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 mRNA distribution in the brain and the coupling to cellular effector systems of four somatostatin receptors (SSTR1-4) was studied. All four SRIF receptor subtypes were expressed in cortex and hippocampus. In addition, SSTR1 mRNA was relatively abundant in the spinal cord whereas SSTR2 mRNA was also present in the striatum. The SSTR3 gene was predominantly expressed in the olfactory bulb and in the cerebellum. Conflicting results about the effector coupling of SSTR1-3 have been published previously. We have stably expressed human SSTR1-4 in HEK 293 human embryonal kidney cells. Agonist binding to the receptor subtypes, including the recently cloned SSTR4, inhibited the formation of forskolin-induced cAMP. Is is concluded that, in an appropriate cellular environment, all four receptor subtypes can functionally couple to the inhibition of adenylyl cyclase.
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PMID:Distribution and second messenger coupling of four somatostatin receptor subtypes expressed in brain. 840 11

We have isolated a gene coding for a fourth human somatostatin (somatotropin release-inhibiting factor) receptor. This additional somatostatin receptor (hSSTR4) is specifically expressed in human fetal and adult brain and lung tissue. The deduced amino acid sequence of the receptor displays both sequence and structural homology to three cloned somatostatin receptors as well as to other members of the family of GTP-binding-protein-coupled seven-helix transmembrane-spanning receptors. Pharmacological characterization of the expressed receptor reveals specific, high-affinity binding of somatostatin 14 and somatostatin 28. Surprisingly, several well-characterized synthetic somatostatin analogs fail to exhibit high-affinity binding to hSSTR4, indicating the existence of pharmacologically different receptor subtypes. Our data suggest that the diverse biological effects exerted by somatostatin are mediated by a family of receptors with discrete patterns of expression and different pharmacological properties.
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PMID:Cloning and characterization of a fourth human somatostatin receptor. 848 34

A variety of human neuroendocrine tumours express SSTR. The five recently cloned human SSTR subtypes have a distinct chromosomal localization and pharmacological profile, and a tissue-specific expression pattern which suggests a differential function of SSTR subtypes in different organ systems. Most tumours carrying SSTR may express multiple SSTR subtypes, while the SSTR2 subtype is most predominantly expressed. The somatostatin analogue, octreotide, binds with high affinity to the SSTR2 and SSTR5 subtype and with a low affinity to the SSTR3 subtype. This analogue does not bind to the SSTR1 and SSTR4 subtypes. No major differences in the binding characteristics have been found between octreotide and two other clinically used octapeptide SST-analogues, BIM-23014 and RC-160. Our preliminary data indicate that an absent hormonal response to octreotide in vitro also implies an absent response to BIM-23014 and RC-160. The expression of the SSTR2 subtype in human tumours is proposed to be related to a clinical beneficial effect of octreotide treatment, while the functional significance of the other SSTR subtypes is not clear at present. In addition it is unclear which subtype(s) is involved in the antimitotic actions of SST(-analogues). Further developments with regard to the oncological application of SST analogues await the identification of the SSTR subtype(s) mediating anti-proliferative effects, as well as the development of analogues which selectively activate this subtype(s). A good correlation has been found between the presence of SSTR2 subtype mRNA and binding of [125I-Tyr3]octreotide in human primary tumours. Therefore, SSTR scintigraphy of human primary tumours and their metastases presumably visualizes SSTR2-expressing tumours, although it is reasonable to assume that SSTR5, and to a lesser extent SSTR3, when expressed simultaneously with SSTR2, also contribute to the visualization of tumours.
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PMID:Somatostatin receptors and disease: role of receptor subtypes. 873 55

Agonist regulation of somatostatin receptors (SSTRs) was investigated in stable CHO-K1 cells individually expressing the 5 human (h) SSTR subtypes. hSSTR 2,3,4, and 5 displayed rapid agonist-dependent internalization of [125I] LTT SST-28 ligand in a time- and temperature-dependent manner over 60 min. Maximum internalization of radioligand occurred with hSSTR3 (78%) followed by hSSTR5 (66%), hSSTR4 (29%) and hSSTR2 (20%). In contrast, hSSTR1 displayed virtually no internalization. Prolonged agonist treatment led to differential upregulation of some of the SSTRs. After 22 h, hSSTR1 was upregulated at the membrane by 110%, hSSTR2 and hSSTR4 by 26% and 22% respectively, whereas hSSTR3 and hSSTR5 showed little change. Agonist-induced recruitment of hSSTR1 to the membrane was confirmed by immunocytochemistry with hSSTR1 antibodies. These results show that SST regulates all 5 hSSTRs by differential subtype selective internalization or upregulation. Subtype selectivity for internalization and upregulation is inversely related.
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PMID:Agonist-dependent regulation of cloned human somatostatin receptor types 1-5 (hSSTR1-5): subtype selective internalization or upregulation. 875 82

Distribution of somatostatin receptors (SSTR1-5) was determined in the rat eye. Reverse transcriptase-polymerase chain reaction (RT-PCR) analyses revealed that SSTR4 and SSTR2 are major subtypes expressed predominantly in the iris/ciliary body and retina, respectively, and that SSTR1, SSTR3 and SSTR5 are minor subtypes expressed preferentially in the posterior eye segments including the retina. In situ hybridization showed predominant SSTR4 expression in the posterior iris epithelium and ciliary body, suggesting functional roles of somatostatin in the autonomic nervous system in the anterior segments of the eye. The differential expression of SSTR1-5 may be related to distinct roles of somatostatin in the physiology of different ocular tissues.
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PMID:Differential expression of somatostatin receptors in the rat eye: SSTR4 is intensely expressed in the iris/ciliary body. 908 Apr 63

Somatostatin (SRIH) analogs can suppress the proliferation of human differentiated thyroid carcinoma cell lines that express SRIH receptors (SSTRs) demonstrated by radioligand binding analysis. Five distinct human SSTR subtypes (hSSTR1-5) that bind native SRIH exhibit diverse affinities to a wide range of SRIH analogs. Reverse transcriptase-PCR amplification of ribonucleic acids (RNAs) obtained from normal thyroid tissues and nine human thyroid carcinoma cell lines, grown as monolayer cultures and xenograft tumors in nude mice, were used to discriminate expression of SSTR subtype messenger RNAs (mRNAs). The cell lines were derived from a follicular adenoma (KAK-1), two follicular carcinomas (MRO-87 and WRO-82), two papillary carcinomas (NPA87 and KAT-10), and four anaplastic thyroid carcinomas (DRO-90, ARO-81, KAT-4, and KAT-18). Most thyroid cancer cell line monolayers and xenografts expressed SSTR3 and SSTR5 mRNAs. SSTR1 expression was more varied between monolayers and xenografts, whereas SSTR2 mRNA was only faintly detectable at the most extreme resolution. SSTR4 mRNA was faintly positive in only one anaplastic carcinoma xenograft. Normal thyroid also expressed SSTR3 and SSTR5 mRNAs, with only faint expression of SSTR1 and SSTR2 mRNAs (in one of five and three of five samples, respectively). SSTR mRNA expression was dependent upon in vitro culture conditions, as xenograft SSTR mRNA expression tended to decrease compared to that in each respective monolayer culture. Characterization of SSTR subtype expression in human thyroid carcinomas may permit targeting of specific SRIH analogs to inhibit proliferation of differentiated and anaplastic thyroid carcinomas in patients.
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PMID:Somatostatin receptor subtype expression in human thyroid and thyroid carcinoma cell lines. 917 96

Somatostatin and its analogues are now of current use in the management of endocrine gastroentero-pancreatic (GEP) tumours for the purpose of inhibiting hormone hypersecretion, carrying scintigraphy imaging and attempting to slow down tumour growth. Recent molecular studies have revealed the existence of up to five membrane somatostatin receptor subtypes termed SSTR1-5. However, whether or not scintigraphy imaging and tumour characteristics are correlated with specific subtype(s) remains unclear. SSTR1-5 messenger RNA (mRNA) transcripts were investigated in 38 endocrine GEP tumours (32 islet cell tumours, six carcinoid) using reverse transcriptase polymerase chain reaction (RT-PCR), and their distribution was analysed with respect to tumour characteristics and scintigraphy imaging. SSTR2, SSTR5 and SSTR4 were detected in most cases of endocrine GEP tumours (92%, 84%, and 82% respectively), but SSTR1 and SSTR3 were less frequently observed (66% and 50% respectively). No clear-cut correlation was found between tumour characteristics and subtype mRNA distribution. Moreover, no differences in mRNA subtype distribution were found between the 17 tumours detected by scintigraphy and the four tumours not detected by this method. Somatostatin receptor mRNA subtypes are widely expressed in endocrine GEP tumours, but their distribution is not correlated with tumour characteristics or scintigraphy positivity.
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PMID:Somatostatin receptor subtype gene expression in human endocrine gastroentero-pancreatic tumours. 927 25

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

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

Ligand-activated somatostatin receptors (SSTRs) initiate cytotoxic or cytostatic antiproliferative signals. We have previously shown that cytotoxicity leading to apoptosis was signaled solely via human (h) SSTR subtype 3, whereas the other four hSSTR subtypes initiated a cytostatic response that led to growth inhibition. In the present study we characterized the antiproliferative signaling mediated by hSSTR subtypes 1, 2, 4, and 5 in CHO-K1 cells. We report here that cytostatic signaling via these subtypes results in induction of the retinoblastoma protein Rb and G1 cell cycle arrest. Immunoblot analysis revealed an increase in hypophosphorylated form of Rb in agonist-treated cells. The relative efficacy of these receptors to initiate cytostatic signaling was hSSTR5 > hSSTR2 > hSSTR4 approximately = hSSTR1. Cytostatic signaling via hSSTR5 also induced a marginal increase in cyclin-dependent kinase inhibitor p21. hSSTR5-initiated cytostatic signaling was G protein dependent and protein tyrosine phosphatase (PTP) mediated. Octreotide treatment induced a translocation of cytosolic PTP to the membrane, whereas it did not stimulate PTP activity when added directly to the cell membranes. C-tail truncation mutants of hSSTR5 displayed progressive loss of antiproliferative signaling proportional to the length of deletion, as reflected by the marked decrease in the effects of octreotide on membrane translocation of cytosolic PTP, and induction of Rb and G1 arrest. These data demonstrate that the C-terminal domain of hSSTR5 is required for cytostatic signaling that is PTP dependent and leads to induction of hypophosphorylated Rb and G1 arrest.
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PMID:C-terminal region of human somatostatin receptor 5 is required for induction of Rb and G1 cell cycle arrest. 989 14


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