Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01189 (beta-endorphin)
 21,003 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neuropeptide precursors synthesized at the rough endoplasmic reticulum are transported and sorted at the trans-Golgi network (TGN) to the granules of the regulated secretory pathway (RSP) of neuroendocrine cells. They are then processed into active peptides and stored in large dense-core granules (LDCGs) until secreted upon stimulation. We have studied the regulation of biogenesis of the LDCGs and the mechanism by which neuropeptide precursors, such as pro-opiomelanocortin (POMC), are sorted into these LDCGs of the RSP in neuroendocrine and endocrine cells. We provide evidence that chromogranin A (CgA), one of the most abundant acidic glycoproteins ubiquitously present in neuroendocrine/endocrine cells, plays an important role in the regulation of LDCG biogenesis. Specific depletion of CgA expression by antisense RNAs in PC12 cells led to a profound loss of secretory granule formation. Exogenously expressed POMC was neither stored nor secreted in a regulated manner in these CgA-deficient PC12 cells. Overexpression of CgA in a CgA- and LDCG-deficient endocrine cell line, 6T3, restored regulated secretion of transfected POMC and the presence of immunoreactive CgA at the tips of the processes of these cells. Unlike CgA, CgB, another granin protein, could not substitute for the role of CgA in regulating LDCG biogenesis. Thus, we conclude that CgA is a key player in the regulation of the biogenesis of LDCGs in neuroendocrine cells. To examine the mechanism of sorting POMC to the LDCGs, we carried out site-directed mutagenesis, transfected the POMC mutants into PC12 cells, and assayed for regulated secretion. Our previous molecular modeling studies predicted a three-dimensional sorting motif in POMC that can bind to a sorting receptor, membrane carboxypeptidase E (CPE). The sorting signal consists of four conserved residues at the N-terminal loop structure of POMC: two acidic residues and two hydrophobic residues. The two acidic residues were predicted to bind to a domain on CPE (CPE254-273) containing two basic residues (R255 and K260) to effect sorting into immature secretory granules. Site-directed mutagenesis of the motif on POMC resulted in accumulation of the mutant in the Golgi, as well as high basal secretion, indicating that the mutant POMC was inefficiently sorted to the RSP. These results support the model that POMC is actively sorted to the RSP granules for processing and secretion by a sorting signal-mediated mechanism.
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PMID:Secretory granule biogenesis and neuropeptide sorting to the regulated secretory pathway in neuroendocrine cells. 1474 11

Cushing's syndrome secondary to ectopic adrenocorticotropic hormone (ACTH) secretion is rarely observed in breast carcinoma and only four cases have been previously published. We report here the case of a 50-year-old woman who presented with a history of diffuse bone pain associated with multiple hepatic, pulmonary, and bone metastases. A core needle biopsy specimen revealed an invasive ductal carcinoma in the right breast. The patient subsequently developed an ACTH-dependent paraneoplastic Cushing's syndrome and she died of arrhythmia and heart failure, despite treatment. At autopsy, immunohistochemical staining showed chromogranin A and ACTH positivity in the breast tumor and a lung metastasis. The mRNA expression of the pro-opiomelanocortin (POMC) gene was detected in tumoral cells by reverse transcriptase polymerase chain reaction (RT-PCR). This is the first case of Cushing's syndrome secondary to ectopic ACTH secretion where the presence of ACTH by immunohistochemistry and the expression of the POMC gene by RT-PCR have both been demonstrated in a breast carcinoma with metastases. The clinical history and the pathologic findings are presented with the methods and results of the molecular analysis. This case illustrates an example of ectopic ACTH syndrome in a breast carcinoma with neuroendocrine (NE) differentiation. This NE phenotype is directly related to the synthesis of ACTH by the tumoral cells. It should be kept in mind that an ectopic ACTH syndrome may be produced not only by small cell carcinoma or endocrine tumors but also by breast cancer. No relationship has been established between NE features and prognostic factors or patient outcome for this peculiar type of breast carcinoma. The demonstration of mRNA POMC in breast carcinoma with NE features suggests a depression and/or an activation of the POMC gene linked to the NE differentiation.
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PMID:Pro-opiomelanocortin expression in a metastatic breast carcinoma with ectopic ACTH secretion. 1523 95

Specimens of testis, excurrent duct including the male accessory glands and urethra, were studied in boars, bulls, horses and donkeys, in order to localize endocrine/paracrine cells. Silver impregnation methods were used to test the argentaffinity and/or argyrophilia of cells. Immunoreactivities to chromogranin A, 5-hydroxytryptamine, somatostatin, [met]- and [leu]- enkephalins, gastrin-releasing peptide, calcitonin gene-related peptide, neuropeptide Y, substance P, vasoactive intestinal peptide, beta-endorphin antisera were tested by a streptavidin-biotin method. In the testis, epididymis, ductus deferens and vesicular gland no endocrine cells were found in any of the animals studied. Chromogranin-A, serotonin, somatostatin and enkephalins were present in endocrine/paracrine cells in the surface or glandular epithelia, whereas all other antisera gave negative results. In the prostatic complex and the urethral epithelium, the most consistent number of endocrine cells was serotonin-immunoreactive. Few cells were also argentaffin and a very limited number of them showed argyrophily and chromogranin-A immunoreactivity. Somatostatin-and enkephalin-immunoreactive cells were rare in the bull and boar, absent in stallions. This comparative study carried out on different species of domestic ungulates has shown deeply different immunophenotypes, even comparing species that are in a very close zoological relationship with one another, such as the horse and the donkey.
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PMID:Endocrine-paracrine cells of the male urogenital apparatus: a comparative histochemical and immunohistochemical study in some domestic ungulates. 1523 14

Proopiomelanocortin processing in corticotroph cells is known to be operated by prohormone convertase (PC) 1/3 which is activating several pro-proteins and prohormones by intracellular limited proteolysis processing. In this study, we hypothesized that PC1/3 expression differs between Cushing's disease (CD) and silent corticotroph adenoma (SCA), and investigated whether PC1/3 expression is involved in the adrenocorticotropin (ACTH) silence of SCA. We performed immunohistochemical analysis of pituitary adenoma specimens for six adenohypophysial hormones, PC1/3 and chromogranin A (CgA). Subjects for this study consisted of 12 anterior pituitary adenomas of CD (1 male, 11 female; 14-70 years old) and 31 non-functioning adenomas (23 male, 8 female; 32-71 years old).ACTH immunoreactivity was observed in all of CD and three of 31 non-functioning adenomas. The three cases diagnosed as SCA were also positive for growth hormone and follicle-stimulating hormone. Cushing's adenomas and SCAs were all positive for PC1/3. PC1/3-positive cells did not always colocalize with ACTH but some of them colocalized with CgA in SCAs. Even if PC1/3 is not present in corticotroph cells, PC1/3 immunoreactivity in SCA may originate from CgA-positive cells. We conclude that immunohistochemistry for PC1/3 is not helpful for differential diagnosis between CD and SCA in clinical practice, though the regulation of PC1/3 expression is likely to be an important etiological factor in ACTH silence of SCA. The diversity of immunohistochemical properties of SCA leads us to speculate that it is not a single entity and may be a general diagnostic term for adenomas of varying etiology.
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PMID:Immunohistochemical properties of silent corticotroph adenoma and Cushing's disease. 1741 Apr 13

Preoperative diagnosis of asymptomatic paraganglioma is difficult due to the lack of specific symptoms. In this report, we present a rare case of a small and asymptomatic para-aortic paraganglioma. A 34-year-old woman who complained of back pain was admitted for further examination. No abnormal findings were observed on physical or laboratory examinations. An abdominal CT scan and an abdominal MRI incidentally noted a mass about 3 cm in diameter adjacent to the right edge of the inferior vena cava. The following aortic angiography showed the tumor with a feeding artery diverting directly from the aorta. The tumor was completely resected by laparotomy. The resected tumor, 3 x 3 x 3 cm in size, was soft, dark-reddish and encapsulated. Immunohistochemical examinations showed that it was positive for neuron-specific enolase, chromogranin A and adrenocorticotropin. Under these findings, the diagnosis of para-aortic paraganglioma was determined. Seven years after the operation, she remains asymptomatic and free of disease.
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PMID:An incidentally discovered small and asymptomatic para-aortic paraganglioma. 1771 20

A case of pancreatic acinar cell tumor (ACC) is presented in a 10-year-old boy. The tumor manifested clinically with Cushing's syndrome, high serum adrenocorticotropic hormone (ACTH) and cortisol concentrations. In addition, excessive serum levels of alpha-fetoprotein (AFP) were detected. Surgical resection was not possible due to retroperitoneal invasion. Biopsy of the mass showed a solid, poorly differentiated ACC of the pancreas. Periodic acid Schiff positive cytoplasmic granules, trypsinogen, keratins, alpha-1-antitrypsin, and AFP were identified in the tumor cells. Electron microscopy demonstrated zymogen granules as well as isolated dense core granules. Using immunochemiluminometric assay, a high quantity of ACTH was found in the fresh frozen tumor extract. ACTH, chromogranin A, and corticotropin-releasing factor were identified only in a few cells by immunohistochemistry. Combined radiochemotherapy was temporarily effective in reducing the tumor mass and serum AFP. Serum ACTH and cortisol levels dropped progressively and definitively to normal values after chemotherapy, and the Cushing's syndrome subsided. Two years later, the patient died with metastatic disease. The presented case of ACC is interesting due to high serum AFP values and ectopic ACTH secretion resulting in Cushing's syndrome.
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PMID:Cushing's syndrome in a child with pancreatic acinar cell carcinoma. 1791

To elucidate more precisely the biological characteristics of neuroblastomas, we examined four human neuroblastomas heterotransplanted into athymic nude mice NB-39 (undifferentiated type), NB-45 (poorly differentiated type with undifferentiated component), NB-52 (poorly differentiated type), and NB-726 (differentiating type) by electron microscopy, immunohistochemistry, and radioimmunoassay for the peptides in tumors. Ultrastructurally, NB-45, NB-52, and NB-726 contained more numerous and variously sized neurosecretory granules than did NB-39. Immunohistochemistry revealed neurofilament proteins, tyrosine hydroxylase, neuropeptide Y (NPY), and chromogranin A-positive cells in the four tumors in the following order of frequency: NB-726, NB-45, NB-52, and NB-39. NB-726, NB-45, and NB-52, but not NB-39, contained galanin-positive tumor cells. NB-45 and NB-726 harbored a few positive cells for calcitonin gene-related peptide. Furthermore, NB-726 exhibited positivity to leu-enkephalin, met-enkephalin, vasoactive intestinal peptide (VIP), and serotonin. Radioimmunoassay substantiated the results of immunohistochemistry, showing NPY in all tumors and either galanin or VIP in three tumors, excepting NB-39. Average doubling time of the tumor was as follows: 2 days in NB-39, 10 days in NB-45, 22 days in NB-52, and 45 days in NB-726. These results indicate that human neuroblastoma cells have different biological characteristics and reduced growth rate with differentiation in terms of ultrastructure and of peptide production abilities.
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PMID:Distinct morphological and immunohistochemical features and different growth rates among four human neuroblastomas heterotransplanted into nude mice. 1880 41

In a carcinogenicity study, a neuronal tumor in the cranial cavity was observed in a 110-week-old female B6C3F1 mouse. At necropsy, the tumor was seen at the site of the pituitary gland. Histologically, the tumor consisted of well-differentiated ganglion cells, nerve fiber/neuropil-like elements and ganglion-like cells. The tumor was composed mainly of ganglion-like cells, which were arranged in solid sheets interspersed with thin fibrovascular stroma. Nissl substance was detected at the margin in the cytoplasm of well-differentiated ganglion cells, and nerve fibers were identified by the Kluever-Barrera method. Immunohistochemically, the well-differentiated ganglion cells were positive for S-100, neurofilament protein (NF), neuron-specific enolase (NSE), synaptophysin, and chromogranin A. The nerve fiber/neuropil-like elements were positive for S-100, NF, NSE, and glial fibrillary acidic protein (GFAP), and the ganglion-like cells were strongly positive only for NSE and synaptophysin. On the other hand, there were no pituitary cells, such as prolactin-positive or adrenocorticotropic hormone (ACTH)-positive cells in the tumor tissue. Detailed histopathological examination suggested that the tumor might be a ganglioneuroma arising from the trigeminal ganglion. This report provides additional histopathological evidence of peripheral nerve neoplasms in mice.
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PMID:Spontaneous ganglioneuroma possibly originating from the trigeminal ganglion in a B6C3F1 mouse. 1938 Aug 43

This study was designed to determine whether maternal stress levels, state and trait anxiety levels, and stress hormones affect fetal heart rate (FHR) patterns after vibroacoustic stimulation (VAS) at 30 weeks of gestation. A total of 24 healthy pregnant women with a single fetus pregnancy were enrolled. Corticotropin releasing hormone (CRH) and adrenocorticotropic hormone in maternal plasma and cortisol, and chromogranin A in saliva were measured. The FHR patterns after VAS were divided into three types: type I, a long period of acceleration or one acceleration lasting > 1 min or at least two accelerations lasting > 15 s; type II, a biphasic response with acceleration followed by deceleration; and type III, no response or prolonged deceleration. In the high trait anxiety group, CRH levels were significantly higher than in the low trait anxiety group, and FHR patterns after VAS showed mostly a type II response pattern. These findings suggest that stress in pregnant women with high trait anxiety may influence FHR patterns after VAS.
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PMID:Effect of maternal stress on fetal heart rate assessed by vibroacoustic stimulation. 2014 76

Exaggerated adrenergic activity is associated with human hypertension. The peptide urocortin 2 (Ucn 2) inhibits catecholamine synthesis and secretion from adrenal chromaffin cells in vitro and administration to mammals lowers blood pressure (BP). The chromogranin A-null mouse (Chga-/-) manifests systemic hypertension because of excessive catecholamine secretion from the adrenal and decreased catecholamine storage. In the present study, we investigated whether systemic administration of Ucn 2 could reduce BP and adrenal and plasma levels of catecholamines in vivo. Ucn 2 peptide was administered to freely moving, conscious Chga-/- and wild-type control mice. Telemetry and HPLC measured changes in BP and catecholamine levels, respectively. In both groups of mice, Ucn 2 dose-dependently decreased BP, and this effect was mediated by corticotropin factor-receptor type 2. However, in Chga-/- mice, the maximal percentage decrease of systolic BP from basal systolic BP was 37% compared with only a 23% reduction in wild-type mice (P=0.04). In Chga-/- mice only, Ucn 2 decreased adrenal and plasma levels of catecholamines as well as adrenal levels of tyrosine hydroxylase protein and phosphorylation. In vitro mechanistic studies demonstrated that Ucn 2 reduces both catecholamine secretion and tyrosine hydroxylase promoter activity, suggesting that the exaggerated action of Ucn 2 to reduce BP in the Chga-/- mouse is mediated through inhibition of both catecholamine synthesis and secretion. The data suggest that Ucn 2 may be therapeutically useful in regulating the exaggerated sympathoadrenal function of hyperadrenergic hypertension.
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PMID:Urocortin 2 lowers blood pressure and reduces plasma catecholamine levels in mice with hyperadrenergic activity. 2066 31


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