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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The thyroid follicular cell requires elevated levels of cAMP for normal growth and optimal expression of the differentiated phenotype. The recent discovery of cAMP-regulated enhancer binding (CREB) proteins prompted us to analyze the possible role of these transcription factors in controlling thyroid cell growth and differentiated phenotype using the FRTL5 thyroid cell line as a model system. FRTL5 cells were stably transfected with an expression vector containing either the gene for wild type CREB (WTCREB) or a dominant negative mutant form of CREB, termed KCREB, which dimerizes with and inactivates endogenous CREB. Transfected clones were found to express the transfected KCREB and WTCREB mRNAs at higher levels than the endogenous CREB mRNA. Transient expression of a somatostatin-chloramphenicol acetyltransferase fusion gene in these clones demonstrated a 60% reduction of cAMP-regulated enhancer-dependent transcriptional activity in the KCREB transfected clones and wild type levels of activity in the WTCREB transfected clones. Parameters of growth (DNA synthesis and growth rate) and differentiation (iodide uptake and thyroglobulin mRNA levels) were then analyzed in the transfected clones. Transfection of WTCREB had no effect on any of the parameters examined in comparison to untransfected cells, presumably because CREB is already constitutively expressed at maximal levels in normal FRTL5 cells. However, cells expressing KCREB showed an 18-40% reduction in TSH-stimulated thymidine incorporation, a 31% increase in the length of the cell cycle, and a 4-fold reduction in TSH-stimulated iodide uptake in comparison with wild type cells or cells tranfected with wild type CREB.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Endocrinol 1992 Oct
PMID:3',5'-cyclic adenosine monophosphate-regulated enhancer binding (CREB) activity is required for normal growth and differentiated phenotype in the FRTL5 thyroid follicular cell line. 133 55

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 (SRIF) receptors are coupled to the catalytic subunit of adenylyl cyclase via pertussis toxin-sensitive guanine nucleotide-binding regulatory proteins (G proteins). To identify which G proteins link SRIF receptors to adenylyl cyclase, G(o) alpha, Gi alpha, and its different subtypes were individually blocked in AtT-20 cell membranes with G alpha subtype-selective antisera. Antiserum directed against the carboxyl-terminal region of Gi alpha blocked SRIF inhibition of forskolin-stimulated adenylyl cyclase activity, and this effect was prevented by the peptide to which the antiserum was generated. However, antiserum directed against the carboxyl-terminal region of G(o) alpha did not affect SRIF inhibition of adenylyl cyclase activity, indicating that Gi alpha couples SRIF receptors to adenylyl cyclase but G(o) alpha does not. Peptide-directed antisera against Gi alpha 1 completely blocked SRIF inhibition of adenylyl cyclase activity. In contrast, antisera directed against either Gi alpha 2 or Gi alpha 3 did not affect the actions of SRIF. The results of these studies indicate that Gi alpha 1 selectively couples SRIF receptors to the catalytic subunit of adenylyl cyclase in AtT-20 cell membranes. Because previous studies have shown that SRIF receptors are able to couple to Gi alpha 1, Gi alpha 3, and G(o) alpha, the results suggest that different G proteins may specify the coupling of SRIF receptors to distinct cellular effector systems.
Mol Pharmacol 1992 Mar
PMID:Gi alpha 1 selectively couples somatostatin receptors to adenylyl cyclase in pituitary-derived AtT-20 cells. 134 39

The cyclic AMP (cAMP) response elements (CREs) of the somatostatin and vasoactive intestinal peptide (VIP) promoters contain binding sites for CRE-binding protein (CREB) that are essential for cAMP-regulated transcription. Using F9 embryonal carcinoma cells, we show that the somatostatin and VIP promoters exhibit a differentiation-dependent cAMP response, demonstrating that these promoters are regulated by transcription factors that become active during differentiation. Lack of cAMP responsiveness of the somatostatin promoter in undifferentiated cells is not due to the absence of known positive-acting factors (the catalytic subunit of protein kinase A [cPKA] and CREB) or a general inhibition of protein kinase A activity. Since overexpression of exogenous cPKA and CREB is sufficient to activate the somatostatin promoter in undifferentiated cells, these findings suggest that a negative factor(s) represses endogenous cPKA and CREB. In contrast to their effects on somatostatin, exogenous CREB and cPKA do not activate the VIP promoter. Thus, despite coregulation during differentiation and the ability to bind CREB, the somatostatin and VIP promoters are not coordinately activated by CREB in undifferentiated F9 cells.
Mol Cell Biol 1992 Mar
PMID:Cyclic AMP response element-binding protein and the catalytic subunit of protein kinase A are present in F9 embryonal carcinoma cells but are unable to activate the somatostatin promoter. 134 42

The expression of the protein products of the immediate-early genes c-fos, Fos B, Fos-related proteins (FRAs), c-jun, jun B, jun D and krox-24 was investigated in the rat hippocampus at various times after electrically-induced hippocampal seizures. Hippocampal seizures induced all the immediate-early gene proteins in dentate granule cells with differing time-courses. In addition, Krox-24, Fos and Jun D were also induced in somatostatin-containing interneurons throughout the hippocampus and also in a small percentage of parvalbumin-containing interneurons. Thus, hippocampal seizures induce waves of immediate-early gene protein expression in dentate granule cells and a selective expression of krox-24, Fos and Jun D in hippocampal somatostatin interneurons. These results suggest that biochemical and/or morphological changes occurring in dentate granule cells and somatostatin interneurons after seizures may be regulated by immediate-early gene expression, and that these immediate-early gene proteins may be involved in seizure development in the nervous system.
Brain Res Mol Brain Res 1992 Mar
PMID:Induction of immediate-early gene proteins in dentate granule cells and somatostatin interneurons after hippocampal seizures. 134 20

The transactivation of genes through the cAMP-regulated enhancer (CRE) is proposed to occur by the binding and phosphorylation of the transcription factor CREB (CRE-binding protein). Originally believed to be a single protein, more than 10 different CREB proteins have been cloned. The contributions of each of these factors to gene regulation have yet to be determined unambiguously. We have isolated a CREB cDNA that contains a mutation of a single amino acid in the DNA-binding domain. In gel shift assays, this mutant, designated KCREB, is unable to bind to the somatostatin (SS) CRE. In addition, KCREB acts as a dominant repressor of the wild-type factor, blocking the ability of wild-type CREB to bind to the CRE when present as a KCREB:CREB heterodimer. The KCREB mutant also acts as a dominant repressor in vivo, completely blocking the ability of wild-type CREB to mediate induction by protein kinase-A of a SS CRE reporter gene in F9 teratocarcinoma cells. We have used this mutant to analyze the participation of CREB in the induction of the SS promoter in CA-77 cells, a medullary thyroid carcinoma cell line that produces high levels of SS. Although KCREB can block a portion of the cAMP induction of the SS promoter in CA-77 cells, approximately 45% of the induction remains insensitive to the mutant. These data support the paradigm that CREB is involved in the cAMP induction of SS in vivo. Furthermore, the inability of KCREB to completely block cAMP-mediated SS expression in CA-77 cells suggests that additional factors may contribute to the cAMP regulation of CRE function.
Mol Endocrinol 1992 Apr
PMID:A dominant repressor of cyclic adenosine 3',5'-monophosphate (cAMP)-regulated enhancer-binding protein activity inhibits the cAMP-mediated induction of the somatostatin promoter in vivo. 135 57

Neuroanatomical data have documented the existence of synaptic contacts between gamma-aminobutyric acid (GABA) terminals and periventricular hypothalamic somatostatin (SRIF) neurons. In other brain regions, like the cortex or hippocampus, GABA and SRIF are colocalized in short interneurons. These observations suggest that GABA modulates SRIF neuronal activity. In order to test this hypothesis, we studied the effects of the in vivo stimulation of the GABAA receptor (muscimol, 0.75 mg/kg + diazepam, 2.5 mg/kg) on SRIF content and preproSRIF mRNA levels, in mouse brain. Chronic (7 days), but not acute, treatment induced a 38% decrease in hypothalamic SRIF content (as estimated by RIA), a 20% decrease in cortex and no effect in the striatum. The decrease in hypothalamic and cortical SRIF levels lasted until 24 h after cessation of the treatment. In the hypothalamus, prosomatostatin mRNA levels were estimated by Northern blot analysis using a 32P-labeled 45-mere oligoprobe. ProSR1F mRNA hypothalamic levels were equally (48%) decreased by the acute and chronic treatments and remained lower than controls 48 h after the last injection. Quantitative in situ hybridization was used to examine the regional distribution of GABA-induced acute inhibition of proSR1F mRNA densities, using the same oligomere labeled with 35S. ProSR1F mRNA levels were decreased by 35% in the periventricular hypothalamic nucleus. In contrast, no significant modification was observed in cortex, striatum and hilus of the dentate gyrus of the dorsal hippocampus. The present data demonstrate a regionally selective inhibitory action of GABA, mediated by GABAA receptors stimulation, on the biosynthetic mechanisms of the long projecting neuroendocrine SRIF neurons of the anterior periventricular nucleus of the hypothalamus.
Brain Res Mol Brain Res 1992 May
PMID:Regulation of somatostatin synthesis by GABAA receptor stimulation in mouse brain. 135 11

The effects of a single intraperitoneal injection of ethanol (3 g/kg b.wt.) on the hypothalamic-pituitary-thyroid system was explored as a possible explanation of the hypothermic effect of ethanol. Serum thyroid hormones were significantly reduced by ethanol injection, but ethanol did not affect the cold-induced increase in serum thyroid hormones or thyroid-stimulating hormone (TSH). Since cold-exposure stimulates serum levels of TSH and thyroid hormones by stimulating thyroid-releasing hormone (TRH) release from neurons of the PVN, these findings demonstrate that ethanol did not block pituitary response to TRH or thyroid response to TSH. Paradoxically, ethanol increased cellular levels of TRH mRNA in the paraventricular nucleus (PVN), and blocked the cold-induced increase in TRH mRNA, suggesting that ethanol uncouples the regulation of TRH gene expression from the regulation of TRH release specifically in neurons of the PVN. Measurements of the effects of ethanol on TRH mRNA in thalamus, and beta-actin, vasopressin, somatostatin and corticotropin-releasing hormone (CRH) mRNAs in the PVN in addition to TRH mRNA revealed very specific effects of ethanol on the TRH neuronal system.
Brain Res Mol Brain Res 1992 May
PMID:Ethanol blocks the cold-induced increase in thyrotropin-releasing hormone mRNA in paraventricular nuclei but not the cold-induced increase in thyrotropin. 135 12

Previous studies have shown that at least two subtypes of somatostatin (SRIF) receptors (SRIF1 and SRIF2) are expressed in mammalian cells. SRIF1 receptors have high affinity for MK 678, whereas SRIF2 receptors have no affinity for MK 678 but selectively bind peptides with structures similar to that of CGP 23996. Recently, two SRIF receptor genes have been cloned from human and mouse genomic libraries. In the present study, the pharmacological properties of these two cloned SRIF receptors, expressed in Chinese hamster ovary (CHO) cells, were investigated, to determine whether they have any similarity to the previously described SRIF1 and SRIF2 receptor subtypes. Both cloned receptors could be labeled with 125I-Tyr11-SRIF and exhibited high affinity for SRIF. The SSTR1 receptor could also bind CGP 23996-like compounds but not MK 678. In contrast, the SSTR2 receptor was insensitive to CGP 23996-like compounds but bound MK 678 with high affinity. These findings indicate that the peptide specificities of the cloned SSTR1 and SSTR2 receptors differ from each other. Pretreatment of CHO cells expressing the two cloned SRIF receptors with SRIF abolished high affinity agonist binding to the cloned SSTR2 receptor but not the cloned SSTR1 receptor. Agonist binding to SSTR1 receptors was not significantly affected by guanosine-5'-)-(3-thiotriphosphate) or pertussis toxin pretreatment, whereas agonist binding to SSTR2 receptors was inhibited by both treatments. These findings suggest that SSTR2 receptors can be regulated and they associate with pertussis toxin-sensitive guanine nucleotide-binding proteins, whereas SSTR1 receptors do not. SRIF is a potent inhibitor of adenylyl cyclase activity in mammalian cells. However, neither the cloned SSTR2 nor SSTR1 receptor mediated SRIF inhibition of adenylyl cyclase activity in stably transformed CHO cells or COS-1 cells transiently expressing the cloned receptors, suggesting that neither cloned receptor couples to adenylyl cyclase. The results of these studies indicate that the two cloned SRIF receptors have different pharmacological properties. The characteristics of the cloned SSTR2 receptor are similar to those of the previously described SRIF1 receptor, and the characteristics of the cloned SSTR1 receptor are similar to those of the previously described SRIF2 receptor.
Mol Pharmacol 1992 Jul
PMID:Pharmacological properties of two cloned somatostatin receptors. 135 50

The present studies were directed to determine whether peptide histidine isoleucine (PHI) affects expression of the gastrin and somatostatin genes and whether such effects may be functionally linked. In separate experiments, the effects of PHI on medium gastrin and somatostatin concentrations, the incorporation of 35S-labelled amino acids into newly synthesized gastrin and somatostatin, and steady state gastrin and somatostatin mRNA were determined. PHI inhibited basal expression of the gastrin gene at all levels examined, while no significant effect on basal somatostatin gene expression could be detected. PHI also decreased carbachol-stimulated antral gastrin release and simultaneously increased somatostatin release. However, in contrast to its structural analogues, secretin and gastric inhibitory peptide, the immunoneutralization of endogenous somatostatin by the administration of specific antibodies did not affect significantly the capacity of PHI to inhibit gastrin release into the culture medium stimulated by carbachol. The results of these studies indicate that PHI exerts a physiological inhibitory effect on antral gastrin cells and that this inhibition may occur at several steps along the biosynthetic pathway. In addition, unlike its structural analogues, PHI inhibition of carbachol-stimulated gastrin release is not functionally linked to its stimulatory effects on somatostatin release.
Mol Cell Endocrinol 1992 Mar
PMID:The effects of peptide histidine isoleucine on antral gastrin and somatostatin. 135 64


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