancreatic beta-cells, which contain insulin granules within secretory vesicles. These findings suggest that histone-deacetylating agents could allow the differentiation of BMSC into insulin-producing beta-cells.
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PMID:Chromatin-remodeling factors allow differentiation of bone marrow cells into insulin-producing cells. 1699 May 88

Treatment options of advanced neuroendocrine tumors (NETs) are unsatisfactory. Hence, innovative therapeutic approaches are urgently needed. Inhibition of histone deacetylases (HDACs) is a promising new approach in cancer therapy. While several HDAC inhibitors have already entered clinical trials, the effect of HDAC inhibition on NET has not been investigated. Therefore, we evaluated the antineoplastic effects of three different HDAC inhibitors, trichostatin A (TSA), sodium butyrate (NaB), and MS-275, on growth and apoptosis of the gastrointestinal NET cell lines CM and BON. We could demonstrate that HDAC inhibition dose-dependently inhibited proliferation of both cell lines with IC50 values varying from the millimolar (NaB) to the micromolar (MS-275) and the nanomolar range (TSA). Moreover, HDAC inhibition potently induced apoptosis, which was accompanied by DNA-fragmentation, an up to 12-fold caspase-3 activation and downregulated Bcl-2 expression. Furthermore, HDAC inhibition resulted in cell cycle arrest at the G1-S-transition, which was associated with the suppression of cyclin D1 expression and induction of p21 and p27 expression. For BON cells, we observed an additional block in the G2/M phase, which was aligned with a downregulation of cyclin B1. In addition, combined treatment with MS-275 and somatostatin or the synthetic somatostatin analog octreotide was evaluated. Neither somatostatin nor its stable analog octreotide augmented the antiproliferative effect of MS-275 in NET cells. To conclude, our data show that HDAC inhibition is a promising new approach in the treatment of NET disease, which should be evaluated in clinical studies.
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PMID:Antiproliferative and proapoptotic effects of histone deacetylase inhibitors on gastrointestinal neuroendocrine tumor cells. 1715 68


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