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)

Interleukin 2 (IL-2) stimulated the differentiation of human peripheral blood leukocytes into lymphokine-activated killer cells, as well as DNA synthesis of human T lymphocytes. Both effects of IL-2 could be inhibited by prostaglandin E2, a potent stimulator of adenylate cyclase; however, the inhibitory effect of prostaglandin E2 could be overcome by increased concentrations of IL-2. The opposite effects of IL-2 and prostaglandin E2 were paralleled by their respective abilities to inhibit and stimulate cAMP production in intact cells. Other agents, which inhibit adenylate cyclase directly (somatostatin, beta-endorphin, UK 14.3041) or indirectly by activation of protein kinase C (phenylephrine), could stimulate both differentiation and proliferation. None of these agents alone or in combination were as effective as maximal concentrations of IL-2. However, all agents potentiated differentiation and proliferation induced by submaximal and maximal concentrations of IL-2. Additionally, combinations of agents which stimulated protein kinase C with those that inhibited adenylate cyclase were additive in the potentiation of IL-2-induced differentiation. Neither inhibition nor potentiation of IL-2-induced lymphokine-activated killer cell differentiation was accompanied by changes in Tac expression or gamma-interferon production. The data indicate that the stimulation of lymphokine-activated killer cell differentiation and lymphocyte proliferation in human cells share a common initial biochemical signal. Although the inhibition of adenylate cyclase is not sufficient to maximally stimulate either process and cannot bypass the requirement for IL-2, modulation of this enzyme complex, positively or negatively, can regulate the ultimate physiologic response to IL-2.
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PMID:Potentiation of lymphokine-activated killer cell differentiation and lymphocyte proliferation by stimulation of protein kinase C or inhibition of adenylate cyclase. 244 68

Patients with medullary thyroid carcinomas (MTC) were analyzed according to age, sex, and tumor stage. In addition, the MTC were screened for the predominant histologic pattern, immunocytochemical spectrum (60 tumors), and DNA content (DNA cytophotometry and DNA flow cytometry, 25 tumors). These findings were correlated with follow-up data available for 45 of these patients. Forty-eight percent of the tumors revealed a polygonal cell pattern, whereas 22% showed spindle-cell predominance. All tumors contained cytokeratin, chromogranin A, and calcitonin (CT). Calcitonin gene-related peptide (CGRP) was present in 92%, carcinoembryonic antigen (CEA) in 77%, neuron-specific enolase (NSE) in 75%, and vimentin in 53% of cases. Positivity for neurotensin, somatostatin, neurofilaments, bombesin, and alpha human chorionic gonadotropin (a-hCG) and serotonin ranged between 3% and 27%. All MTC were negative for substance P, adrenocorticotropic hormone (ACTH), thyroglobulin (TG), or S-100 protein. Local recurrences and regional lymph node metastases revealed identical staining patterns as the primaries. Prognosis of MTC was found not to be related to histologic features (dominant architectural pattern, cellular shape, presence of amyloid deposits) or immunocytochemical pattern. Instead, survival was significantly correlated to age, sex, and stage of disease. The best prognosis was seen in women younger than 40 years and revealing an early stage of disease. DNA measurements added valuable information in assessing the prognosis of MTC.
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PMID:Prognostic factors in medullary thyroid carcinomas. Survival in relation to age, sex, stage, histology, immunocytochemistry, and DNA content. 244 25

The two mammalian neuropeptides substance P (SP) and neurokinin A (NKA) have been demonstrated to stimulate DNA synthesis in connective tissue cells, suggesting that peripheral neurons may play a role in development and tissue regeneration. In this study we have tried to identify intracellular messengers required for SP- and NKA-induced DNA synthesis. SP and NKA, as well as platelet-derived growth factor (PDGF) stimulated formation of inositol phosphates in smooth muscle cells (SMC), whereas no effect on inositol phosphates formation occurred in response to nonmitogenic neuropeptides. Pretreatment of the cells with pertussis toxin markedly decreased DNA synthesis induced by NKA. This toxin inhibits formation of inositol phosphates by acting on a regulatory G-protein. Calcium and calmodulin antagonists also inhibited NKA-induced DNA synthesis. These results imply that the mitogenic signal(s) produced by activated neuropeptide receptors involves formation of inositol phosphate and activation of a calcium/calmodulin dependent process. We further report that other neuropeptides occurring in peripheral neurons, i.e., vasoactive intestinal polypeptide, calcitonin gene-related peptide, neuropeptide Y, somatostatin, or cholecystokinin, are without growth-stimulatory effect on cultured SMC.
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PMID:Coupling between inositol phosphate formation and DNA synthesis in smooth muscle cells stimulated with neurokinin A. 245 38

The neuropeptides substance P (SP), somatostatin (SOM), and vasoactive intestinal peptide (VIP) have been shown to modulate lymphocyte DNA, RNA, and immunoglobulin synthesis. We have previously shown that SP enhances while SOM and VIP inhibit proliferation of murine splenic and Peyer's patch lymphocytes when cells were cultured with concanavalin A and neuropeptides for 72 h. Here we show that the effect of neuropeptides, in particular SP, is dependent on the amount of time that lymphocytes are incubated with NP. We found that SOM and VIP always inhibited cell proliferation for incubation times of 2 to 72 h. In contrast when cells were exposed to SP for 24 h or less, there was inhibition of [3H]thymidine uptake by both Peyer's patches and splenic lymphocytes. Significant enhancement in DNA synthesis by lymphocytes from both organs was only seen when cells were incubated with SP for the whole 72 h. We believe that our data may explain some of the conflicting reports regarding the effects of neuropeptides on cell proliferation.
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PMID:The differential effect with time of neuropeptides on the proliferative responses of murine Peyer's patch and splenic lymphocytes. 246 78

The glycoprotein hormone alpha-gene is preferentially expressed in placental cell lines, but it is also expressed in several other cell lines indicating that the differential activity of the alpha-gene regulatory elements in various cell types is more quantitative than qualitative. The 5'-flanking region of the alpha-gene contains several distinct DNA regulatory sequences including an upstream regulatory element [(URE) -181 to -150 base pairs (bp)] that stimulates basal expression and an 18 bp twice-repeated cAMP-responsive element [(CRE) -146 to -111 bp]. We constructed an array of fusion genes containing the URE and/or the CRE linked to different truncated promoters [alpha-gene, somatostatin (SRIF), glucagon, Simian Virus 40]. These constructions were transiently expressed in placental, fibroblast, or islet cell lines to identify regulatory sequences involved in cell-specific expression as well as interactions between the URE, the CRE, and different promoter elements. The URE, CRE, and alpha-promoter elements contribute approximately 3-, 6-, and 5-fold, respectively, to preferential expression in JEG-3 cells. In JEG-3 cells, the URE is strictly dependent on the CRE for activity, but it functions in a promoter-independent manner. In contrast, the CRE is markedly promoter dependent. When linked to heterologous enhancers, the alpha-promoter is more active in JEG-3 cells than in other cell lines, thereby contributing substantially to preferential expression in placental cells. Although the CREs derived from the alpha and SRIF genes both activate expression of the alpha promoter, only the alpha CRE activates the SRIF promoter in JEG-3 cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Enhancer and promoter element interactions dictate cyclic adenosine monophosphate mediated and cell-specific expression of the glycoprotein hormone alpha-gene. 247 27

The insulin release from isolated pancreatic islets grafted under the kidney capsule was examined by means of a modified kidney-perfusion technique. The grafts, consisting of 150 C57BL/6 or 250 C57BL/Ks mouse islets, were implanted syngeneically under the left kidney capsule of normoglycemic or alloxan-induced diabetic recipients 4 wk before the perfusion. In both mouse strains, islets grafted to normoglycemic animals showed an immediate distinct peak of insulin release when challenged with high glucose, whereas no response was observed from islets grafted to hyperglycemic mice. In a similar way in C57BL/Ks mice, arginine stimulated insulin release from the islet grafts in normoglycemic but not in hyperglycemic recipients. Insulin treatment of the diabetic recipients, however, partially normalized the insulin response to glucose. Islet grafts were removed in toto and analyzed for contents of insulin, glucagon, somatostatin, and DNA or rates of glucose-stimulated (pro)insulin biosynthesis. In both mouse strains, islets implanted into hyperglycemic animals contained significantly less insulin, and their rates of (pro)insulin biosynthesis were markedly decreased. Insulin treatment only marginally affected these parameters. The glucagon content of the grafted islets was unaffected by the hyperglycemia in both strains of mice, whereas a significant decrease in the somatostatin content was observed in the C57BL/Ks mice. We concluded that grafted islets exposed to prolonged hyperglycemic stress become functionally impaired in mice of both strains. Our perfusion technique of islet-graft-bearing kidneys in combination with biochemical studies on the removed grafts provides a suitable model for studies of the effects of prolonged hyperglycemia on islet beta-cell function.
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PMID:Effects of hyperglycemia on function of isolated mouse pancreatic islets transplanted under kidney capsule. 249 93

The functional responses of the pancreatic B-cells after cytotoxic damage are still largely unknown. Using in vitro models to clarify this issue, we have recently observed a preferential reduction of glucose-stimulated insulin production and release in mouse pancreatic islets maintained in culture after in vitro exposure to streptozotocin. In order to evaluate the relevance of these findings in vivo, two sets of experiments were performed. First, mouse pancreatic islets were exposed in vitro to 2.2 mmol/l streptozotocin or vehicle alone, cultured for 6 days, and finally grafted under the kidney capsule of normoglycemic nude mice. Two weeks after transplantation there was no difference in the total DNA and insulin content between the two groups of islet grafts, but the insulin concentration, as expressed per microgram DNA, was decreased by 40% in the streptozotocin-treated islets. The insulin release of the grafts, during perfusion of the graft-bearing kidney in situ with 16.7 mmol/l glucose was diminished in the streptozotocin group, whilst perfusion with 16.7 mmol/l glucose plus 5 mmol/l theophylline was able partially to counteract the reduction in insulin release. In the second set of experiments, NMRI mice were injected iv with 160 mg/kg streptozotocin or vehicle alone, and their islets isolated 15 min after the injections. After 6 days in culture, there was no decrease in DNA, glucagon and somatostatin contents, but the insulin content was decreased by 40% in the streptozotocin exposed islets. These islets also showed a 60% decrease in the insulin response to glucose, which was partly counteracted by incubation with 16.7 mmol/l glucose plus 5 mmol/l theophylline.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Persistent impairment of the insulin response to glucose both in vivo and in vitro after streptozotocin exposure: studies with grafted pancreatic islets and islets maintained in culture. 253 50

Phenotypically distinct islet tumor cell lines may recapitulate certain of the developmental pathways of normal islet cell differentiation by expressing a combinatorial set of positively and negatively acting DNA-binding proteins to allow for the programmed expression of genes encoding polypeptide hormones. The structure of one of these DNA-binding proteins, a cyclic AMP-responsive protein (CREB) that binds specific DNA regulatory elements in the somatostatin gene, has been deduced from the sequence of a cloned cDNA. The CREB protein contains a DNA-binding domain separate from a cAMP-dependent protein kinase A activation domain. Further characterizations of the genes encoding the DNA-binding proteins should help to elucidate the cellular processes involved in islet cell differentiation and the genesis of tumors.
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PMID:Factors that determine cell-specific gene expression in pancreatic endocrine tumor cells. 255 19

A 43-kDa DNA binding protein which recognizes the TGACGTCA element of the rat somatostatin promoter has been purified from rat brain. Purification of the protein involved initial separation of three sequence-specific binding activities, b1-b3, from each other using DEAE-Sepharose chromatography. The protein corresponding to the b2 complex was further purified to apparent homogeneity by two cycles of sequence-specific DNA affinity chromatography, yielding a single species with an apparent mass of 43,000 daltons on a silver-stained polyacrylamide gel. Sequence-specific DNA binding of this purified protein was demonstrated by Southwestern blotting, renaturation, and DNase I footprinting studies. The 43-kDa protein was phosphorylated on serine residue(s) by the catalytic subunit of cAMP-dependent protein kinase, as shown by phosphoamino acid analysis. Furthermore, the purified protein specifically stimulated transcription from the rat somatostatin promoter in an in vitro transcription system. These results indicate that this 43-kDa protein is a transcription factor required for somatostatin gene expression.
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PMID:Purification and characterization of a 43-kDa transcription factor required for rat somatostatin gene expression. 256 50

Somatostatin is a peptide synthesized in the pancreatic islets, nervous system, gastrointestinal tract, and thyroid gland. Factors that control islet cell-specific expression of the somatostatin gene were analyzed by expression of fusion genes consisting of 5' rat somatostatin gene sequences linked to coding sequences of the receptor genes, bacterial chloramphenicol acetyltransferase, and human growth hormone. Fusion genes containing 900 and 250 base pairs (bp) of 5'-flanking DNA were preferentially expressed at 5-10-fold higher levels in somatostatin-producing islet cell lines, as compared with islet cell lines that produced insulin and glucagon, and in three non-islet cell lines. A deletional mutation consisting of only 65 bp of 5'-flanking sequence of the rat somatostatin gene expressed in all islet cell lines but not in non-islet lines, indicating the existence of a negative-acting islet cell-specific element located between nucleotides -250 and -65. The 65-bp sequence contains the octameric cAMP-responsive enhancer (CRE) TGACGTCA (nucleotides -48 to -41). Fine mapping of sequences responsible for islet-specific expression by substitution of synthetic oligonucleotide cassettes revealed full retention of expression by deletion to nucleotides -48 and complete loss of expression at nucleotides -42 of the CRE. Substitution of the 9 bp adjacent 3' to the CRE of the somatostatin gene (nucleotides -40 to -32) with the corresponding sequence located 3' to the CRE of the glucagon gene abolished expression. By gel mobility shift and DNaseI footprinting analyses, proteins in extracts of islet cells bound to the 24 bp including the CRE and downstream adjacent 9 bp (nucleotides -58 to -35). An additional upstream region of DNA was protected from DNase I digestion (nucleotides -110 to -80). Proteins from non-islet cells bound to the region from nucleotides -58 to -35, but patterns of DNase I protection differed from those using proteins from islet cells. These observations indicate that several DNA-binding proteins interact with cis-acting elements located between 35 and 58 bp upstream of the transcriptional start site of the rat somatostatin gene to determine islet cell-specific gene expression. CRE-binding protein(s) is ubiquitous among phenotypically different cells, and expression of the somatostatin gene in non-somatostatin-producing islet cells appears to be inhibited by a negative-acting element located upstream of the CRE.
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PMID:Somatostatin gene expression in pancreatic islet cells is directed by cell-specific DNA control elements and DNA-binding proteins. 256 13


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