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)

Transcription of proto-oncogene fos is induced by elevated levels of intracellular cAMP. We report that human c-fos promoter recombinants transfected into rat pheochromocytoma cells (PC12) and human choriocarcinoma cells (JEG-3) are induced by stimulation of adenylate cyclase and that this induction is diminished considerably in the mutant PC12 cell line A126-1B2, which is deficient in cAMP-dependent protein kinase II. An element centered at position -60 of the c-fos promoter, which encompasses a consensus cAMP response element (CRE), is sufficient to confer cAMP responsiveness to a herpes thymidine kinase/CAT fusion gene. The specific binding of a nuclear protein to the c-fos CRE can be competed by the somatostatin and alpha-chorionic gonadotropin (alpha-CG) promoter regions that contain CREs. Gel mobility shift assays with double-stranded oligonucleotides containing either the wild-type or mutated c-fos CRE sequence have demonstrated that binding occurs only to the wild-type CRE. The nuclear factor binding to the c-fos CRE is likely to be transcription factor CREB (CRE nuclear binding protein), because an affinity-purified 43-kD CREB isolated from PC12 cells binds efficiently in a DNA footprinting assay. Thus, regulation of the c-fos gene transcription appears to involve a mechanism common to many genes that respond to cAMP as a second message leading to cell growth and differentiation.
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PMID:Induction of proto-oncogene fos transcription through the adenylate cyclase pathway: characterization of a cAMP-responsive element. 285 Sep 67

We have examined the regulation of somatostatin gene expression by cAMP in PC12 rat pheochromocytoma cells transfected with the rat somatostatin gene. Forskolin at 10 microM caused a 4-fold increase in somatostatin mRNA levels within 4 hr of treatment in stably transfected cells. Chimeric genes containing the somatostatin gene promoter fused to the bacterial reporter gene encoding chloramphenicol acetyltransferase were also induced by cAMP in PC12 cells. To delineate the sequences required for response to cAMP, we constructed a series of promoter deletion mutants. Our studies defined a region between 60 and 29 base pairs upstream from the transcriptional initiation site that conferred cAMP responsiveness when placed adjacent to the simian virus 40 promoter. Within the cAMP-responsive element of the somatostatin gene, we observed an 8-base palindrome, 5'-TGACGTCA-3', which is highly conserved in many other genes whose expression is regulated by cAMP. cAMP responsiveness was greatly reduced when the somatostatin fusion genes were transfected into the mutant PC12 line A126-1B2, which is deficient in cAMP-dependent protein kinase 2. Our studies indicate that transcriptional regulation of the somatostatin gene by cAMP requires protein kinase 2 activity and may depend upon a highly conserved promoter element.
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PMID:Identification of a cyclic-AMP-responsive element within the rat somatostatin gene. 287 59

Many hormones act on neuroendocrine cells by activating second messenger pathways. Two of these, the phosphoinositol and cAMP-dependent pathways, cause changes in cellular activity through specific protein kinases. By phosphorylating cytoplasmic and nuclear proteins, these kinases apparently coordinate cellular processes, including the biosynthesis and release of neuropeptides. Somatostatin biosynthesis and release, for example, are both positively regulated by the second messenger cAMP in hypothalamic cells, and cAMP also induces somatostatin gene transcription 8-10-fold in transfected PC12 pheochromocytoma cells. Transcriptional induction requires a 30-nucleotide cAMP response element (CRE) which is conserved in other cAMP-responsive genes. This element also confers cAMP responsiveness when placed upstream of the heterologous simian virus 40 (SV40) promoter. The somatostatin gene does not, however, respond to cAMP in mutant PC12 cells which lack cAMP-dependent protein kinase type II activity. Activation of somatostatin gene transcription may consequently require the phosphorylation of a nuclear protein which binds to the CRE. Using a DNase I protection assay, we have characterized a nuclear protein in PC12 cells which binds selectively to the CRE in the somatostatin gene. We have purified this protein which is of relative molecular mass 43,000 (Mr 43K) by sequence-specific DNA affinity chromatography. This 43K CRE binding protein (CREB) is phosphorylated in vitro when it is incubated with the catalytic subunit of cAMP-dependent protein kinase. Stimulating PC12 cells with forskolin, an activator of adenyl cyclase, causes a 3-4-fold increase in the phosphorylation of this protein. We conclude that the cAMP-dependent pathway may regulate gene transcription in response to hormonal stimulation by phosphorylating this CREB protein.
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PMID:Binding of a nuclear protein to the cyclic-AMP response element of the somatostatin gene. 288 56

Early in adenovirus infection, the E1A (early region 1A) oncogene products trans-activate the other early viral transcription units, as well as some cellular promoters. The mechanism by which E1A elicits its activity is still unknown. In this report, I show that the adenovirus E2a and E3 promoters are cAMP inducible in rat pheochromocytoma PC12 cells and that this activation requires the presence of the cAMP-dependent protein kinase II. Using deletion mutants of the E2a promoter, it was found that the sequence TACGTCAT located between positions -70 and -77 is involved in both the cAMP response and the E1A trans-activation. Also, in the mutant PC12 cell line A126-2B, which lacks the cAMP-dependent protein kinase II, E1A is still able to activate E2a and E3 promoters. This suggests that E1A products may circumvent the lack of the kinase by activating an alternative signal transduction pathway, which could mimic the effect of agonists of adenylate cyclase. I propose that E1A is capable of modifying by phosphorylation, either directly or indirectly, the transcription factor that binds the ACGTCA motif. Such a factor, termed ATF (adenovirus transcription factor), has already been characterized and appears to have strong similarities to the transcriptional factor CREB (cAMP responsive element binding protein), which binds homologous sequences in cAMP responsive genes, such as somatostatin and c-fos.
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PMID:Cyclic AMP induction of early adenovirus promoters involves sequences required for E1A trans-activation. 290 26

Rat GH-releasing factor (rGRF) stimulated GH release and intracellular cAMP accumulation in cultured rat anterior pituitary cells with EC50 values of approximately 10 and 150 pm, respectively. Consistent with an effect on cellular cAMP levels, rGRF stimulated the adenylate cyclase activity of rat anterior pituitary membranes with an EC50 value of approximately 60 pm. Using antisera directed against the regulatory subunits of type I and II cAMP-dependent protein kinases, these enzymes were immunoprecipitated from the cytosolic fraction of cultured cells in order to monitor the degree of their activation by rGRF. Both isoenzymes were rapidly activated in cells incubated with rGRF but with different kinetics; full activation of protein kinase I was evident within 3-5 min and activation of protein kinase II occurred between 5 and 15 min. The magnitude of activation was differentially regulated by rGRF in a concentration-dependent manner. Somatostatin only partially attenuated rGRF-stimulated GH release, cAMP accumulation, and adenylate cyclase activation. Somatostatin was effective in partially antagonizing activation of protein kinase II at all concentrations of rGRF and of protein kinase I only at intermediate concentrations of rGRF. The significance of this rGRF-induced differential activation of the two isoenzymes of cAMP-dependent protein kinase is discussed in terms of the multiple effects of rGRF on somatotropic cells of the rat anterior pituitary.
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PMID:Differential activation of type I and type II 3',5'-cyclic adenosine monophosphate-dependent protein kinases by growth hormone-releasing factor. 313 53

Isolated rat pancreatic islets, incubated in the presence of extracellular 32Pi to a state of steady 32P incorporation into cellular phosphopeptides, were exposed to glucagon, (Bu)2cAMP, or somatostatin for 10 min. In other experiments, homogenates of rat islets were phosphorylated using [gamma-32P]ATP with or without cAMP. Proteins were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and phosphorylation of proteins was measured by liquid scintillation counting of gel slices. Glucagon (2.9 X 10(-7) M) stimulated the phosphorylation of 15 polypeptides (by approximately 20-50%) with major phosphorylation of proteins with mol wts of 138,000, 93,000, 53,000, 49,000, 35,000, 27,000 and 15,000 in intact rat islets and also stimulated insulin release by 202%. Somatostatin (6.6 X 10(-7) M) inhibited all the glucagon-stimulated phosphorylation by approximately 15-30% and also inhibited the glucagon-stimulated insulin release by 46%. (Bu)2cAMP (10(-3) M) stimulated 32P incorporation (by approximately 20-50%) into the same 15 peptides as did glucagon and also stimulated insulin release by 169%. When homogenates of rat islets were used. cAMP (10(-6) M) stimulated the phosphorylation of proteins (by approximately 25-60%) to an extent similar to that seen in the presence of glucagon or (Bu)2cAMP in intact islets. These findings indicate that the glucagon-stimulated phosphorylation of rat islet proteins may be mediated by cAMP-dependent protein kinase and that protein phosphorylation may be important in mediating the glucagon-stimulated insulin release.
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PMID:Effect of glucagon and cyclic adenosine 3',5'-monophosphate on protein phosphorylation in rat pancreatic islets. 612 26

We have prepared a fluorescent conjugate of porcine calmodulin with 5-(dimethylamino)-1-naphthalene-sulfonyl chloride that is highly sensitive to both calcium binding and protein binding. We have used the fluorescence of this conjugate in addition to the intrinsic peptide fluorescence to show that adrenocorticotropic hormone (ACTH), beta-endorphin, glucagon, and substance P undergo calcium-dependent binding by calmodulin, with competition for common binding sites. The dissociation constants determined in the presence of 0.85 mM CaCl2 and 0.2 N KC1, pH 7.3 at 25 degrees C, range from 1.5 muM to 3.4 muM. The alpha-melanocyte-stimulating hormone, bombesin, and somatostatin also bind, with dissociation constants between 60 muM and 90 muM. Angiotensins I and III, bradykinin, neurotensin, physalaemin, substance P octapeptide, insulin, and Leu- and Met-enkephalin show little or no binding. Sequence comparisons show that the peptides that bind calmodulin well contain regions structurally similar to the recognition sequence for the cAMP-dependent protein kinase and to the sequences surrounding phosphorylated serine residues in several calmodulin binding proteins. This result suggests that modification of calmodulin binding sites in calmodulin-dependent proteins is one of the functions of protein kinase. Calcium has a dual role in peptide binding by calmodulin. The occupation of calcium binding sites having a pK approximately 4 results in a 2-fold increase in peptide binding affinity.
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PMID:Binding of simple peptides, hormones, and neurotransmitters by calmodulin. 618 Jul 61

Somatostatin has been reported to inhibit the increases in cAMP levels induced by glucagon in isolated islets of Langerhans. The present study was undertaken to test whether the reported effects of somatostatin on islet cAMP levels were also reflected in changes in the cAMP-dependent protein kinase activity. Isolated islets were found to contain both isoenzymes of the cAMP-dependent protein kinase. In the presence of theophylline (2 mM), glucagon (2.9 X 10(-6) M) increased the islet protein kinase activity ratio from 0.24 +/- 0.02 to 0.55 +/- 0.02. Somatostatin (6.6 X 10(-7) M) fully inhibited both the glucagon (2.9 X 10(-7) M)- and theophylline (2 mM)-induced increases in the protein kinase activity ratio. Omission of Ca2+ from the islet incubation media did not alter the inhibitory effect of somatostatin on the glucagon-dependent activation of the cAMP-dependent protein kinase. The present study has demonstrated that in the islets of Langerhans, glucagon-dependent activation of the cAMP-dependent protein kinase can be modulated by somatostatin.
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PMID:The effect of somatostatin on the activation of adenosine 3',5'-monophosphate-dependent protein kinase in isolated rat islets of Langerhans. 624 48

We have investigated the molecular basis of the variability of the somatostatin cAMP response element (CRE) function in different cell lines. All cells tested contain detectable levels of the CRE-binding protein CREB-1, which mediates transactivation in response to the cAMP-dependent protein kinase (protein kinase-A), in forms that can bind to a somatostatin CRE. Although both responsive and nonresponsive cells contain CREB-1 in heterodimers with activating transcription factor-1 (ATF-1), only cells that allow a cAMP response have a significant proportion of CREB-1 in a homodimeric form. Transfection experiments demonstrate that ATF-1 is capable of antagonizing CREB-1-dependent activation, suggesting that the ability of CREB-1 to mediate a cAMP response is down-regulated by heterodimer formation with ATF-1.
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PMID:Activating transcription factor-1 is a specific antagonist of the cyclic adenosine 3'.5'-monophosphate (cAMP) response element-binding protein-1-mediated response to cAMP. 777 75

In this study we investigated the short-term effect of somatostatin on histamine synthesis in a cell population isolated from rabbit gastric mucosa and enriched in enterochromaffin-like cells. Somatostatin inhibited basal and gastrin-stimulated histamine synthesis through a dual mechanism involving a decrease in the affinity of histidine decarboxylase (HDC) for its substrate (L-histidine) and a reduction in the number of functional HDC molecules. H-89 (an inhibitor of cAMP-dependent protein kinase) mimicked somatostatin-induced reduction of HDC affinity, which, on the contrary, was selectively reversed by pertussis toxin (PTX). Furthermore, forskolin was shown to reverse the inhibitory effect of H-89 and to prevent the somatostatin-induced reduction in HDC affinity for L-histidine. Thus, the somatostatin-induced reduction in affinity seems to involve a PTX-sensitive G protein and an inhibition of the cAMP-dependent pathway. On the other hand, the somatostatin-induced decrease in the number of functional HDC molecules seems to be PTX insensitive and independent from a modulation of the cAMP pathway, and does not seem to involve a significant change in HDC messenger RNA expression or a regulation of protein kinase C. The exact nature of this second mechanism will need further studies to be elucidated.
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PMID:Short-term inhibitory effect of somatostatin on gastric histamine synthesis. 904 95


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