Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P61278 (somatostatin)
 22,083 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The pathophysiology of mammosomatotroph adenomas remains unclear. We studied a mammosomatotroph adenoma removed from an 8-year old boy with a 5-year history of growth acceleration and acromegalic gigantism at presentation. Elevated basal GH (mean 28 micrograms/l) and PRL (mean 120 micrograms/l) plasma levels were observed, as well as paradoxical responses of GH to L-dopa, TRH and oral glucose administration; PRL was reduced by L-dopa and slightly increased by TRH; GHRH stimulated release of both GH and PRL. Two operations were required to remove the very large tumour and the patient was treated with bromocriptine before the second. Hormonal secretion by tumour explants in culture was evaluated under basal conditions and after stimulation or inhibition. High levels of GH and PRL were secreted for up to 24 days. Furthermore, GHRH and TRH caused a dose-related stimulation of both hormones, while somatostatin and dopamine were effective in suppressing either basal or stimulated hormone release only at very high (microM) concentrations. Intracellular events were studied by determination of the guanosine triphosphate binding (G) protein levels and adenylate cyclase (AC) activity in the tumour tissue. Before bromocriptine treatment, AC activity was very high in the tumour and could be further stimulated by various agents; very high levels of the AC-stimulatory G protein alpha subunit Gs alpha and very low amounts of the AC-inhibiting G protein alpha subunit Gi3 alpha and of the phospholipase C-stimulating G protein alpha subunit Gq alpha were found in the tumour. After bromocriptine, baseline AC activity was normalized and could no longer be stimulated; Gs alpha and Gi3 alpha levels were unchanged while those of Gq alpha were normalized. Screening of tumour DNA after amplification by polymerase chain reaction followed by single-strand conformational polymorphism analysis did not reveal any mutations in the hot spots of G protein alpha subunits (alpha s, alpha i2, alpha o2 and alpha 11) genes or in the H-ras and p53 genes. Gs alpha and GH transcription factor-1 (pit-1) expression were evaluated by amplification of cDNA. While the mRNA expression of pit-1 decreased after bromocriptine treatment, that of Gs alpha increased. These data suggest the possibility of an oncogenic process involving overexpression of Gs alpha, resulting in chronic activation of adenylate cyclase. Furthermore, our results suggest that the anti-secretory and anti-proliferative effects of bromocriptine may be mediated through a decrease in Pit-1 secondary to the inhibition of adenylate cyclase activity.
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PMID:Mammosomatotroph adenoma causing gigantism in an 8-year old boy: a possible pathogenetic mechanism. 762 75

Multiple carcinomas of the pancreatico-biliary tree are rare. A 53 year old Japanese man was diagnosed as having an adenocarcinoma in the papilla of Vater. During the operation, he was also found to have a polypoid mass in the common bile duct. While cutting the operative specimen into stepwise sections, a small tumor was also detected incidentally in the main pancreatic duct of the pancreatic head. Histologically, all three tumors proved to be papillary adenocarcinomas and were restricted to the mucosa. Immunohistochemically, all three tumors were positive for carcinoembryonic antigen, carbohydrate antigen 19-9, chromogranin A and serotonin, while they were negative for somatostatin. Immunoreactivity to the tumor suppressor gene p53 protein (PAb 1801) was found in all three tumors. A flow cytometric analysis of the cellular DNA content revealed all three tumors to be aneuploid. The above results suggested that these three tumors from different sites all had the same histological, immunohistochemical and flow cytometrical characteristics.
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PMID:Three synchronous carcinomas of the papilla of Vater, common bile duct and pancreas. 804

We report a case of somatostatinoma of the ampulla of Vater associated with von Recklinghausen's disease in a 44-year-old woman. On admission the patient was jaundiced, and percutaneous Cholangio-drainage was performed. Cholangiography revealed stenosis of the common bile duct at the lower end Duodenoscopy showed a yellowish tumor of the ampulla of Vater, and the biopsy specimens showed no malignant cells. Pylorus-preserving pancreaticoduo-denectomy was performed. Histologically, the tumor was composed of small round cells with a solid or trabecular pattern and with multiple psammoma bodies. Immunohistochemical examination showed that the tumor cells stained for somatostatin. Genomic examination showed neither K-ras nor p53 gene mutations of the resected specimen.
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PMID:Ampullary somatostatinoma in a patient with von Recklinghausen's disease. 872 43

We report a series of new in vitro and in vivo data proving the selective antitumor activity of our somatostatin structural derivative, TT-232. In vitro, it inhibited the proliferation of 20 different human tumor cell lines in the range of 50-95% and induced a very strong apoptosis. In vivo TT-232 was effective on transplanted animal tumors (Colon 26, B16 melanoma, and S180 sarcoma) and on human tumor xenografts. Treatment of MDA-MB-231 human breast cancer xenografted in mice with low submaximal doses of TT-232 [0.25 and 0.5 mg/kg of body weight (b.w.)] caused an average 80% decrease in the tumor volume resulting in 30% tumor-free animals surviving for longer than 200 days. Treatment of prostate tumor (PC-3) xenografted animals with 20 mg/kg of b.w. of TT-232 for 3 weeks resulted in 60% decrease in tumor volume and 100% survival even after 60 days, while 80% of nontreated animals perished. We have demonstrated that TT-232 did not bind to the membrane preparation of rat pituitary and cortex and had no antisecretory activity. TT-232 was not toxic at a dose of 120 mg/kg of b.w. in mice. Long-term incubation (24 h) of tumor cells with TT-232 caused significant inhibition of tyrosine kinases in good correlation with the apoptosis-inducing effect. The level of p53 or KU86 did not change following TT-232 treatment, suggesting a p53-independent apoptotic effect. Preincubation of human breast cancer cells (MDA-MB-453) with TT-232 for 2 h decreased the growth factor receptor autophosphorylation. All of these data suggest that TT-232 is a promising and selective antitumor agent.
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PMID:A tumor-selective somatostatin analog (TT-232) with strong in vitro and in vivo antitumor activity. 890 13

Somatostatin (SST) exerts direct antiproliferative effects in tumor cells, triggering either growth arrest or apoptosis. The cellular actions of SST are transduced through a family of five distinct somatostatin receptor subtypes (SSTR1-5). Whereas growth inhibition has been reported to follow stimulation of protein tyrosine phosphatase via SSTR2 or inhibition of Ca2+ channels via SSTR5 in heterologous expression systems, the subtype selectivity for signaling apoptosis has not been investigated. The tumor suppressor protein p53 and the protooncogene product c-Myc regulate cell cycle progression (growth factors present) or apoptosis (growth factors absent). The p53-induced G1 arrest requires induction of p21, an inhibitor of cyclin-dependent kinases, whereas apoptosis requires induction of Bax. c-Myc is capable of abrogating p53-induced G1 arrest by interfering with the inhibitory action of p21 on cyclin-dependent kinases. We have, therefore, investigated the regulation of p53, p21, c-Myc, and Bax and cellular apoptosis in relation to cell cycle progression in CHO-K1 cells stably expressing individual human SSTR1-5. We demonstrate that apoptosis is signaled uniquely through human SSTR3 and is associated with dephosphorylation-dependent conformational change in wild-type (wt) p53 as well as induction of Bax. The induction of wt p53 occurs rapidly and precedes the onset of apoptosis. We show that the increase in wt p53 is not associated with the induction of p21 or c-Myc when octreotide-induced apoptosis becomes evident, suggesting that such apoptosis does not require G1 arrest and is not c-Myc dependent. These findings provide the first evidence for hormonal induction of wt p53-associated apoptosis via G protein-coupled receptor in a subtype-selective manner.
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PMID:Subtype-selective induction of wild-type p53 and apoptosis, but not cell cycle arrest, by human somatostatin receptor 3. 896 Dec 77

Somatostatin (SST) analogs inhibit tumor cell growth by exerting direct anti-proliferative effects with cytostatic (growth arrest) or cytotoxic (apoptosis) consequences. The SST analog SMS 201-995 (octreotide, OCT) inhibits growth of MCF-7 human breast adenocarcinoma cells, which express multiple SSTRs. Its action has been reported to result in either apoptosis or growth arrest, but the underlying mechanisms have not been elucidated in this tumor cell model. Here, we report that OCT elicits cytotoxic response in these cells, leading to apoptosis, which is associated with a rapid, time-dependent induction of wild-type p53 and an increase in Bax. There was no G1 cell-cycle arrest in these cells during OCT treatment as suggested by the decrease in G1/S ratio and the lack of induction of pRb and p21. Additionally, we demonstrate that OCT-induced DNA fragmentation in this cell line is due to selective activation of a cation-insensitive acidic endonuclease. Our data provide a rationale for utilizing SST analogs to treat SSTR-positive breast cancer cells expressing wild-type p53.
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PMID:Induction of wild-type p53, Bax, and acidic endonuclease during somatostatin-signaled apoptosis in MCF-7 human breast cancer cells. 953 89

Expression of 18 genes was examined at 8 different time points between 1 h and 28 days following cryogenic rat brain injury. The genes include thymidine kinase (TK), p53 tumor suppressor, c-fos, renin, myelin basic protein (MBP), proteolipid protein (PLP), transferrin, transferrin receptor, platelet-derived growth factor A (PDGF A), platelet-derived growth factor B (PDGF B), platelet-derived growth factor receptor alpha (PDGF alpha receptor), platelet-derived growth factor receptor beta (PDGF beta receptor), glial fibrillary acidic protein (GFAP), transforming growth factor-beta 1 (TGF-beta 1), basic fibroblast growth factor (bFGF), fibroblast growth factor receptor-1 (FGF-R1), insulin-like growth factor-1 (IGF-1), and somatostatin. Time courses of gene expression were determined for RNAs derived from hippocampus and cortex. Genes were divided into categories based upon those in which statistically significant changes in expression were first observed at or before 24 h (early genes) and those in which changes were first observed at or after 72 h (late genes). In the present model, many genes demonstrate elevated RNA levels in the cortex prior to hippocampus, following injury. RNAs transcribed from late genes tend to be elevated concurrently in cortex and hippocampus.
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PMID:Temporal changes in gene expression following cryogenic rat brain injury. 964 55

KET is a member of the newly discovered family of proteins that is related to the tumor suppressor p53. Here we describe the molecular cloning of a human cDNA of 4846 bp encoding a protein of 680 amino acids. The human KET protein shares 98% identity with the previously characterized rat homolog. The remarkably high degree of conservation lends support to the notion that KET proteins have important basic functions in development and differentiation. Using the GeneBridge 4 radiation hybrid panel, we have mapped KET to human Chromosome (Chr) 3q27. KET is located between the somatostatin gene SST (proximal) and the apolipoprotein D gene APOD (distal) in a region of conserved synteny to mouse Chr 16. This chromosomal region is deleted in early stages of tumorigenesis of mouse islet cell carcinomas and contains the hitherto unidentified Loh2 gene, a putative suppressor of angiogenesis. The murine homolog Ket was mapped in an interspecific backcross panel and falls into this region of loss of heterozygosity. From our mapping data we infer that KET might act as a tumor suppressor and is considered as a candidate for Loh2.
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PMID:Cloning and chromosomal mapping of the human p53-related KET gene to chromosome 3q27 and its murine homolog Ket to mouse chromosome 16. 979 41

The G protein-coupled receptor agonist somatostatin (SST)-induces apoptosis in MCF-7 human breast cancer cells. This is associated with induction of wild-type p53, Bax, and an acidic endonuclease. We have shown recently that its cytotoxic signaling is mediated via membrane-associated SHP-1 and is dependent on decrease in intracellular pH (pHi) to 6.5. Here we investigated the relationship between intracellular acidification and SHP-1 in cytotoxic signaling. Clamping of pHi at 7.25 by the proton-ionophore nigericin abolished SST-signaled apoptosis without affecting its ability to regulate SHP-1, p53, and Bax. Apoptosis could be induced by nigericin clamping of pHi to 6.5. Such acidification-induced apoptosis was not observed at pHi <6.0 or >6.7. pHi-dependent apoptosis was associated with the translocation of SHP-1 to the membrane, enhanced in cells overexpressing SHP-1, and was abolished by its inactive mutant SHP-1C455S. Acidification caused by inhibition of Na+/H+ exchanger and H+ ATPase (pHi = 6.55 and 6.65, respectively) also triggered apoptosis. The effect of concurrent inhibition of Na+/H+ exchanger and H(+)-ATPase on pHi and apoptosis was comparable with that of SST. Acidification-induced, SHP-1-dependent apoptosis occurred in breast cancer cell lines in which SST was cytotoxic (MCF-7 and T47D) or not (MDA-MB-231). We conclude that: (a) SST-induced SHP-1-dependent acidification occurs subsequent to or independent of the induction of p53 and Bax; (b) SST-induced intracellular acidification may arise due to inhibition of Na+/H+ exchanger and H(+)-ATPase; and (c) SHP-1 is necessary not only for agonist-induced acidification but also for the execution of acidification-dependent apoptosis. We suggest that combined targeting of SHP-1 and intracellular acidification may lead to a novel strategy of anticancer therapy bypassing the need for receptor-mediated signaling.
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PMID:Interdependent regulation of intracellular acidification and SHP-1 in apoptosis. 1019 42

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


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