Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We previously reported the cloning of two distinct somatostatin receptor (SSTR) subtypes, SSTR1 and SSTR2. Although both SSTR1 and SSTR2 bound somatostatin specifically and with high affinity, neither was coupled to adenylyl cyclase, a major cellular effector of somatostatin's actions. Here we report the cloning and functional characterization of a third member of the SSTR family. Human SSTR3 is a protein of 418 amino acids and has 45% and 46% identity with human SSTR1 and SSTR2, respectively. RNA blotting studies showed that SSTR3 mRNA could be readily detected in brain and pancreatic islets. The pharmacological properties of human SSTR3 were characterized by transiently expressing the human SSTR3 gene in COS-1 cells. Membranes from cells expressing human SSTR3 bound the somatostatin agonist [125I]CGP 23996 specifically and with high affinity, with a rank order of potency of somatostatin-28 = CGP 23996 > somatostatin-14 > SMS-201-995. Studies using cells transiently coexpressing the human dopamine D1 receptor and human SSTR3 showed that somatostatin was able to inhibit dopamine-stimulated cAMP formation in a dose-dependent manner, indicating that SSTR3 was functionally coupled to adenylyl cyclase. These results indicate that the diverse biological effects of somatostatin are mediated by a family of receptor with distinct, but overlapping, tissue distributions, unique pharmacological properties, and potentially different functions.
Mol Endocrinol 1992 Dec
PMID:Somatostatin receptors, an expanding gene family: cloning and functional characterization of human SSTR3, a protein coupled to adenylyl cyclase. 133 45

Somatostatin analogs are used in the control of hormonal hypersecretion and tumor growth of patients with acromegaly, islet cell carcinomas and carcinoids. Recently we showed that somatostatin receptor positive tumors can be visualized in vivo after the administration of radioactive isotope-labelled somatostatin analogs. Receptor imaging was positive in 18/21 islet cell tumors, 30/31 carcinoids, 26/28 paragangliomas, 9/14 medullary thyroid carcinomas, 5/7 small cell lung cancers, 6/7 neuroblastomas, 38/49 primary breast cancers, and 0/18 pancreatic adenocarcinomas. Also 11/11 meningiomas, 4/4 astrocytomas and 0/3 glioblastomas could be visualized. Somatostatin receptor imaging is an easy, harmless and painless diagnostic method. It is an in vivo method for the recognition of neuroendocrine cancers. It localizes multiple and/or metastatic tumors, predicts the successful control of hormonal hypersecretion by octreotide and seems of prognostic value in certain types of cancer. This scintigraphic method might help in patient selection for clinical trials with somatostatin analogs in the treatment of neuroendocrine cancers.
J Steroid Biochem Mol Biol 1992 Sep
PMID:Somatostatin receptor imaging in the diagnosis and treatment of neuroendocrine tumors. 135 13

Forty-nine primary breast tumors were analyzed for the expression of the somatostatin receptor (SSR) and genetic changes in the RB tumor suppressor gene. Twenty-four tumor samples were shown to contain receptors for somatostatin and in eight of these SSR-positive tumors we observed a mutation in the RB gene. However, since also in the group of SSR-negative tumors in eight of the 25 cases an alteration of the RB gene was observed, loss of this tumor suppressor gene is not specific for the SSR-positive subgroup of breast tumors. A similar, equal distribution between SSR-positive and SSR-negative breast tumors was observed for the six tumor samples which showed amplification of the neu proto-oncogene.
J Steroid Biochem Mol Biol 1990 Dec 20
PMID:Genetic changes in somatostatin receptor positive breast tumors. 198 Oct 16

The GH-releasing factor (GRF) analogue [His1,Nle27]-GRF(1-29) amide was used to study GRF receptor internalization in cultured rat anterior pituitary cells. The half-life of occupied receptors on the surface was approximately 10 min. Uptake of the analogue was followed by lysosomal breakdown, and receptors taken up were replaced to some extent by newly synthesized receptors, as indicated by reduced surface binding in the presence of cycloheximide. 2,3-Epoxy-4-oxo-7,10-dodecadienamide (cerulenin) inhibited internalization without affecting breakdown of the reduced amount of GRF analogue that entered the cells. The effect was half-maximal at 3 micrograms/ml for 1 h. Cerulenin inhibits fatty acid acylation of proteins. One explanation for its effect on GRF receptor internalization is that fatty acid acylation of a protein (possibly the receptor) is necessary for internalization, because cerulenin also inhibited internalization of the transferrin receptor which is known to be acylated. Cerulenin did not affect internalization of the somatostatin receptor present on the same cells, indicating the specificity of the inhibition.
J Mol Endocrinol 1990 Feb
PMID:Internalization of growth hormone-releasing factor by rat anterior pituitary cells: inhibition by cerulenin, an inhibitor of fatty acid acylation. 215 53

Somatostatin receptors have been visualized in the adrenal by autoradiography using the iodinated Tyr3 derivative of the somatostatin octapeptide analog SMS 201-995 (H-D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr(ol), Sandostatin*). In the rat adrenal gland somatostatin receptors are not exclusively restricted to the glomerulosa cell layer, but can also be found in the adrenal medulla, particularly after in vitro incubation. The receptor sites in the adrenal are saturable and have affinity constants of 0.42 nM in the adrenal cortical and 0.15 nM in medullary membranes. The distribution of somatostatin receptors in the adrenal visualized in vitro is strongly species specific. Whereas only the adrenal medulla is labelled in the hamster, mouse and rhesus monkey, solely the glomerulosa layer shows somatostatin receptor sites in the cow and the guinea pig. The rat is the only species with a high density of somatostatin receptor sites in both the glomerulosa cell layer and the adrenal medulla.
Mol Cell Endocrinol 1986 Apr
PMID:Somatostatin receptors in the adrenal. 300 49

A gastric mucosal somatostatin receptor was isolated from the solubilized epithelial cell membrane by affinity chromatography on a column consisting of covalently coupled [D-Tryp8]SRIF-14 to Affi-Gel 10. The receptor protein displayed a molecular weight of 61kDa and exhibited specific affinity towards 125I-labeled [Tyr11]SRIF-14 with the optimum range of 4-8 micrograms/ml. The binding of somatostatin to its mucosal receptor was inhibited by lipopolysaccharide from H. pylori. The inhibitory effect was proportional to the concentration of lipopolysaccharide up to 50 micrograms/ml and reached a maximum of 94.1% inhibition. The results suggest that H. pylori, through its lipopolysaccharide, is capable of interfering with somatostatin regulatory effect on gastric mucosal G-cell function.
Biochem Mol Biol Int 1995 Jul
PMID:Helicobacter pylori lipopolysaccharide inhibition of gastric mucosal somatostatin receptor. 754 46

A detailed analysis of structural and functional aspects of G-protein-coupled receptors, as well as discovery of novel pharmacophores that exert their effects on members of this class of receptors, will be facilitated by development of a yeast-based bioassay. To that end, yeast strains that functionally express the rat somatostatin receptor subtype 2 (SSTR2) were constructed. High-affinity binding sites for somatostatin ([125I-Tyr-11]S-14) comparable to those in native tissues were detected in yeast membrane extracts at levels equivalent to the alpha-mating pheromone receptor (Ste2p). Somatostatin-dependent growth of strains modified by deletion of genes encoding components of the pheromone response pathway was detected through induction of a pheromone-responsive HIS3 reporter gene, enabling cells to grow on medium lacking histidine. Dose-dependent growth responses to S-14 and related SSTR2 subtype-selective agonists that were proportional to the affinity of the ligands for SSTR2 were observed. The growth response required SSTR2, G alpha proteins, and an intact signal transduction pathway. The sensitivity of the bioassay was affected by intracellular levels of the G alpha protein. A mutation in the SST2 gene, which confers supersensitivity to pheromone, was found to significantly enhance the growth response to S-14. In sst2 delta cells, SSTR2 functionally interacted with both a chimeric yeast/mammalian G alpha protein and the yeast G alpha protein, Gpa1p; to promote growth. These yeast strains should serve as a useful in vivo reconstitution system for examination of molecular interactions of the G-protein-coupled receptors and G proteins.
Mol Cell Biol 1995 Nov
PMID:Functional coupling of a mammalian somatostatin receptor to the yeast pheromone response pathway. 756 71

Ectopic ACTH syndrome represents a cancer-induced amplification of a property [proopiomelanocortin (POMC) peptides production] normally present in the cells from which the cancer originated but with aberrant posttranslational processing of POMC resulting in a greatly elevated secretion of ACTH precursors. The classic ectopic ACTH-producing tumors described in the 1960s were highly malignant but more recently slowly growing tumors such as carcinoids are reported with increasing frequency. Clinical features of patients with ectopic ACTH were analyzed, including biochemical abnormalities, plasma ACTH, cortisol and urinary steroids. Dynamic tests such as high-dose dexamethasone suppression, metyrapone and ovine-CRH (oCRH) stimulation were explored, as well as inferior petrosal sinus ACTH sampling before and after oCRH. Among the tumor markers examined, elevation of ACTH precursors was uniformly present followed by increased output of calcitonin, gut hormones, oncofetal and placental hormones in decreasing order. Since more than 90% of ectopic ACTH tumors are neuroendocrine in nature exhibiting APUD characteristics, their 2 markers, neuron-specific enolase and chromogranins are very useful. The imaging procedures for localization of the tumor ranged from chest X-rays to computed tomography and magnetic resonance of the chest and abdomen. Abdominal ultrasonography was also useful. Finally somatostatin receptor scintigraphy permitted demonstration of unrecognized tumors and/or metastases, even when the tumors were occult. The ACTH content, immunostaining for APUD markers and altered POMC processing were evaluated in ectopic tumors and/or metastases. Occult ectopic ACTH syndrome of more than 4-6 months of symptoms without the emergence of an obvious source was reviewed. Since the tumors are often clinically and biochemically undistinguishable from pituitary-dependent Cushing's disease, inferior petrosal sinus sampling for ACTH after oCRH stimulation established the diagnosis in over 90% of the cases. 60% of the occult tumors were thoracic carcinoids (3/4 bronchial carcinoids), followed by small cell lung cancer and pancreatic neuroendocrine tumors. In 12% the primary etiology was not detected. The rare syndrome of ectopic CRH syndrome (6 published cases) leading to excessive stimulation of the pituitary which became hyperplastic and secreted excessive amounts of ACTH is discussed. Finally, the 12 published cases and 1 unreported patient with ectopic CRH-ACTH tumors were reviewed, the majority being metastatic small cell lung carcinomas, bronchial and thymic carcinoids.
J Steroid Biochem Mol Biol 1995 Jun
PMID:Ectopic ACTH syndrome. 762 46

Four of the five somatostatin receptor (SSTR) subtypes bind the two native forms of somatostatin, i.e., somatostatin-14 (S-14) and amino-terminally extended somatostatin-28 (S-28), with comparable affinities (approximately 0.2 nM). The SSTR5 subtype exhibits 10-50-fold higher affinity for S-28 than for S-14 (0.2 and 5 nM, respectively). To determine which domains in SSTR5 are responsible for the observed pharmacological selectivity, a series of SSTR2/SSTR5 chimeras were constructed and expressed in Chinese hamster ovary cells. Saturation and competition radioligand binding studies demonstrated that the region encompassing transmembrane domain 6 (TM6) through the carboxyl terminus plays a critical role in the lower binding affinity of S-14 for SSTR5. Substitution of this region with the corresponding region of SSTR2 produced chimeric receptors with high affinity for both S-28 and S-14. Examination of amino acid sequences revealed both a specific conserved hydrophobic residue and a conserved tyrosine in TM6 of SSTR1-4. At comparable positions in SSTR5, these residues are glycine (G258) and phenylalanine (F265), respectively. Substitution of G258 with phenylalanine did not alter the preference of SSTR5 for S-28 over S-14. However, substitution of F265 with tyrosine increased the binding affinity of S-14 by 20-fold, to an affinity comparable to that observed for the SSTR2 subtype. These data indicate that replacement of phenylalanine with tyrosine at position 265 in SSTR5 can modify ligand binding selectivity and abolish the preference for S-28 over S-14. This finding suggests that the tyrosine in the predicted TM6 may be an important contact point between somatostatin and SSTR.
Mol Pharmacol 1995 Jan
PMID:A single amino acid substitution in somatostatin receptor subtype 5 increases affinity for somatostatin-14. 783 36

Somatostatin receptors are abundantly expressed on a variety of human endocrine and epithelial tumors. The ability of these receptors to couple to effector pathways that inhibit the growth of these tumor cells has prompted the use of somatostatin agonists in the treatment of human neoplasms. It has been demonstrated that somatostatin stimulates a phosphotyrosine phosphatase in human tumor cells through a receptor-mediated process. This stimulation may counteract the growth-promoting properties of growth factors and the receptor tyrosine kinases that they activate. The recent cloning and characterization of distinct somatostatin receptor subtypes raise the possibility that different receptor subtypes mediate distinct effector pathways. To determine whether cloned somatostatin receptors could mediate coupling to phosphotyrosine phosphotyrosine phosphatase activity, we examined phosphatase activity after somatotostatin activation of the rat somatostatin receptors SSTR1 and SSTR2 after their stable expression in heterologous Chinese Hamster Ovary (CHO-K1) cells. We found that stimulation of SSTR1 cells was capable of increasing phosphotyrosine phosphatase activity, despite the coupling of both receptors to the inhibition of adenylyl cyclase in these cells. This activation was characterized by an EC50 of 70 nM and was sensitive to pertussis toxin. In addition, we demonstrate that activation of phosphotyrosine phosphatase activity in pituitary cell lines correlates with the endogenous expression of the SSTR1 gene within these cells.
Mol Endocrinol 1994 Oct
PMID:The somatostatin receptor SSTR1 is coupled to phosphotyrosine phosphatase activity in CHO-K1 cells. 785 46


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