Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01275 (glucagon)
 26,492 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Early passage in vitro cultures of colorectal adenocarcinoma cells were used to determine if glucagon exerts a direct effect on growth of human colon cancer cells. Growth response assays indicated that glucagon generally stimulated growth between 2 and 10 micrograms/ml, with peak responses at 5 to 10 micrograms/ml. When glucagon-treated and control cultures were compared, 12 of the 14 cultures (86 percent) were stimulated by glucagon, with an increase in cells from 41 to 100 percent. The other two cultures did not respond to glucagon. These in vitro results suggest that glucagon may enhance growth of most colon cancer cells. Further studies on responsiveness to glucagon may help elucidate mechanisms of oncogenesis and suggest new therapeutic protocols for patients with colorectal cancer.
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PMID:Glucagon enhances growth of cultured human colorectal cancer cells in vitro. 407 59

The high oncogenic efficiency of woodchuck hepatitis virus (WHV) has been correlated with the ability of this virus to provoke insertional activation of myc family genes. To assess the impact of viral integration on liver cell transformation, we have generated transgenic mice carrying the mutated c-myc gene and adjacent viral DNA from a woodchuck tumor, in original configuration. Virtually all mice from two different strains developed hepatocellular carcinoma with a mean latency period of 8-12 months. The c-myc transgene was expressed transiently in neonatal livers, and re-expressed at preneoplastic and neoplastic stages in adult livers. Woodchuck c-myc mRNA driven by the normal P1 and P2 promoters and WHV-specific transcripts encoding viral surface antigens were produced in a strictly co-regulated fashion during development and tumorigenesis, indicating a predominant regulatory influence of the viral enhancer. Furthermore, the activity of the viral enhancer in response to various biological stimuli was apparently modulated by glucose uptake and glucagon/insulin balance in differentiated hepatocytes. In this model, a viral integration event selected from a naturally occurring tumor proved to be determinant for induction of hepatocarcinogenesis, although enforced, liver-specific expression of c-myc was limited to a particular developmental stage.
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PMID:Liver-specific expression and high oncogenic efficiency of a c-myc transgene activated by woodchuck hepatitis virus insertion. 810 15

The tumorigenesis of insulinomas is unclear. Hyperglycemia has been found in many short term experiments to be one of the strongest stimuli for proliferation of the pancreatic beta-cells. After isologous islet transplantation into the livers of streptozotocin-diabetic rats it has been shown by our group that the proliferative activity of islet graft epithelial cells is strongly increased in a hyperglycemic environment (low-number islet transplantation) compared with normoglycemic conditions (high-number islet transplantation). The aim of this study was to investigate the long-term fate of these hyperproliferative islet grafts. 66 out of 91 streptozotocin-diabetic male Lewis rats persisted in a mild diabetic state after transplantation of 250-450 islets (main group), 25 animals became normoglycemic immediately after transplantation of 1000-2000 islets (control group). 5-Bromo-2'-desoxyuridine was administered prior to sacrifice. For the determination of the proliferative activity of the different cell types immunohistochemistry for insulin, glucagon and somatostatin was combined with a 5-Bromo-2'-desoxyuridine immunohistochemistry. Six animals of the main group developed insulinomas in their livers between 18 and 24 months after islet transplantation (i.e. 18% of the animals which lived more than 18 months after transplantation). The insulinomas induced severe hypoglycemia (12-36 mg/dl blood glucose), and the tumor cells showed a high proliferative activity, a positive immunoreactivity for insulin, and typical electron dense granules. The normoglycemic control group animals did not develop endocrine tumors. This study shows for the first time that insulinomas develop in transplanted islets of Langerhans under the influence of the long-term proliferative stimulus hyperglycemia.
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PMID:[Insulinoma originating from transplanted pancreatic cells after low dose portal embolic islet transplantation in streptozotocin diabetic rats]. 947 68

Although pancreatic neuroendocrine tumors (NETs) in von Hippel-Lindau (VHL) disease have been reported, their pathological features have not been characterized. In addition, it is unknown whether alterations of the VHL gene are responsible for pancreatic NET development. To evaluate NETs in VHL patients, we performed histopathological analysis of 30 pancreatic tumors in 14 patients. In addition, DNA from NETs and normal pancreatic tissue from 6 patients with documented germ-line VHL gene mutations was studied for allelic deletions of the second copy of the VHL gene by fluorescence in situ hybridization and polymerase chain reaction-based single-strand conformational polymorphism analysis. Morphologically, the tumors were characterized by solid, trabecular, and/or glandular architecture and prominent stromal collagen bands. Sixty percent of the tumors revealed at least focally clear-cell cytology. All tumors were positive for panendocrine immunohistochemistry markers (chromogranin A and/or synaptophysin); 35% of NETs demonstrated focal positivity for pancreatic polypeptide, somatostatin, insulin, and/or glucagon; and no immunostaining for pancreatic and gastrointestinal hormones was observed in 65% of tumors. Dense core neurosecretory granules were evident by electron microscopic examination, and the clear cells additionally revealed abundant intracytoplasmic lipid. All NETs that were subjected to genetic analysis showed allelic loss of the second copy of the VHL gene. We conclude that multiple, nonfunctional pancreatic NETs occur in VHL patients. Stromal collagen bands and clear-cell morphology are important histological features of VHL-associated NETs. The presence of allelic deletions of the VHL gene in pancreatic NETs provides direct molecular evidence for a role of the gene in their tumorigenesis and establishes NET as an independent tumor type of VHL disease.
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PMID:Multiple neuroendocrine tumors of the pancreas in von Hippel-Lindau disease patients: histopathological and molecular genetic analysis. 966 83

Transgenic mice containing an upstream glucokinase (betaGK) promoter- simian virus 40 T antigen (Tag) fusion gene develop neuroendocrine tumors primarily in the pancreas, gut, and pituitary. Pancreatic tumors from a line with delayed tumorigenesis were of two different types: insulinomas and noninsulinomas. The noninsulinomas are often periductal in location, express none of the four major islet peptide hormones, Glut-2, Pdx1, tyrosine hydroxylase, Pax4, Pax6, or Nkx6.1, but do express glucokinase, Sur1, Isl1, Hnf3beta, Hnf6, Beta2/NeuroD, and Nkx2.2. Cells from two different noninsulinoma tumors, when adapted to culture, began to express either insulin, glucagon, or somatostatin. Given the partial gene expression repertoire of the noninsulinoma tumors, their apparent periductal origin, and the ability of these cells to partially cytodifferentiate in culture, we suggest that these tumors are derived from islet progenitor cells. Thus, betaGK-Tag transgenic mice provide a new model system for studying the events that occur during both islet cell neogenesis and normal embryonic development.
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PMID:Targeted oncogenesis of hormone-negative pancreatic islet progenitor cells. 967 33

Comparative genomic hybridization (CGH) was used to investigate changes in DNA copy numbers in 25 paraffin-embedded samples of pancreatic endocrine tumors from 23 patients. Insulin was the dominant hormone in 12, glucagon in 7, somatostatin in 1, and pancreatic polypeptide in 2 tumors. One to 15 (mean, 8.1) changes in DNA copy numbers were observed in 22 of the 25 tumors. The most recurrent aberration, found in 68% of the tumors, involved gains in chromosome 7 with a minimal overlapping region at 7q11.2. Other frequent gains included chromosomes 19 (60%) and 14 (56%). Chromosome arm 20q was amplified in 48% of the cases with the minimal overlapping region of 20q11.1-13.1. The two most frequent DNA losses were found at 11q21-22 in 32% and at 11p13-15 in 24% of the cases. The amplified chromosomal regions contain several candidate genes that may be involved in islet cell tumorigenesis. The regions with most frequent losses are likely to contain still uncharacterized tumor suppressor genes. Wiley-Liss, Inc.
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PMID:Chromosomal alterations in human pancreatic endocrine tumors. 1091 98

Proliferative changes in the neuroendocrine cells that precede neoplasia are of interest for the understanding of tumorigenesis and the early recognition of neuroendocrine tumors. This review focuses on precursor lesions of duodenal and pancreatic neuroendocrine tumors in multiple endocrine neoplasia type 1 (MEN1) and also discusses 2 new disease entities of pancreatic microadenomatosis. The gastrinomas observed in MEN1 are almost exclusively localized in the duodenum and are multicentric. It has been shown that, in contrast to sporadic duodenal gastrinomas, they are associated with hyperplastic gastrin cell lesions and tiny gastrin-producing microtumors less than 500 microm in diameter. In the pancreas, microadenomatosis (multiple tumors up to 5 mm in diameter) is a feature of MEN1. These microadenomas predominantly express glucagon and pancreatic polypeptide, but do not cause a hormonal syndrome. Approximately 50% of MEN1 minigastrinomas in the duodenum and almost all microadenomas in the pancreas show allelic deletion of the MEN1 gene and therefore may represent 'initial' neoplasms. In contrast, endocrine cell precursor lesions retain heterozygosity. Pancreatic microadenomatosis was also found unassociated with hereditary syndromes and 2 monohormonal types were identified: (1) glucagon-producing microadenomatosis and (2) insulin-producing microadenomatosis, both associated with macrotumors. Whether these types of microadenomatosis represent novel disease entities and how to diagnose and treat these patients remains to be clarified by further studies.
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PMID:Endocrine precursor lesions and microadenomas of the duodenum and pancreas with and without MEN1: criteria, molecular concepts and clinical significance. 1789 Aug 93

It is well known that activating protein-1 (AP-1) is involved in a variety of cellular functions such as proliferation, differentiation, apoptosis, and oncogenesis. AP-1 is a dimer complex consisting of different subunits, and c-Jun is known to be one of its major components. In addition, it has been shown that mice lacking c-Jun are embryonic lethal and that c-Jun is essential for liver and heart development. However, the role of c-Jun in the pancreas is not well known. The aim of this study was to examine the possible role of c-Jun in the pancreas. First, c-Jun was strongly expressed in pancreatic duct-like structures at an embryonic stage, while a lower level of expression was observed in some part of the adult pancreas, implying that c-Jun might play a role during pancreas development. Second, to address this point, we generated pancreas-specific c-Jun knock-out mice (Ptf1a-Cre; c-Jun(flox/flox) mice) by crossing Ptf1a-Cre knock-in mice with c-Jun floxed mice. Ptf1a is a pancreatic transcription factor and its expression is confined to pancreatic stem/progenitor cells, which give rise to all three types of pancreatic tissue: endocrine, exocrine, and duct. Contrary to our expectation, however, there was no morphological difference in the pancreas between Ptf1a-Cre; c-Jun(flox/flox) and control mice. In addition, there was no difference in body weight, pancreas weight, and the expression of various pancreas-related factors (insulin, glucagon, cytokeratin, and amylase) between the two groups. Furthermore, there was no difference in glucose tolerance between Ptf1a-Cre; c-Jun(flox/flox) and control mice. Taken together, although we cannot exclude the possibility that c-Jun ablation is compensated by some unknown factors, c-Jun appears to be dispensable for pancreas development at least after ptf1a gene promoter is activated.
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PMID:Tissue-specific deletion of c-Jun in the pancreas has limited effects on pancreas formation. 1792 May 62

Type 2 diabetes is characterized by insulin resistance, insulin deficiency, and hyperglycemia. Susceptibility to type 2 diabetes has been linked to Wnt signaling, which plays an important role in intestinal tumorigenesis. Carriers of variants of the transcription factor 7-like 2 gene, an important component of the Wnt pathway, are at enhanced risk for developing type 2 diabetes. The modulation of proglucagon expression by Wnt activity may partially explain the link between Wnt signaling and diabetes, and one of the transcriptional and processing products of the proglucagon gene, the glucagon-like peptide-1 (GLP-1), exhibits a wide variety of antidiabetogenic activities. GLP-1 stimulates Wnt signaling in pancreatic beta cells, enhancing cell proliferation; thus, positive feedback between GLP-1 and Wnt signaling may result in increased proliferation, and suppressed apoptosis, of pancreatic cells. Since beta-cell protection is a potential treatment for type 2 diabetes, stimulation of Wnt activity may represent a valid therapeutic approach.
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PMID:Role of Wnt signaling in the development of type 2 diabetes. 1925 Oct 50

The von Hippel-Lindau (VHL) syndrome is a pleomorphic familial disease characterized by the development of highly vascularized tumors, such as hemangioblastomas of the central nervous system, pheochromocytomas, renal cell carcinomas, cysts and neuroendocrine tumors of the pancreas. Up to 75% of VHL patients are affected by VHL-associated pancreatic lesions; however, very few reports in the published literature have described the cellular origins and biological roles of VHL in the pancreas. Since homozygous loss of Vhl in mice resulted in embryonic lethality, this study aimed to characterize the functional significance of VHL in the pancreas by conditionally inactivating Vhl utilizing the Cre/LoxP system. Specifically, Vhl was inactivated in different pancreatic cell populations distinguished by their roles during embryonic organ development and their endocrine lineage commitment. With Cre recombinase expression directed by a glucagon promoter in alpha-cells or an insulin promoter in beta-cells, we showed that deletion of Vhl is dispensable for normal functions of the endocrine pancreas. In addition, deficiency of VHL protein (pVHL) in terminally differentiated alpha-cells or beta-cells is insufficient to induce pancreatic neuroendocrine tumorigenesis. Most significantly, we presented the first mouse model of VHL-associated pancreatic disease in mice lacking pVHL utilizing Pdx1-Cre transgenic mice to inactivate Vhl in pancreatic progenitor cells. The highly vascularized microcystic adenomas and hyperplastic islets that developed in Pdx1-Cre;Vhl f/f homozygous mice exhibited clinical features similar to VHL patients. Establishment of three different, cell-specific Vhl knockouts in the pancreas have allowed us to provide evidence suggesting that VHL is functionally important for postnatal ductal and exocrine pancreas, and that VHL-associated pancreatic lesions are likely to originate from progenitor cells, not mature endocrine cells. The novel model systems reported here will provide the basis for further functional and genetic studies to define molecular mechanisms involved in VHL-associated pancreatic diseases.
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PMID:Deciphering von Hippel-Lindau (VHL/Vhl)-associated pancreatic manifestations by inactivating Vhl in specific pancreatic cell populations. 1934 Mar 11


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