UNIPROT:P61278 - FACTA Search

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Query: UNIPROT:P61278 (somatostatin)
22,083 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Apoptosis associated oligonucleosomal fragmentation of DNA can result from the activation of endonucleases that exhibit different pH optima and are either sensitive or insensitive to divalent cations. DNA fragmentation due to activation of cation sensitive endonucleases occurs in the absence of a change in intracellular pH whereas intracellular acidification is a feature of apoptosis characterized by activation of cation insensitive acidic endonuclease. We have reported earlier that somatostatin (SST) induced DNA fragmentation and apoptosis is signaled in a receptor subtype selective manner uniquely via human somatostatin receptor subtype 3 (hSSTR3). In the present study we investigated the pH dependence and cation sensitivity of endonuclease induced in hSSTR3 expressing CHO-K1 cells by the SST agonist octreotide (OCT) and its effect on intracellular pH. We show that OCT induced apoptosis is associated with selective stimulation of a divalent cation insensitive acidic endonuclease. The intracellular pH of of cells undergoing OCT induced apoptosis was 0.9 pH units lower than that of control cells. The effect of OCT on endonuclease and pH was inhibited by orthovanadate as well as by pretreatment with pertussis toxin, suggesting that hSSTR3 initiated cytotoxic signaling is protein tyrosine phosphatase mediated and is G protein dependent. These findings suggest that intracellular acidification and activation of acidic endonuclease mediate wild type p53 associated apoptosis signaled by hormones acting via G protein coupled receptors.
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PMID:G protein coupled receptor signaled apoptosis is associated with activation of a cation insensitive acidic endonuclease and intracellular acidification. 943 24

Somatostatin analogues are in clinical use for the diagnosis and treatment of several oncological indications, namely pituitary adenomas and endocrine gastrointestinal tumors. In addition for a variety of malignancies their potential value is being studied. It has been speculated that somatostatin plays a role in the homeostasis of gliomas, and that gliomas could be susceptible to antiproliferative effects of somatostatin analogues. These assumptions were tested in 20 human cell lines derived from malignant gliomas and 4 glioblastoma tissue specimens, which were analyzed for their expression of the five known somatostatin receptor genes (SSTR1-5) and for the receptor function. Using semiquantitative PCR techniques, SSTR2 transcripts were found in all 20 cell lines and 4 glioblastomas, SSTR1 transcripts were detected in 9 cell lines and 4 glioblastomas, and SSTR3 transcripts were noted in 7 cell lines and 1 glioblastoma. SSTR4 and SSTR5 transcripts were only rarely detected. Gene expression profiles in glioblastoma tissue specimens resembled those of the cell lines in quality as well as quantity, with average transcript levels being highest for the SSTR2, followed by SSTR1 and SSTR3. However, when compared to GH3 anterior pituitary tumor cells, the relative amounts of PCR amplified DNA fragments were found to be at least 120 fold lower in glioblastoma cell lines and tumor specimens. Binding studies indicated that glioblastoma derived cells contained only minute amounts of SSTRs. No inhibition of proliferation was observed when 10 selected cell lines were incubated with somatostatin-14 (SST-14) or octreotide (SMS 201-995) at concentrations ranging from 10(-9) M to 10(-6) M, however, the proliferation of two cell lines was weakly stimulated after 6 days of incubation with 10(-6) M octreotide. The activity of adenylate cyclase, stimulated by forskolin, was inhibited by maximally 25% at 10(-6) M SST-14 or octreotide in one of 5 selected glioblastoma cell lines. Somatostatin peptides do not seem to exert anti-proliferative effects on glioblastoma cells and therefore appear to be of no obvious value for glioblastoma therapy. Most likely the amount of cell surface SSTRs is not sufficient to mediate antiproliferative effects. Since it has been described that SSTRs are detectable on most differentiated gliomas as well as astrocytes, it may be speculated that SSTRs may be relevant only in the context of well differentiated cellular programs but lose their significance with progressive dedifferentiation.
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PMID:Somatostatin and somatostatin receptors in the diagnosis and treatment of gliomas. 944 32

Somatostatin and its receptors are widely distributed in the central nervous system and peripheral tissues including those of the gastrointestinal tract (GI tract). The expression patterns of the five known SSTR genes have been analysed in detail by reverse transcription polymerase chain reaction amplifications and in situ hybridizations using tissues dissected from different parts of rat stomach and gut. While SSTR1 mRNA is present at relatively high amounts throughout the gastrointestinal tract, the levels of SSTR2, 3 and 4 mRNAs vary in different regions and SSTR5 mRNA has not been detected. In situ hybridizations revealed the presence of SSTR3 mRNA in enterocytes and in neurons of the myenteric and submucous plexus. These findings are consistent with a role of SSTR3 in the observed somatostatin-mediated inhibition of acetylcholine release from myenteric neurons and of secretomotor neuron activity in the submucous plexus. Sequence analyses of the SSTR1 gene promoter revealed the absence of the canonical TATA and CAAT motifs and the presence of a variety of potential binding sites for transcriptional regulators. Among these are binding sites for GCF, AP-2, AP-4, response elements for somatostatin (SOM-RE), epidermal growth factor (EGF-RE) and cytocines (GAS and NFIL) as well as for tissue-specific factors such as Pit-1 (pituitary) and IDX-1 (pancreatic cells). Mobility shift assays have confirmed that nuclear proteins of pancreatic RIN1046-38 and pituitary GH3 tumour cells bind to oligonucleotides containing the overlapping Pit-1 and IDX-1 binding sites. Thus, the Pit-1/IDX-1 sites may be critical for the activation of the SSTR1 gene in these cell-types.
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PMID:Localization of somatostatin receptor subtype mRNA in the rat gastrointestinal tract and regulation of SSTR1 gene expression. 955 32

Detection of recurrence of medullary thyroid carcinoma (MTC) remains a diagnostic problem. Increased serum tumour marker levels frequently indicate recurrence while conventional imaging techniques (CIT) are non-diagnostic. In this study, we performed indium-111 octreotide scintigraphy and CIT in a series of 20 patients with MTC presenting with elevated serum tumour markers after surgery. 111In-octreotide whole-body studies detected 15 pathological uptake foci in 11 of the 20 patients studied and CIT detected 17 lesions in 11 of the 20 patients. Ten patients underwent reoperation, five of them with positive 111In-octreotide scintigraphy and CIT and two with positive isotopic exploration and negative CIT. Surgical findings demonstrated that the results of isotopic study and CIT had been false-positive for MTC in one case (sarcoidosis). The six patients with true-positive 111In-octreotide studies had significantly higher basal calcitonin (CT) and carcinoembryonic antigen (CEA) levels than the patients with negative isotopic studies. The expression of somatostatin receptor (SSTR) subtypes by PC-PCR could be investigated in four cases with a positive isotopic study. Among the three cases with a true-positive study, SSTR2, the SSTR subtype that preferentially binds to the somatostatin analogue octreotide, was detected in two, SSTR5 was demonstrated in the three, and SSTR3 was detected in one. No subtype of SSTR was detected in the case with a final diagnosis of sarcoidosis. We conclude that 111In-octreotide has limited sensitivity in detecting recurrence in patients with MTC, although its sensitivity may improve with high serum CT levels. This radionuclide imaging technique should be employed when conventional imaging techniques are negative or inconclusive or when the presence of somatostatin receptors may provide the basis for treatment with somatostatin analogues.
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PMID:Use of somatostatin analogue scintigraphy in the localization of recurrent medullary thyroid carcinoma. 979 43

A sequence motif of 20 amino acid residues within the C-terminal portion of the rat somatostatin receptor subtype 4 (SSTR4) has been shown to prevent rapid agonist-dependent receptor internalization in transfected human embryonic kidney (HEK) cells. Molecular dissection of this motif by biochemical ligand-binding assays revealed that the block was released by mutating a single residue (threonine 331) to an alanine. These data are in line with confocal microscopic analysis of cultured primary neurons microinjected with cDNA constructs encoding either SSTR4 or the mutant T331A. Immunocytochemical analysis showed that the mutant receptor, but not SSTR4, was internalized. However, internalized T331A was not recycled to the cell surface, suggesting that it lacks sequence elements that determine intracellular sorting after endocytosis. Neither wildtype SSTR nor the mutant T331A exhibited functional desensitization when assayed for their ability to inhibit adenylate cyclase. In agreement with this, the wt receptor and its mutant were not phosphorylated in response to agonist treatment. Lack of desensitization of SSTR4 has been electrophysiologically verified by coexpressing the receptor with a G-protein-gated, inwardly rectifying potassium channel in Xenopus oocytes. A strong somatostatin 14 (SST14)-activated inward potassium current was observed that was long-lasting and which decayed only slowly after washout of the agonist. This is in contrast to another somatostatin receptor subtype, SSTR3, which mediates rapidly desensitizing currents. Binding experiments on HEK cells transfected with either SSTR3 or 4 indicated that this difference is not attributable to slow dissociation of the agonist from the receptor, suggesting that SSTR4 mediates long-lasting signalling, a property which may be relevant for clinical therapy.
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PMID:Rat somatostatin receptor subtype 4 can be made sensitive to agonist-induced internalization by mutation of a single threonine (residue 331). 980 48

Our laboratory reported previously that somatostatin (SST) is transiently expressed in rat motoneurons during the first 14 days after birth. We investigated the possibility that the SST receptor (SSTR) is expressed in skeletal muscle. We found that two of the five subtypes of SSTR (SSTR3 and SSTR4) are expressed in skeletal muscle with a time course that correlates with the transient expression of SST in motoneurons. In addition, SSTR2A is expressed from birth to adulthood in skeletal muscle. Both SSTR2A and SSTR4 are also expressed in L6 cells, a skeletal muscle cell line. Somatostatin acting through its receptors has been shown to stimulate tyrosine phosphatase activity in a number of different tissues. We found that several proteins (50, 65, 90, 140, 180 and 200 kDa) exhibited a reduced degree of tyrosine phosphorylation following SST treatment. Inhibition of tyrosine phosphatase activity with sodium orthovanadate increased expression of the nicotinic acetyl-choline receptor (nAChR) epsilon subunit mRNA by three fold. Somatostatin reversed the elevated epsilon mRNA following orthovanadate treatment. These findings show that SSTR is expressed in skeletal muscle and that SST acting via the SSTR regulates tyrosine phosphorylation and expression of the epsilon subunit of the AChR in the rat skeletal muscle.
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PMID:Expression of somatostatin receptor genes and acetylcholine receptor development in rat skeletal muscle during postnatal development. 985 5

Treatment of restenosis after angioplasty with octapeptide somatostatin (SST) analogs has met with variable success. These analogs bind with high affinity to only two SST receptor (SSTR) subtypes (2 and 5), display moderate affinity for SSTR3, and low affinity for SSTR1 and 4. To optimize the vasculoprotective effect of SST, we have investigated the pattern of expression of all five SSTRs in rat thoracic aorta in the resting state and at 15 min, 3, 7, and 14 days after balloon endothelial denudation. SSTR1-5 were analyzed as mRNA by semiquantitative reverse transcriptase-polymerase chain reaction and as protein by immunocytochemistry. All five SSTRs were expressed in rat aorta both as mRNA and protein and displayed a time-dependent, subtype-selective response to endothelial denudation. mRNA for SSTR1 and 2 increased acutely (SSTR1 > SSTR2) on days 3 and 7, coincident with smooth muscle cell (SMC) proliferation, and declined to basal levels by day 14. SSTR3 and 4 displayed a different pattern with a delayed, more gradual increase in mRNA beginning at days 3-7 and continued to increase thereafter. SSTR5 mRNA was constitutively expressed at a low level and showed no change during the 2 wk postinjury period. By immunohistochemistry, SSTR1-5 antigens were localized predominantly in SMC that were present in the media or had migrated into the intima; antigen expression correlated with receptor mRNA expression. Notably, only SSTR1,3,4 were expressed in the intima: SSTR1 and 4 during the proliferative burst and SSTR3 and 4 after proliferation, when SMC migration into the intima continues. These results demonstrate dynamic changes in SSTR1-5 expression after vascular trauma localized to areas of vascular SMC migration and replication. In view of their early and prominent induction, SSTR1 may be the optimal subtype to target for inhibition of myointimal proliferation, and SSTR3 and 4 for migration and remodeling.
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PMID:Differential regulation of somatostatin receptor types 1-5 in rat aorta after angioplasty. 997 27

Somatostatin (SST), a regulatory peptide, is produced by neuroendocrine, inflammatory, and immune cells in response to ions, nutrients, neuropeptides, neurotransmitters, thyroid and steroid hormones, growth factors, and cytokines. The peptide is released in large amounts from storage pools of secretory cells, or in small amounts from activated immune and inflammatory cells, and acts as an endogenous inhibitory regulator of the secretory and proliferative responses of target cells that are widely distributed in the brain and periphery. These actions are mediated by a family of seven transmembrane (TM) domain G-protein-coupled receptors that comprise five distinct subtypes (termed SSTR1-5) that are endoded by separate genes segregated on different chromosomes. The five receptor subtypes bind the natural SST peptides, SST-14 and SST-28, with low nanomolar affinity. Short synthetic octapeptide and hexapeptide analogs bind well to only three of the subtypes, 2, 3, and 5. Selective nonpeptide agonists with nanomolar affinity have been developed for four of the subtypes (SSTR1, 2, 3, and 4) and putative peptide antagonists for SSTR2 and SSTR5 have been identified. The ligand binding domain for SST ligands is made up of residues in TMs III-VII with a potential contribution by the second extracellular loop. SSTRs are widely expressed in many tissues, frequently as multiple subtypes that coexist in the same cell. The five receptors share common signaling pathways such as the inhibition of adenylyl cyclase, activation of phosphotyrosine phosphatase (PTP), and modulation of mitogen-activated protein kinase (MAPK) through G-protein-dependent mechanisms. Some of the subtypes are also coupled to inward rectifying K(+) channels (SSTR2, 3, 4, 5), to voltage-dependent Ca(2+) channels (SSTR1, 2), a Na(+)/H(+) exchanger (SSTR1), AMPA/kainate glutamate channels (SSTR1, 2), phospholipase C (SSTR2, 5), and phospholipase A(2) (SSTR4). SSTRs block cell secretion by inhibiting intracellular cAMP and Ca(2+) and by a receptor-linked distal effect on exocytosis. Four of the receptors (SSTR1, 2, 4, and 5) induce cell cycle arrest via PTP-dependent modulation of MAPK, associated with induction of the retinoblastoma tumor suppressor protein and p21. In contrast, SSTR3 uniquely triggers PTP-dependent apoptosis accompanied by activation of p53 and the pro-apoptotic protein Bax. SSTR1, 2, 3, and 5 display acute desensitization of adenylyl cyclase coupling. Four of the subtypes (SSTR2, 3, 4, and 5) undergo rapid agonist-dependent endocytosis. SSTR1 fails to be internalized but is instead upregulated at the membrane in response to continued agonist exposure. Among the wide spectrum of SST effects, several biological responses have been identified that display absolute or relative subtype selectivity. These include GH secretion (SSTR2 and 5), insulin secretion (SSTR5), glucagon secretion (SSTR2), and immune responses (SSTR2).
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PMID:Somatostatin and its receptor family. 1043 61

A new line (FP) of human foetal lung fibroblasts was analysed for the expression of functional, G-protein coupled somatostatin receptors (SSTR). By means of RT-PCR, we identified the expression of SSTR1, SSTR2, SSTR3 and SSTR4, but not SSTR5, subtypes. The same technical approach evidenced the expression of stimulatory (alphas) and inhibitory (alphai1, alphai2 and alphai3) G-protein subunits. The functionality of SSTR was established from the observation of a dose-dependent inhibitory role of SST upon isoproterenol-stimulated adenylyl cyclase activity, an effect that involves G-protein action. Moreover, the functionality of G-proteins was assessed by means of experiments with forskolin and a nonhydrolysable GTP analogue that showed either Gi or Gs activation in the regulation of adenylyl cyclase. Present results represent a first pharmacological characterization of this new line of human foetal lung fibroblasts. The selective presence of some SSTR subtypes and G-protein subunits in addition to the regulatory network of the adenylyl cyclase pathway are features of recognized involvement in cell growth mechanisms. It is of interest for a cell class widely used to study this topic but also important in lung physiology and pathophysiology.
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PMID:Identification of functional somatostatin receptors and G-proteins in a new line of human foetal lung fibroblasts. 1101 9

Malignant melanoma is a neuroendocrine tumor that contains somatostatin receptors (SSTRs). Adjuvant therapy for melanoma is limited. Because melanomas arise from neural crest cells, we sought to evaluate the distribution of SSTR subtypes found in these tumors and their functional significance by imaging with 111In-pentetreotide scintigraphy (OctreoScan). Octreotide binds with greatest affinity to SSTR2 and SSTR5. Studying the expression of SSTRs in melanoma may demonstrate a potential role for octreotide in the treatment of melanoma. A series of 23 melanomas from 17 patients who underwent resection of regional or distant metastases were evaluated for the presence of SSTRs by the reverse transcriptase-polymerase chain reaction (RT-PCR) using primers specific for SSTR1 through SSTR5. Identity of RT-PCR products was confirmed by Southern blot analysis. Sixteen patients underwent preoperative OctreoScan. SSTR1 was expressed in 96% of tumors, SSTR2 in 83%, SSTR3 in 61%, SSTR4 in 57%, and SSTR5 in 9%. OctreoScan imaged 63% of tumors. There was no correlation between SSTR subtype expression and OctreoScan result. Most of the melanomas expressed mRNA for SSTR1 and SSTR2, with approximately half expressing SSTR3 and SSTR4. The SSTR mRNA for SSTR2 appears to be transcribed into functional protein that binds 111In-pentetreotide in more than half of these patients. Although OctreoScan has limited sensitivity for localizing melanomas, tumors that can be imaged by OctreoScan may be amenable to adjuvant therapy with octreotide or targeted therapy with high-energy radioisotope-labeled octreotide. These studies clearly define melanoma as a neuroendocrine tumor, which may open new avenues for tumor control.
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PMID:Distribution and functional significance of somatostatin receptors in malignant melanoma. 1134 89

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