Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P61278 (somatostatin)
 22,083 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The human sst(4) receptor, recombinantly expressed in Chinese hamster ovary cells, mediates proliferative activity of the peptide hormone somatostatin. This effect was shown to involve activation of pertussis toxin-sensitive G proteins and was inhibited by overexpression of the betagamma-sequestrant, transducin. Somatostatin-induced proliferation was abolished by the MEK1 inhibitor, PD 98059, whereas the Src inhibitor, PP1, had no effect. A marked increase was observed in the phosphorylation of extracellular signal-regulated kinase 1 and 2 (ERK1 and ERK2) 10 min after sst(4) receptor activation, which was blocked by pertussis toxin, decreased by PP1 and the betagamma-sequestrant, but unaffected by PD 98059. In contrast, the somatostatin-induced phosphorylation of ERK obtained at 4 h, although sensitive to both pertussis toxin and transducin, was unaffected by PP1 but ablated by PD 98059. Protein kinase C inhibition also abolished this somatostatin-induced sustained phosphorylation of ERK, together with the associated increase in cell proliferation. Expression of dominant negative Ras (N17) failed to significantly reduce the proliferative effect mediated by the sst(4) receptor but markedly attenuated the acute phase of the somatostatin-induced phosphorylation of ERK obtained at 10 min. In contrast, the phosphorylation induced at 4 h was unaffected. We conclude that ERK activation by G(i/o)-coupled sst(4) receptors involves a Src and Ras-dependent acute phase, but the proliferative response is dependent upon the prolonged ERK-induced activity, mediated by protein kinase C.
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PMID:Prolonged activation of extracellular signal-regulated kinase by a protein kinase C-dependent and N17Ras-insensitive mechanism mediates the proliferative response of G(i/o)-coupled somatostatin sst(4) receptors. 1044 4

The opposing effects on proliferation mediated by G-protein-coupled receptor isoforms differing in their COOH termini could be correlated with the abilities of the receptors to differentially activate p38, implicated in apoptotic events, or phosphatidylinositol 3-kinase (PI 3-K), which provides a source of survival signals. These contrasting growth responses of the somatostatin sst(2) receptor isoforms, which couple to identical Galpha subunit pools (Galpha(i3) > Galpha(i2) >> Galpha(0)), were both inhibited following betagamma sequestration. The sst(2(a)) receptor-mediated ATF-2 activation and inhibition of proliferation induced by basic fibroblast growth factor (bFGF) were dependent on prolonged phosphorylation of p38. In contrast, cell proliferation and the associated transient phosphorylation of Akt and p70(rsk) induced by sst(2(b)) receptors were blocked by the PI 3-K inhibitor LY 294002. Stimulation with bFGF alone had no effect on the activity of either p38 or Akt but markedly enhanced p38 phosphorylation mediated by sst(2(a)) receptors, suggesting that a complex interplay exists between the transduction cascades activated by these distinct receptor types. In addition, although all receptors mediated a sustained activation of extracellular signal-regulated kinases (ERK1 and ERK2), induction of the tumor suppressor p21(cip1) was detected only following amplification of ERK and p38 phosphorylation by concomitant bFGF and sst(2(a)) receptor activation. Expression of constitutively active Akt in the presence of a p38 inhibitor enabled a proliferative response to be detected in sst(2(a)) receptor-expressing cells. These findings demonstrate that the duration of activation and a critical balance between the mitogen-activated protein kinase and PI 3-K pathways are important for controlling cell proliferation and that the COOH termini of the sst(2) receptor isoforms may determine the selection of appropriate betagamma-pairings necessary for interaction with distinct kinase cascades.
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PMID:Receptor isoforms mediate opposing proliferative effects through gbetagamma-activated p38 or Akt pathways. 1091 80

The aim of this study was the characterization of the intracellular effectors of the antiproliferative activity of somatostatin in PC Cl3 thyroid cells. Somatostatin inhibited PC Cl3 cell proliferation through the activation of a membrane phosphotyrosine phosphatase. Conversely, PC Cl3 cells stably expressing the v-mos oncogene (PC mos) were completely insensitive to the somatostatin antiproliferative effects since somatostatin was unable to stimulate a phosphotyrosine phosphatase activity. In PC mos cells basal phosphotyrosine phosphatase activity was also reduced, suggesting that the expression of a specific phosphotyrosine phosphatase was impaired in these transformed cells. We suggested that this phosphotyrosine phosphatase could be r-PTP eta whose expression was abolished in the PC mos cells. To directly prove the involvement of r-PTP eta in somatostatin's effect, we stably transfected this phosphatase in PC mos cells. This new cell line (PC mos/PTP eta) recovered somatostatin's ability to inhibit cell proliferation, showing dose-dependence and time course similar to those observed in PC Cl3 cells. Conversely, the transfection of a catalytically inactive mutant of r-PTP eta did not restore the antiproliferative effects of somatostatin. PC mos/PTP eta cells showed a high basal phosphotyrosine phosphatase activity which, similarly to PC Cl3 cells, was further increased after somatostatin treatment. The specificity of the role of r-PTP eta in somatostatin receptor signal transduction was demonstrated by measuring its specific activity after somatostatin treatment in an immunocomplex assay. Somatostatin highly increased r-PTP eta activity in PCCl3 and PC mos/PTP eta (+300%, P < 0.01) but not in PCmos cells. Conversely, no differences in somatostatin-stimulated SHP-2 activity, (approximately +50%, P < 0.05), were observed among all the cell lines. The activation of r-PTP eta by somatostatin caused, acting downstream of MAPK kinase, an inhibition of insulin-induced ERK1/2 activation with the subsequent blockade of the phosphorylation, ubiquitination, and proteasome degradation of the cyclin-dependent kinase inhibitor p27(kip1). Ultimately, high levels of p27(kip1) lead to cell proliferation arrest. In conclusion, somatostatin inhibition of PC Cl3 cell proliferation requires the activation of r-PTP eta which, through the inhibition of MAPK activity, causes the stabilization of the cell cycle inhibitor p27(kip1).
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PMID:The activation of the phosphotyrosine phosphatase eta (r-PTP eta) is responsible for the somatostatin inhibition of PC Cl3 thyroid cell proliferation. 1157 15

Here we characterize the intracellular effectors of the antiproliferative activity of somatostatin in glioma cell lines and post-surgical specimens. The responsiveness to somatostatin correlated with the expression of the phosphotyrosine phosphatase DEP-1/PTPeta, identified in C6 and U87MG cells, in which somatostatin inhibited cell growth. The expression of a dominant negative mutant of DEP-1/PTPeta in C6 cells abolished somatostatin effects, confirming the involvement of this phosphotyrosine phosphatase in such effects. Somatostatin treatment increased the activity of DEP-1/PTPeta and inhibited ERK1/2 activation. Conversely, basic fibroblast growth factor-dependent MEK phosphorylation was not affected, suggesting a direct effect on ERK1/2. In vitro experiments showed that PTPeta was able to interact and dephosphorylate ERK1/2 activated by basic fibroblast growth factor. Furthermore, by transfecting PTPeta in the somatostatin-unresponsive, DEP-1/PTPeta-deficient U373MG cells, the somatostatin-dependent control of cell proliferation was recovered. Finally we evaluated the requirement for DEP-1/PTPeta in somatostatin inhibition of cell proliferation in post-surgical specimens derived from different grade human gliomas. Although all of the glioma analyzed expressed somatostatin receptor mRNA, DEP-1/PTPeta expression was limited to 8 of 22 of the tumors. Culturing seven gliomas, a correlation between the expression of DEP-1/PTPeta and the somatostatin antiproliferative effects was identified. In conclusion we propose that the expression and activation of DEP-1/PTPeta is required for somatostatin inhibition of glioma proliferation.
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PMID:The expression of the phosphotyrosine phosphatase DEP-1/PTPeta dictates the responsivity of glioma cells to somatostatin inhibition of cell proliferation. 1512 17

Somatostatin (somatotropin release inhibitory factor; SRIF) is an endogenous peptide produced at sites of inflammation, making the SRIF a candidate in regulating vascular inflammation. We have used primary human coronary artery endothelial cells (hCAEC) as a model to study SRIF's vascular actions. RT-PCR analysis of hCAEC total mRNA demonstrated the presence of the sst(4) receptor subtype, providing a target for SRIF intracellular signaling. Western blotting with phospho-specific ERK1/2 antibodies showed that SRIF-14 acutely inhibited basal phosphorylation of the extracellular regulated kinases (ERK1/2) by 80%. In addition, SRIF-14 treated hCAEC cell lysates showed a 2.6-fold increase in phosphatase activity, which was inhibited by sodium vanadate. Furthermore, SRIF-14 appeared to be anti-inflammatory in hCAEC as IL-1beta-induced adhesion molecule expression was reduced by 50%. Together, these results show that the coronary artery endothelium is a direct target of SRIF action.
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PMID:Somatostatin regulates intracellular signaling in human carotid endothelial cells. 1519 97

Somatostatin (SST) controls the proliferation of a variety of cell types. Its effects are mediated by five G protein-coupled receptors (SSTR1-SSTR5), variably expressed in normal and cancer tissues. SST inhibition of cell proliferation can be exploited by both direct and indirect mechanisms: the main direct pathway involves the modulation of phosphotyrosine phosphatase (PTP) activity. Here we show that SST cytostatic activity is mediated by the activation of a receptor-like PTP, named PTPeta. The role of this PTP in the antiproliferative activity of SST in five glioma cell lines (C6, U87MG, U373MG, DBTRG05MG, and CAS1) and in four postsurgical human glioblastoma specimens, has been studied. SST inhibited growth only in C6 and U87MG that express PTPeta. In C6 cells, SST antiproliferative effects were reverted by pretreatment with pertussis toxin and vanadate, indicating the involvement of G proteins and PTPs. The role of PTPeta in the SST inhibitory effects was demonstrated by testing the PTPeta activity: it was increased by SST treatment and paralleled by inhibition of ERK1/2 activation. Since basic fibroblast growth factor-dependent MEK phosphorylation was not affected by SST, we propose a direct effect of SST-activated PTPeta on ERK1/2 phosphorylation. Finally, the SSTR mRNAs were identified in all of the 36 gliomas analyzed, whereas PTPeta expression was found in 33% of cases. Culturing four gliomas, a precise correlation between the expression of PTPeta and the SST antiproliferative effects was identified. In conclusion, in glioma cells, SST antiproliferative activity requires the expression and activation of PTPeta, which directly dephosphorylates ERK1/2.
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PMID:The phosphotyrosine phosphatase eta mediates somatostatin inhibition of glioma proliferation via the dephosphorylation of ERK1/2. 1565 6

Somatostatin (somatotropin release inhibitory factor; SRIF) peptides are widely distributed throughout the mammalian body and act through a family of genetically distinct, guanine nucleotide regulatory protein coupled (G-protein-coupled), cell surface receptors (sst(1-5)). Compelling evidence shows that SRIF and SRIF peptidyl analogs modulate vascular function, with actions upon smooth muscle and endothelium. SRIF receptors are known to exist in the carotid endothelium, a principal target for the pro-inflammatory cascade that accompanies coronary artery disease. SRIF-14 and SRIF analogs are anti-inflammatory but the molecular mechanism involved remains unclear. Since crucial steps in the endothelial inflammation response include endothelial activation by cytokines, adhesion molecule expression and cell-monocyte interactions, peptide agents that inhibit these steps might provide a novel strategy for reducing vascular inflammation. SRIF, acting through its cognate receptors, modulates a variety of intracellular effectors that are linked to inflammation including phosphotyrosine phosphatases, the extracellular regulated protein kinase 1 and 2 (ERK1/2) cascade, adenylyl cyclase and endothelial nitric oxide synthase. Directly or indirectly, SRIF also functions to inhibit endothelial cell proliferation and induce apoptosis. A detailed understanding of SRIF actions could provide a rational basis for using SRIF ligands in controlling vascular inflammation and inhibiting cytokine signaling, critical events in atherogenesis.
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PMID:Somatostatin: a hormone for the heart? 1585 32

Activity-dependent Ca2+ influx into neurones and the subsequent changes in gene expression are thought to be important in shaping neuronal development. In this study, we investigated whether an important mediator of neuronal migration, somatostatin (Srif), alongside its receptors, is controlled in this manner in cerebellar granule cells. We show that Ca2+ influx increases the expression of somatostatin mRNA (srif), while somatostatin receptor 2 (sst2) mRNA expression is decreased. Both genes appear to be regulated independently of each other and in a calcineurin-dependent manner that does not depend on either the ERK1/2 MAP kinase or the cAMP/CREB pathway. Nonetheless, a second pathway is required to induce changes in srif and sst2 expression, since constitutively active calcineurin alone is not sufficient to induce these changes. Furthermore, calcineurin activation reciprocally regulates the expression of brain-derived neurotrophic factor, bdnf, and its receptor trkb, which have also been shown to play a role in neuronal migration. Finally, calcineurin appears to control the expression of the neuronal marker transient axonal glycoprotein 1, tag-1, thereby strongly suggesting that calcineurin activation in vivo occurs during the late stages of neuronal migration, possibly during synaptogenesis with mossy fibres. We therefore propose that calcineurin might play an important role as a switch between transcriptional programs during neuronal development.
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PMID:Somatostatin and the somatostatin receptor 2 are reciprocally controlled by calcineurin during cerebellar granule cell maturation. 1600 Jan 55

In mammary epithelial cells (MEC) TGF-beta(1) is the auto-/paracrine growth inhibitor and inducer of apoptosis and therefore is considered as an important local regulator of mammary tissue involution. However, the mechanisms of controlled TGF-beta(1) expression in the course of bovine mammary gland remodelling are still unclear. Recent study performed in this laboratory support the evidence that TGF-beta(1) expression in bovine MEC is regulated by hormones of somatotropic axis (GH, IGF-I and somatostatin). Present study was focused on the contribution of IGF-I-induced signaling pathways in anti-TGF-beta(1) and anti-apoptotic effects of IGF-I. Laser scanning cytometry was applied for the measurement of TGF-beta(1) content and apoptotic cell number in bovine BME-UV1 MEC. Involution of the bovine mammary gland in vitro was modeled by decreasing the availability of FBS for bovine MEC. Reducing FBS content in the medium from 10% to 0.5% evoked highly significant increase of TGF-beta(1) expression and increase of apoptotic cell number. IGF-I (50 ng/ml) completely abrogated FBS deficiency-induced TGF-beta(1) expression and apoptosis in bovine MEC. In order to establish which of the IGF-I signaling pathways contributed to anti-TGF-beta(1) and anti-apoptotic effects, the inhibitors of PI3-kinase - (LY 294002) and MEK- (MAPKK for ERK) (PD 098059) mediated signaling pathways were applied to our model. The results clearly showed that inhibition of PI3-K reverses the ability of IGF-I to suppress TGF-beta(1) expression and apoptosis. An inhibition of ERK1/2 pathway even potentiated inhibitory effect of IGF-I on TGF-beta(1) expression, but partially abrogated anti-apoptotic effect of IGF-I. In conclusion, the results of the study indicate that PI3-K/Akt pathway contributed significantly to the inhibition of TGF-beta(1) expression by IGF-I, whereas both PI3-K/Akt and ERK1/2 pathways are involved in the anti-apoptotic effect of IGF-I in bovine MEC.
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PMID:Dissimilar effects of LY 294002 and PD 098059 in IGF-I-mediated inhibition of TGF-beta1 expression and apoptosis in bovine mammary epithelial cells. 1607 2

Pancreatic cancer is a devastating disease because of the lack of early detection markers and effective treatments. It is the fourth leading cause of cancer-related death in western countries, including the United States. The mechanisms of pancreatic cancer progression remain unknown. Transforming growth factor beta (TGF-beta), a multifunctional cytokine, regulates cell growth and differentiation in healthy tissues, yet fails to do so in pancreatic cancer. Alterations of the TGF-beta and TGF-beta receptor/Smad signal transduction pathway have been implicated in pancreatic cancer. Furthermore, both the TGF-beta receptor and Smad proteins interact with a variety of cellular signal pathways, such as the somatostatin receptors (SSTRs), ERK1/2, and Wnt signal transduction cascades. This suggests that pancreatic cancer is a multi-gene-controlled malignancy and that effective treatments for pancreatic cancer should be aimed at multiple targets. In this review, we summarized the major signal intermediates involved in pancreatic cancer signal transduction pathways and specifically discussed how alterations in the regulatory functions of TGF-beta and Smad proteins allow for pancreatic carcinogenesis.
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PMID:Signal transduction in human pancreatic cancer: roles of transforming growth factor beta, somatostatin receptors, and other signal intermediates. 1631 22


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