The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
John E Taylor - One of the best experts on this subject based on the ideXlab platform.
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distinct functional properties of native somatostatin Receptor Subtype 5 compared with Subtype 2 in the regulation of acth release by corticotroph tumor cells
American Journal of Physiology-endocrinology and Metabolism, 2005Co-Authors: Joost Van Der Hoek, Marlijn Waaijers, Peter M Van Koetsveld, Diana Sprijmooij, Richard A Feelders, Herbert A Schmid, Philippe Schoeffter, Daniel Hoyer, Davide Cervia, John E TaylorAbstract:In a series of human corticotroph adenomas, we recently found predominant mRNA expression of somatostatin (SS) Receptor Subtype 5 (sst5). After 72 h, the multiligand SS analog SOM230, which has a v...
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somatostatin Receptor Subtype 1 selective activation reduces cell growth and calcitonin secretion in a human medullary thyroid carcinoma cell line
Biochemical and Biophysical Research Communications, 2002Co-Authors: Maria Chiara Zatelli, John E Taylor, Federico Tagliati, Daniela Piccin, Michael D Culler, Marta Bondanelli, Ettori Degli C UbertiAbstract:Abstract Medullary thyroid carcinoma (MTC) is a rare and aggressive tumor and so far medical therapy has provided inconclusive results. In the human MTC cell line TT, expressing all somatostatin (SST) Receptor Subtypes, cell proliferation decreases with SST and SST Receptor Subtype 2 (sst2), but not sst5, selective agonist treatment, whereas calcitonin (CT) expression and secretion are reduced by SST, but not by sst2 and sst5 agonists. The effectiveness of two new SST analogs, BIM-23926 and BIM-23745, selectively interacting with sst1, was investigated in the TT cell line. DNA synthesis is significantly reduced by BIM-23926 (27–40% at 10−10–10−6 M) and BIM-23745 (32–90% at 10−8–10−6 M). Viable cell number is also significantly reduced by both BIM-23926 (40% at 10−12–10−6 M) and BIM-23745 (∼40% at 10−10–10−6 M). Treatment with sst1-selective agonists significantly reduces CT secretion and gene expression, with a reduction of CREB phosphorylation. These findings suggest that potent sst1-selective agonists could have a therapeutic role in MTC.
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detection of somatostatin Receptor Subtype 2 sstr2 in established tumors and tumor cell lines evidence for sstr2 heterogeneity
Peptides, 1994Co-Authors: John E Taylor, Magali Theveniau, Roya Bashirzadeh, Terry Reisine, P EdenAbstract:The somatostatin Receptor Subtype 2 (SSTR2) was detected in a wide range of human and rat tumors using in vitro Receptor binding ([125I]MK-678), Receptor gene expression analysis, and immunoblotting techniques. The highest Receptor concentrations were observed in the rat AR42J pancreatic and human small cell lung cancer (SCLC) cell lines, NCI-H69 and NCI-H345, with much lower levels detected in breast, prostate, melanoma, and hepatic tumors. Several human pancreas tumors were devoid of SSTR2. For all tumors showing detectable [125I]MK-678 binding, SSTR2 Receptor mRNA was expressed. Furthermore, a mRNA transcript corresponding to a truncated isoform of SSTR2 was detected at low levels in the human SCLC NCI-H69 cell line, and likely represents a human homologue of rodent SSTR2B. Immunoblotting analysis using the SSTR2-specific antibody, 2e3, detected multiple immunoreactive protein species, including a predominant 150-kDa molecule, which could be blocked by the SSTR2-derived 2e3 peptide. Somatostatin (SRIF) peptides with high SSTR2 affinity and antiproliferative properties were potent inhibitors of [125I]MK-678 binding to several tumor types, suggesting that they may exert antitumor effects via the SSTR2 Receptor.
Dietmar Richter - One of the best experts on this subject based on the ideXlab platform.
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agonist dependent interaction of the rat somatostatin Receptor Subtype 2 with cortactin binding protein 1
Journal of Biological Chemistry, 1999Co-Authors: Heike Zitzer, Dietmar Richter, Hansjurgen KreienkampAbstract:We report here an interaction between the C terminus of the rat somatostatin Receptor Subtype 2 (SSTR2) and a protein that has recently been identified as cortactin-binding protein 1 (CortBP1). Interaction is mediated by the PDZ (PSD-95/discs large/ZO-1) domain of CortBP1. As shown by in situ hybridization, SSTR2 and cortactin-binding protein are coexpressed in the rat brain. The association between SSTR2 and the PDZ-domain of CortBP1 was verified by overlay assays and by coprecipitation after transfection in human embryonic kidney (HEK) cells. Analysis by confocal microscopy indicates that CortBP1 is distributed diffusely throughout the cytosol in transfected cells and that it becomes concentrated at the plasma membrane when SSTR2 is present. This process is largely increased when the Receptor is stimulated by somatostatin; as CortBP1 interacts with the C terminus of SSTR2, our data suggest that the binding of agonist to the Receptor increase the accessibility of the Receptor C terminus to the PDZ domain of CortBP1. Our data for the first time establish a link between a G-protein coupled Receptor and constituents of the cytoskeleton.
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characterization of the 5 flanking promoter region of the rat somatostatin Receptor Subtype 3 gene
FEBS Letters, 1998Co-Authors: Michael Glos, Hansjurgen Kreienkamp, Holger Hausmann, Dietmar RichterAbstract:We investigated the 5′-flanking promoter region of the rat somatostatin Receptor Subtype 3 (rSSTR3). Using a cDNA probe, genomic clones containing the 5′-flanking promoter region of the rSSTR3 gene were isolated. A sequence of 5.4 kb directly upstream from the start codon was analyzed and two introns were found in the 5′ untranslated region (UTR) of the cDNA sequence. The transcriptional initiation site was determined by 5′ rapid amplification of cDNA ends (RACE), primer extension and RNase protection analysis with cerebellar RNA. Two major transcriptional initiation sites were found at position −1040 (tsp1) and −856 (tsp2) relative to the translational initiation site. Like a number of other promoters of G-protein-coupled Receptors, the rSSTR3 gene lacks TATA and CAAT motifs and includes G+C-rich regions. Functional analysis of the promoter region by transfecting rSSTR3 luciferase-reporter gene constructs into rat pituitary GH3 cells and HEK 293 cells indicated that a 107-bp region upstream of tsp2 was sufficient to drive transcription. Furthermore a 562-bp region at position −1304 to −1865 upstream of the ATG start codon exerted a negative regulatory effect on transcriptional activity.
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rat somatostatin Receptor Subtype 4 can be made sensitive to agonist induced internalization by mutation of a single threonine residue 331
DNA and Cell Biology, 1998Co-Authors: Hansjurgen Kreienkamp, Adelheid Roth, Dietmar RichterAbstract: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 recept...
Jean Claude Reubi - One of the best experts on this subject based on the ideXlab platform.
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somatostatin Receptor Subtype 2a immunohistochemistry using a new monoclonal antibody selects tumors suitable for in vivo somatostatin Receptor targeting
The American Journal of Surgical Pathology, 2012Co-Authors: Meike Korner, Agnes Schonbrunn, Beatrice Waser, Aurel Perren, Jean Claude ReubiAbstract:High overexpression of somatostatin Receptors in neuroendocrine tumors allows imaging and radiotherapy with radiolabeled somatostatin analogues. To ascertain whether a tumor is suitable for in vivo somatostatin Receptor targeting, its somatostatin Receptor expression has to be determined. There are specific indications for use of immunohistochemistry for the somatostatin Receptor Subtype 2A, but this has up to now been limited by the lack of an adequate reliable antibody. The aim of this study was to correlate immunohistochemistry using the new monoclonal anti-somatostatin Receptor Subtype 2A antibody UMB-1 with the gold standard in vitro method quantifying somatostatin Receptor levels in tumor tissues. A UMB-1 immunohistochemistry protocol was developed, and tumoral UMB-1 staining levels were compared with somatostatin Receptor binding site levels quantified with in vitro I-[Tyr]-octreotide autoradiography in 89 tumors. This allowed defining an immunohistochemical staining threshold permitting to distinguish tumors with somatostatin Receptor levels high enough for clinical applications from those with low Receptor expression. The presence of >10% positive tumor cells correctly predicted high Receptor levels in 95% of cases. In contrast, absence of UMB-1 staining truly reflected low or undetectable somatostatin Receptor expression in 96% of tumors. If 1% to 10% of tumor cells were stained, a weak staining intensity was suggestive of low somatostatin Receptor levels. This study allows for the first time a reliable recommendation for eligibility of an individual patient for in vivo somatostatin Receptor targeting based on somatostatin Receptor immunohistochemistry. Under optimal methodological conditions, UMB-1 immunohistochemistry may be equivalent to in vitro Receptor autoradiography.
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internalized somatostatin Receptor Subtype 2 in neuroendocrine tumors of octreotide treated patients
The Journal of Clinical Endocrinology and Metabolism, 2010Co-Authors: Jean Claude Reubi, Beatrice Waser, Renzo Cescato, Beat Gloor, Christoph Stettler, Emanuel ChristAbstract:Context: Somatostatin Receptor Subtype 2 (sst2) is widely expressed in neuroendocrine tumors and can be visualized immunohistochemically at the cell membrane for diagnostic purposes. Recently, it has been demonstrated in animal sst2 tumor models in vivo that somatostatin analog treatment was able to induce a complete internalization of the tumor sst2. Patients and Methods: In the present study, we evaluated whether sst2 expressed in neuroendocrine tumors of patients treated with octreotide are also internalized. Tumor samples were assessed in patients that were treated with various octreotide modalities before and during surgery and compared with tumor samples from untreated patients. Sst2 immunohistochemistry was performed in all samples with three different sst2 antibodies (R2-88, UMB-1, and SS-800). Sst2 Receptor expression was confirmed by immunoblotting and in vitro Receptor autoradiography. Results: Patients receiving a high dose of octreotide showed predominantly internalized sst2, and patients wit...
Hansjurgen Kreienkamp - One of the best experts on this subject based on the ideXlab platform.
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agonist dependent interaction of the rat somatostatin Receptor Subtype 2 with cortactin binding protein 1
Journal of Biological Chemistry, 1999Co-Authors: Heike Zitzer, Dietmar Richter, Hansjurgen KreienkampAbstract:We report here an interaction between the C terminus of the rat somatostatin Receptor Subtype 2 (SSTR2) and a protein that has recently been identified as cortactin-binding protein 1 (CortBP1). Interaction is mediated by the PDZ (PSD-95/discs large/ZO-1) domain of CortBP1. As shown by in situ hybridization, SSTR2 and cortactin-binding protein are coexpressed in the rat brain. The association between SSTR2 and the PDZ-domain of CortBP1 was verified by overlay assays and by coprecipitation after transfection in human embryonic kidney (HEK) cells. Analysis by confocal microscopy indicates that CortBP1 is distributed diffusely throughout the cytosol in transfected cells and that it becomes concentrated at the plasma membrane when SSTR2 is present. This process is largely increased when the Receptor is stimulated by somatostatin; as CortBP1 interacts with the C terminus of SSTR2, our data suggest that the binding of agonist to the Receptor increase the accessibility of the Receptor C terminus to the PDZ domain of CortBP1. Our data for the first time establish a link between a G-protein coupled Receptor and constituents of the cytoskeleton.
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characterization of the 5 flanking promoter region of the rat somatostatin Receptor Subtype 3 gene
FEBS Letters, 1998Co-Authors: Michael Glos, Hansjurgen Kreienkamp, Holger Hausmann, Dietmar RichterAbstract:We investigated the 5′-flanking promoter region of the rat somatostatin Receptor Subtype 3 (rSSTR3). Using a cDNA probe, genomic clones containing the 5′-flanking promoter region of the rSSTR3 gene were isolated. A sequence of 5.4 kb directly upstream from the start codon was analyzed and two introns were found in the 5′ untranslated region (UTR) of the cDNA sequence. The transcriptional initiation site was determined by 5′ rapid amplification of cDNA ends (RACE), primer extension and RNase protection analysis with cerebellar RNA. Two major transcriptional initiation sites were found at position −1040 (tsp1) and −856 (tsp2) relative to the translational initiation site. Like a number of other promoters of G-protein-coupled Receptors, the rSSTR3 gene lacks TATA and CAAT motifs and includes G+C-rich regions. Functional analysis of the promoter region by transfecting rSSTR3 luciferase-reporter gene constructs into rat pituitary GH3 cells and HEK 293 cells indicated that a 107-bp region upstream of tsp2 was sufficient to drive transcription. Furthermore a 562-bp region at position −1304 to −1865 upstream of the ATG start codon exerted a negative regulatory effect on transcriptional activity.
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rat somatostatin Receptor Subtype 4 can be made sensitive to agonist induced internalization by mutation of a single threonine residue 331
DNA and Cell Biology, 1998Co-Authors: Hansjurgen Kreienkamp, Adelheid Roth, Dietmar RichterAbstract: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 recept...
Kjell Oberg - One of the best experts on this subject based on the ideXlab platform.
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determination of somatostatin Receptor Subtype 2 in carcinoid tumors by immunohistochemical investigation with somatostatin Receptor Subtype 2 antibodies
Cancer Research, 1998Co-Authors: Eva Tiensuu Janson, Mats Stridsberg, Anders Gobl, Janerik Westlin, Kjell ObergAbstract:Determination of somatostatin Receptor Subtype 2 in carcinoid tumors by immunohistochemical investigation with somatostatin Receptor Subtype 2 antibodies.
