Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q07644 (polypeptide)
 72,197 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endocrine tumors of the parathyroid and pancreas are encountered either as sporadic type or as part of multiple endocrine neoplasia type 1 (MEN 1). A high frequency of the loss of heterozygosity (LOH) has been observed in tumors of the sporadic type in the locus of the MEN 1 gene, which has recently been cloned and designated the menin gene. It would be of great interest to determine whether somatic mutations in the menin gene are responsible for the sporadic endocrine tumors. For this purpose, we have investigated the menin gene mutations in 21 sporadic parathyroid adenomas, 2 parathyroid carcinomas, 4 sporadic insulinomas, and 1 malignant VIP (vasoactive intestinal polypeptide)oma with WDHA (watery diarrhea, hypokalemia, and achlorhydria) syndrome, using PCR-single strand conformation polymorphism analysis and DNA sequencing. In none of these cases did the patient have a family history or other possible association with MEN 1. We have discovered somatic point mutations in two parathyroid adenomas (A340T and A541T), in one insulinoma (T429K), and in the malignant VIPoma (W198X). In addition, we have found two polymorphisms (D418D and V367V) in two parathyroid carcinomas and two parathyroid adenomas. Of these mutations and polymorphisms, three (A340T, T429K, and V367V) are first reported here, in the present article. Our results indicate that somatic mutations of the menin gene are responsible for a proportion of the sporadic parathyroid adenomas and pancreatic islet cell tumors.
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PMID:Somatic mutations of multiple endocrine neoplasia type 1 gene in the sporadic endocrine tumors. 956 91

The incretin hormones, glucagon-like peptide 1 and pituitary adenylyl cyclase-activating polypeptide, are proposed to activate a maitotoxin (MTX)-sensitive, Ca2+-dependent nonselective cation current in pancreatic beta-cells and insulinoma cells. This MTX-sensitive current is present in human beta-cells as well as in mouse and rat beta-cells, and is accompanied by a rise in cytosolic Ca2+ in voltage-clamped cells in which the activation of voltage-dependent Ca2+ channels is prevented. Activation of the nonselective cation current is inhibited by reduction of disulfide bonds with intracellular, but not extracellular, dithiothreitol, and is also abolished by intracellular dialysis with trypsin. The nonselective cation channels that carry this current have a conductance of about 30 pS, with Na+ as the major extracellular cation. We estimate that these cation channels are expressed on beta-cells at a density similar to that of ATP-sensitive potassium channels (K(ATP) channels) and exhibit spontaneous activity at basal glucose concentrations. We propose that this spontaneous cation channel activity constitutes at least part of the depolarizing background conductance that permits changes in the activity of K(ATP) channels to regulate the resting potential of beta-cells.
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PMID:A role for Ca2+-sensitive nonselective cation channels in regulating the membrane potential of pancreatic beta-cells. 964 30

We have studied the localization, receptor occupancy and potency of the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) in insulin-producing tissues. Immunocytochemistry showed that PACAP-like immunoreactivity (PACAP-IR) was localized to pancreatic nerves with accumulation in intrapancreatic ganglia in both mouse and rat. In contrast, PACAP-IR could not be demonstrated in endocrine cells. Furthermore, in situ hybridization, using oligodeoxyribonucleotide probes recognizing mRNA for PACAP receptors, demonstrated that mouse and rat pancreas, and the insulinoma cell lines HIT-T15 and RINm5F, expressed both the PACAP type 1 and the VIP2/PACAP receptors. Moreover, both PACAP27 and PACAP38 dose-dependently (0.1 nM to 100 nM) and equipotently stimulated insulin secretion in isolated mouse and rat islets and in HIT-T15 and RINm5F cells. Furthermore, in mouse islets, vasoactive intestinal polypeptide (VIP) was of equal potency as PACAP at stimulating insulin secretion. In mouse, PACAP also stimulated insulin secretion in a subfraction of the isolated islets also at the low dose of 1 fM. Thus, (1) PACAP is exclusively a neuropeptide in the pancreas, (2) insulin-producing cells express PACAP type 1 and VIP2/PACAP receptors and (3) the two forms of PACAP equipotently stimulate insulin secretion. Based on these results, we suggest that PACAP is involved in the neural regulation of insulin secretion.
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PMID:PACAP and PACAP receptors in insulin producing tissues: localization and effects. 971 78

Synapsin I is a synaptic vesicle-associated protein involved in neurotransmitter release. The functions of this protein are apparently regulated by Ca2+/calmodulin-dependent protein kinase II (CaM kinase II). We reported evidence for CaM kinase II and a synapsin I-like protein present in mouse insulinoma MIN6 cells (Matsumoto, K., Fukunaga, K., Miyazaki, J., Shichiri, M., and Miyamoto, E. (1995) Endocrinology 136, 3784-3793). Phosphorylation of the synapsin I-like protein in these cells correlated with the activation of CaM kinase II and insulin secretion. In the present study, we screened the MIN6 cDNA library with the full-length cDNA probe of rat brain synapsin Ia and obtained seven positive clones; the largest one was then sequenced. The largest open reading frame deduced from the cDNA sequence of 3695 base pairs encoded a polypeptide of 670 amino acids, which exhibited significant sequence similarity to rat synapsin Ib. The cDNA contained the same sequence as the first exon of the mouse synapsin I gene. These results indicate that synapsin Ib is present in MIN6 cells. Synapsin I was expressed in normal rat islets, as determined by reverse transcriptase-polymerase chain reaction analysis. Immunoblot analysis after subcellular fractionation of MIN6 cells demonstrated that synapsin Ib and delta subunit of CaM kinase II co-localized with insulin secretory granules. By analogy concerning regulation of neurotransmitter release, our results suggest that phosphorylation of synapsin I by CaM kinase II may induce the release of insulin from islet cells.
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PMID:Cloning from insulinoma cells of synapsin I associated with insulin secretory granules. 989 Sep 64

alpha-Latrotoxin is a presynaptic neurotoxin isolated from the venom of the black widow spider Latrodectus tredecimguttatus. It exerts toxic effects in the vertebrate central nervous system by depolarizing neurons, by increasing [Ca2+]i and by stimulating uncontrolled exocytosis of neurotransmitters from nerve terminals. The actions of alpha-latrotoxin are mediated, in part, by a GTP-binding protein-coupled receptor referred to as CIRL or latrophilin. Exendin-4 is also a venom toxin, and it is derived from the salivary gland of the Gila monster Heloderma suspectum. It acts as an agonist at the receptor for glucagon-like peptide-1(7-36)-amide (GLP-1), thereby stimulating secretion of insulin from pancreatic beta-cells of the islets of Langerhans. Here is reported a surprising structural homology between alpha-latrotoxin and exendin-4 that is also apparent amongst all members of the GLP-1-like family of secretagogic hormones (GLP-1, glucagon, vasoactive intestinal polypeptide, secretin, pituitary adenylyl cyclase activating polypeptide). On the basis of this homology, we report the synthesis and initial characterization of a chimeric peptide (Black Widow GLP-1) that stimulates Ca2+ signaling and insulin secretion in human beta-cells and MIN6 insulinoma cells. It is also reported here that the GTP-binding protein-coupled receptors for alpha-latrotoxin and exendin-4 share highly significant structural similarity in their extracellularly-oriented amino-termini. We propose that molecular mimicry has generated conserved structural motifs in secretagogic toxins and their receptors, thereby explaining the evolution of defense or predatory strategies that are shared in common amongst distantly related species including spiders, lizards, and snakes. Evidently, the toxic effects of alpha-latrotoxin and exendin-4 are explained by their ability to interact with GTP-binding protein-coupled receptors that normally mediate the actions of endogenous hormones or neuropeptides.
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PMID:Black widow spider alpha-latrotoxin: a presynaptic neurotoxin that shares structural homology with the glucagon-like peptide-1 family of insulin secretagogic hormones. 997 93

It has been previously demonstrated that pituitary adenylate cyclase-activating polypeptide (PACAP) regulates insulin secretion. PACAP exerts its biological action by binding to at least three different receptor subtypes coupled to different signal transduction mechanisms. The signaling pathways underlying the insulinotropic effect of PACAP involve mainly the activation of adenylate cyclase to form cAMP, which directly and indirectly, through increased intracellular Ca2+, stimulates insulin exocytosis. In the present study we have characterized the functional and molecular expression of PACAP/vasoactive intestinal polypeptide receptors isoforms and subtypes and its isoforms in a beta-cell line and in isolated rat pancreatic islets. Although insulinoma cells express the messenger RNA encoding PAC1 (-R and -hop variants), VPAC1 and VPAC2, binding experiments indicate the preponderance of PAC1 over VPAC 1-2 receptors. We have also shown that the main signaling pathway of PACAP in beta-cells is mediated by adenylate cyclase, whereas the inositol 1,4,5-trisphosphate pathway is almost inactive. Furthermore, we have demonstrated that PACAP exerts long-term effects on beta-cells, such as transcriptional regulation of the insulin gene and genes of the glucose-sensing system (GLUT1 and hexokinase 1).
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PMID:Molecular and functional characterization of pituitary adenylate cyclase-activating polypeptide (PACAP-38)/vasoactive intestinal polypeptide receptors in pancreatic beta-cells and effects of PACAP-38 on components of the insulin secretory system. 1057 16

The polypeptide beta-cellulin, identified in conditioned media from insulinoma cell cultures and produced by pancreatic islet cells, was recently identified as a possible autocrine growth factor for the pancreatic islet beta-cell. In this study, we investigated the short- and long-term actions of beta-cellulin, and the structurally related transforming growth factor-alpha (TGF-alpha), on beta-cell function in fetal rat pancreatic islets in vitro. We found that neither beta-cellulin nor TGF-alpha (10 nM each), in contrast to glucose (20 mM), acutely influenced beta-cell levels of cytosolic-free Ca2+. Additionally, whereas glucose markedly increased short-term (60-min) insulin release, neither beta-cellulin nor TGF-alpha (10 nM each) influenced the rate of hormone secretion at basal (3 mM) or stimulatory (20 mM) concentrations of glucose. Likewise, long-term (24-h) exposure of islets to a high glucose concentration significantly augmented the secretion of insulin. This effect was slightly potentiated by TGF-alpha (10 nM), but not beta-cellulin (10 nM), at high (but not low) glucose concentrations. Conversely, the islet insulin content was not significantly affected by beta-cellulin or TGF-alpha at any glucose concentration tested. We conclude that, although beta-cellulin is produced by islet cells, the peptide does not seem to be of importance for the regulation of insulin production by isolated pancreatic beta-cells.
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PMID:Short- and long-term effects of beta-cellulin and transforming growth factor-alpha on beta-cell function in cultured fetal rat pancreatic islets. 1070 67

Islet cell autoantigen (ICA) 512 of type I diabetes is a receptor tyrosine phosphatase-like protein associated with the secretory granules of neurons and endocrine cells including insulin-secreting beta-cells of the pancreas. Here we show that in a yeast two-hybrid assay its cytoplasmic domain binds beta2-syntrophin, a modular adapter which in muscle cells interacts with members of the dystrophin family including utrophin, as well as the signaling molecule neuronal nitric oxide synthase (nNOS). The cDNA isolated by two-hybrid screening corresponded to a novel beta2-syntrophin isoform with a predicted molecular mass of 28 kDa. This isoform included the PDZ domain, but not the C-terminal region, which in full-length beta2-syntrophin is responsible for binding dystrophin-related proteins. In vitro binding of the beta2-syntrophin PDZ domain to ICA512 required both ICA512's C-terminal region and an internal polypeptide preceding its tyrosine phosphatase-like domain. Immunomicroscopy and co-immunoprecipitations from insulinoma INS-1 cells confirmed the occurrence of ICA512-beta2-syntrophin complexes in vivo. ICA512 also interacted in vitro with the PDZ domain of nNOS and ICA512-nNOS complexes were co-immunoprecipitated from INS-1 cells. Finally, we show that INS-1 cells, like muscle cells, contain beta2-syntrophin-utrophin oligomers. Thus, we propose that ICA512, through beta2-syntrophin and nNOS, links secretory granules with the actin cytoskeleton and signaling pathways involving nitric oxide.
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PMID:The receptor tyrosine phosphatase-like protein ICA512 binds the PDZ domains of beta2-syntrophin and nNOS in pancreatic beta-cells. 1104 3

We report a patient with insulinoma associated with Zollinger-Ellison syndrome. A 67-year-old woman was first admitted to our hospital for an abdominal mass. Abdominal computed tomography (CT) revealed a large pancreatic tumor, which was then diagnosed as an unresectable pancreatic adenocarcinoma. At the age of 71, she presented symptoms of hypoglycemia. Fasting blood glucose was 21 mg/dl and plasma immunoreactive insulin level was 846 microU/ ml. Plasma gastrin, glucagon, vasoactive intestinal polypeptide and somatostatin levels were all normal. At the age of 73, hypoglycemic attacks occurred more frequently and she was admitted to our hospital. Abdominal CT scan showed multiple liver metastases. Chemotherapy with 5-fluorouracil and doxorubicin was performed. Three months later, she had an emergency laparotomy because of a perforated duodenal ulcer. Plasma gastrin level was 1,960 pg/ml at that time. Gastric hypersecretion was well controlled with a proton pump inhibitor (lansoprazole) but she died of widespread cancer dissemination 8 years after her first admission. On autopsy, histologic examination revealed a mixed acinar-endocrine carcinoma of the pancreas. Immunohistochemical stains were positive for insulin, gastrin, and alpha1-antitrypsin.
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PMID:Insulinoma with subsequent association of Zollinger-Ellison syndrome. 1139 7

Gastroenteropancreatic (GEP) neoplasms originate from any of the various cell types belonging to the neuroendocrine system. A general characteristic of GEP endocrine tumours is that the vast majority produce and secrete a multitude of peptide hormones and amines. Many patients with malignant metastasising tumours present clinical symptoms related to hormone hyperproduction. These include the so-called carcinoid syndrome, characterised by flushing, diarrhoea, wheezing and right heart disease, which is predominantly associated with the serotonin- and tachykinins-producing carcinoids of the midgut. Several types of syndrome associated with GEP endocrine tumors are caused by overproduction of a specific hormone. For instance, the well-known Zollinger-Ellison syndrome is gastrin-mediated. The so-called 'insulinoma syndrome' depends on excessive production of insulin and proinsulin, resulting in hypoglycemia. The 'glucagonoma syndrome' is characterised by necrolytic migratory erythema, diabetes and diarrhoea. The Verner-Morrison syndrome, which is brought about by high circulating levels of vasointestinal peptide (VIP). produces severe secretory diarrhoea. Finally the 'somatostatinoma syndrome' involves gallbladder dysfunction and gallstones, diarrhoea with or without steatorrhea, and impaired glucose tolerance. The biochemical diagnosis of endocrine digestive tumors is based on general and specific markers. The best general markers are chromogranin A (CgA) and pancreatic polypeptide (PP). Specific markers for endocrine tumors include insulin, gastrin, glucagon, vaso intestinal polypeptide (VIP), somatostatin and the primary cathabolic product of serotonin, 5-hydroxyndoleacetic acid (5-HIAA). Localisation procedures commonly applied, in the diagnosis of endocrine tumours include ultrasound (US), computed tomography (CT) and somatostatin receptor scintigraphy (SRS).
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PMID:Epidemiology, clinical features and diagnosis of gastroenteropancreatic endocrine tumours. 1176 60


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