Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0031511 (pheochromocytoma)
 14,622 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Plasma levels of chromogranin A (CgA) were measured by ELISA in 22 patients with pheochromocytoma (18 non-metastatic, 3 metastatic, and 1 mixed neuroendocrine-neural tumor), 9 patients with primary hyperparathyroidism, and 9 patients with pituitary adenoma. The plasma levels of CgA were compared with norepinephrine, epinephrine, parathyroid hormone and pituitary hormones, i.e., growth hormone and prolactin. In pheochromocytoma, CgA in preoperative plasma of the patients without metastasis was 228 +/- 38 U/L (mean +/- SEM) and significantly higher than healthy controls (30 +/- 11 U/L, n = 40). Plasma CgA was decreased after removal of the tumors (28 +/- 6.0 U/L), except in three patients with metastatic pheochromocytoma and a mixed neuroendocrine neural tumor. The concentration of CgA in the patients with non-metastatic pheochromocytoma was significantly correlated with that of plasma norepinephrine (P < 0.005, r = 0.68) and urinary norepinephrine (P < 0.05, r = 0.65), but not with that of epinephrine. There was an exceptional case in which CgA was extremely high, but the CA level was normal. This tumor was a highly malignant pheochromocytoma with extensive metastases composed of small tumor cells which were occasionally positive for tyrosine hydroxylase immunohistochemically. These cells were considered to be poorly differentiated tumor cells and synthesized a very small amount of norepinephrine. Plasma levels of the patients with primary hyperparathyroidism and the patients with pituitary adenoma were 44 +/- 4 U/L and 48 +/- 8 U/L, respectively. Only one patient with a growth hormone-producing pituitary adenoma had a high level of CgA. Plasma CgA is a useful tumor marker for pheochromocytoma, even for malignant pheochromocytoma without elevated CA level, but not for hyperparathyroidism, or pituitary adenoma.
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PMID:Plasma chromogranin A in pheochromocytoma, primary hyperparathyroidism and pituitary adenoma in comparison with catecholamine, parathyroid hormone and pituitary hormones. 922 69

Catecholamine secretory vesicle core proteins (chromogranins) contain an activity that inhibits catecholamine release, but the identity of the responsible peptide has been elusive. Size-fractionated chromogranins antagonized nicotinic cholinergic-stimulated catecholamine secretion; the inhibitor was enriched in processed chromogranin fragments, and was liberated from purified chromogranin A. Of 15 synthetic peptides spanning approximately 80% of chromogranin A, one (bovine chromogranin A344-364 [RSMRLSFRARGYGFRGPGLQL], or catestatin) was a potent, dose-dependent (IC50 approximately 200 nM), reversible secretory inhibitor on pheochromocytoma and adrenal chromaffin cells, as well as noradrenergic neurites. An antibody directed against this peptide blocked the inhibitory effect of chromogranin A proteolytic fragments on nicotinic-stimulated catecholamine secretion. This region of chromogranin A is extensively processed within chromaffin vesicles in vivo. The inhibitory effect was specific for nicotinic cholinergic stimulation of catecholamine release, and was shared by this chromogranin A region from several species. Nicotinic cationic (Na+, Ca2+) signal transduction was specifically disrupted by catestatin. Even high-dose nicotine failed to overcome the inhibition, suggesting noncompetitive nicotinic antagonism. This small domain within chromogranin A may contribute to a novel, autocrine, homeostatic (negative-feedback) mechanism controlling catecholamine release from chromaffin cells and neurons.
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PMID:Novel autocrine feedback control of catecholamine release. A discrete chromogranin a fragment is a noncompetitive nicotinic cholinergic antagonist. 929 31

This report presents the clinical, laboratory, imaging, and pathologic findings in 61 dogs with pheochromocytoma by retrospective evaluation of medical records. Pheochromocytomas were diagnosed by histopathologic examination of tissue specimens in all dogs. Special stains (chromogranin A and synaptophysin) also were used to confirm the chromaffin cell origin of the tumors. Epidemiologic findings were in agreement with previous studies, indicating that pheochromocytomas affect middle-aged to older dogs with no apparent gender or breed predilection. The tumor was considered clinical in 21 dogs (34%), was responsible for abnormalities related to a space-occupying mass in 7 dogs (11%), and was an incidental finding in 35 dogs (57%). The hematologic and biochemical findings were nonspecific. Hypertension was detected in 10 of 23 (43%) dogs tested, but all hypertensive dogs had concurrent diseases that may have contributed to hypertension. Abdominal ultrasonography was the most commonly used imaging procedure, with a mass detected in the region of the adrenal glands in 20 of 40 (50%) dogs examined. In 4 of the 20 dogs (20%), invasion of the caudal vena cava was identified. Surgery was performed in 17 dogs (28%) with immediate death or euthanasia of 5 dogs. Survival after surgery ranged from 1 day to 3.25 years. Pheochromocytomas were locally invasive in 39% of affected dogs and produced metastases in 13% of the cases. Common sites for metastases included regional lymph nodes, liver, lung, kidney, spleen, and bone. A high frequency of concurrent neoplasia (54%), including endocrine neoplasia, was identified.
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PMID:Pheochromocytoma in dogs: 61 cases (1984-1995). 934 93

Neuroendocrine (NE) cells are present in both benign and malignant human prostate. However, their function is poorly understood, mainly due to the lack of suitable experimental models. The nerve growth factor-beta (NGF-beta) promotes the rat pheochromocytoma cell line PC-12 to differentiate into neuronal like cells. We have studied the effect of NGF-beta on four human prostate cancer cell lines, LNCaP, DU-145, PC-3, and TSU-pr1. NGF-beta stimulates the growth rate in all these cell lines, but does not induce a neuronal phenotype. NE tumour markers (chromogranin A [CgA] and chromogranin B[CgB]) could not be demonstrated by immunocytochemistry (CgA and CgB), Northern blotting (CgA), or ELISA techniques (CgA), neither in control nor in NGF-beta stimulated cells. Consequently, other experimental models have to be sought in the study of NE cells in the human prostate.
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PMID:NGF-beta, NE-cells and prostatic cancer cell lines. A study of neuroendocrine expression in the human prostatic cancer cell lines DU-145, PC-3, LNCaP, and TSU-pr1 following stimulation of the nerve growth factor-beta. 956 67

The mitogen-activated protein kinase (MAPK) pathway plays a pivotal role in intracellular signaling, and this cascade may impinge on cAMP response elements (CREs) of target genes. Both the MAPK pathway and chromogranin A expression may be activated by cytosolic calcium influx, and calcium-dependent signals map onto the chromogranin A promoter proximal CRE. We therefore probed the role of the MAPK pathway in chromogranin A biosynthesis after secretory stimulation of PC12 pheochromocytoma cells by the nicotinic cholinergic pathway, the physiological secretory trigger. Chemical inhibition of either MAPK or MAPK kinase blocked the response of a transfected chromogranin A promoter to nicotine or protein kinase C activation [by phorbol-12-myristate-13-acetate (PMA)], although nicotine-evoked catecholamine secretion was unaffected. Activation of the MAP kinase cascade (Ras, Raf, MAPK, or CREB kinase) by cotransfection of pathway components stimulated the chromogranin A promoter. Cotransfection of MAPK pathway dominant negative mutants (for Raf, MAPK, or CREB kinase) blocked nicotinic or PMA activation of chromogranin A, although a dominant negative Ras mutant was without effect. MAPK pathway enzymatic activity was stimulated by both nicotine and PMA. Point mutations of the chromogranin A CRE suggested that this element was necessary in cis for stimulation by nicotine, PMA, or chemical activation of the MAPK pathway. Transfer of the CRE to a heterologous promoter conferred inducibility by not only nicotine or cAMP but also MAPK activation. Expression of the CREB antagonist KCREB blocked the response of the chromogranin A promoter to nicotine, cAMP, or MAPK pathway activation by either chemical stimulation or cotransfection of active cascade components. Chromogranin A mRNA responded to MAPK pathway manipulation in a fashion similar to the transfected chromogranin A promoter, in both direction and magnitude. We conclude that the MAPK pathway is a necessary intermediate in signaling from the nicotinic receptor to secretory protein transcription, although not to catecholamine secretion. In trans, this response seems to involve the following signal cascade: protein kinase C --> Raf --> MAPK kinase --> MAPK --> CREB kinase --> CREB. In cis, activation by the cascade maps onto the chromogranin A promoter proximal CRE, which is both necessary and sufficient to confer the response.
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PMID:A crucial role for the mitogen-activated protein kinase pathway in nicotinic cholinergic signaling to secretory protein transcription in pheochromocytoma cells. 965 90

Chromogranin A is present in the secretory granules of endocrine cells and functions in hormone packaging, secretory granule stabilization, and regulation of hormone secretion. Immunohistochemical identification of chromogranin A can facilitate diagnosis of endocrine neoplasia. Normal and neoplastic canine tissues were stained immunohistochemically for chromogranin A. Staining of normal endocrine tissues demonstrated chromogranin A in chromaffin cells of the adrenal medulla, C cells of the thyroid gland, and pancreatic islets. The parathyroid chief cells and anterior pituitary stained lightly positive for chromogranin A. Pheochromocytomas (7/7), chemodectomas (5/7), islet cell carcinomas (2/6), pituitary adenomas (4/6), parathyroid adenomas (3/7), and a C-cell carcinoma (1/1) stained positive for chromogranin A. The data indicate that chromogranin A is widely distributed in canine endocrine tissues, and immunohistochemical staining of chromogranin A can be used to confirm the presence of secretory granules in endocrine tumors.
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PMID:Immunohistochemical localization of chromogranin A in endocrine tissues and endocrine tumors of dogs. 968 78

In 15-20% of the cases pheochromocytoma (pheo) localizes in extraadrenal sites and in about 15% of all cases it seems to be multiple. We analyze our 20-year experience in surgical treatment of pheos, studying the differences between typical and extraadrenal or multiple tumors. From 1977 to 1996 we operated 55 patients (patients) with pheos, 28 (50.9%) males and 27 females (mean age 41 years, range 10-63). Two groups have been distinguished: classic pheos (Group 1, 45 patients) and extraadrenal or multiple pheos (Group 2, 10 patients). Hypertensive crises were present in 37/45 (82.2%) patients of Group 1 and in 7/10 patients of Group 2. Five (11.1%) masses were nonfunctioning and incidentally discovered (4 in Group 1 and one in Group 2). In 4 cases association with familial syndromes was observed (3 MEN IIb, 1 von Recklinghausen syndrome); no further significant differences in clinical features and laboratory data were found between the two Groups. At immunohistochemical analysis 26/26 patients resulted positive for chromogranin A and NSE and 17/26 (11/20 in Group 1 and 4/6 in Group 2) resulted positive for S 100 protein. Five (11.1%) malignant pheos were discovered and removed (Group 1); average survival of these patients was 54.4 months, two patients underwent radioactive iodine (131-I-MIBG) therapy after surgery and only one patient is still alive at 24-month follow-up. Recurrence for benign sporadic pheo (Group 1) occurred in one patient 183 months after adrenalectomy. Ectopic, associated with familial syndromes and multiple pheos are not uncommon and although recovery in surgically treated patients is excellent, lifelong follow-up is necessary also in benign tumors.
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PMID:Extraadrenal and multiple pheochromocytomas. Are there really any differences in pathophysiology and outcome? 989 66

IGF-I is known to support growth and to prevent apoptosis in neuronal cells. Activation of the nuclear transcription factor cAMP response element-binding protein (CREB) has emerged as a central determinant in neuronal functions. In the present investigation, we examined the IGF-I-mediated phosphorylation and transcriptional activation of CREB in rat pheochromocytoma (PC12) cells, a cellular model for neuronal differentiation, and defined three distinct postreceptor signaling pathways important for this effect including the p38 mitogen-activated protein kinase (MAPK) pathway. CREB phosphorylation at serine 133 and its transcriptional activation as measured by a CREB-specific Gal4-CREB reporter and the neuroendocrine-specific gene chromogranin A was induced 2-3.3-fold by insulin-like growth factor (IGF)-I. This activation was significantly blocked (p < 0.001) by the dominant negative K-CREB or by mutation of the CRE site. IGF-I stimulated chromogranin A gene expression by Northern blot analysis 3.7-fold. Inhibition of MAPK kinase with PD98059, PI 3-kinase with wortmannin, and p38 MAPK with SB203580 blocked IGF-I-mediated phosphorylation and transcriptional activation of CREB by 30-50% (p < 0.001). Constitutively active and dominant negative regulators of the Ras and PI 3-kinase pathways confirmed the contribution of these pathways for CREB regulation by IGF-I. Cotransfection of PC12 cells with p38beta and constitutively active MAPK kinase 6 resulted in enhanced basal as well as IGF-I-stimulated chromogranin A promoter. IGF-I activated p38 MAPK, which was blocked by the inhibitor SB203580. This is the first description of a p38 MAPK-mediated nuclear signaling pathway for IGF-I leading to CREB-dependent neuronal specific gene expression.
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PMID:Insulin-like growth factor I-mediated activation of the transcription factor cAMP response element-binding protein in PC12 cells. Involvement of p38 mitogen-activated protein kinase-mediated pathway. 991 17

Nicotinic cholinergic receptors undergo desensitization upon repeated or prolonged exposure to agonist. We investigated the effects of a novel chromogranin A catecholamine release-inhibitory fragment, catestatin (chromogranin A344-364), on agonist-induced desensitization of catecholamine release from pheochromocytoma cells. In a dose-dependent fashion, the nicotinic antagonist catestatin blocked agonist desensitization of both catecholamine release (IC50 approximately 0.24 microM) and 22Na+ uptake (IC50 approximately 0.31 microM), the initial step in nicotinic cationic signal transduction; both secretion inhibition and blockade of desensitization were noncompetitive with agonist. Desensitizing effects of the nicotinic agonists nicotine and epibatidine were blocked. This antagonist action was specific to desensitization by nicotinic agonists, since catestatin did not block desensitization of catecholamine release induced by agents which bypass the nicotinic receptor. Hill plots with slopes near unity suggested noncooperativity for catestatin effects on both nicotinic responses (secretory antagonism and blockade of desensitization). Human, bovine, and rat catestatins (as well as substance P) had similar potencies. IC50 values for secretion inhibition and blockade of desensitization paralleled each other (r = 0.76, n = 10 antagonists, p = 0.01) for several noncompetitive nicotinic antagonists. Peptide nicotinic antagonists (catestatins, substance P) were far more potent inhibitors of both secretion (p = 0.019) and desensitization (p = 0.005) than nonpeptide antagonists (trimethaphan, hexamethonium, procaine, phencyclidine, cocaine, or clonidine), and the peptides displayed enhanced selectivity to block desensitization versus secretion (p = 0.003). We conclude that catestatin is a highly potent, dose-dependent, noncompetitive, noncooperative, specific inhibitor of nicotinic desensitization, an effect which may have implications for control of catecholamine release.
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PMID:Desensitization of catecholamine release. The novel catecholamine release-inhibitory peptide catestatin (chromogranin a344-364) acts at the receptor to prevent nicotinic cholinergic tolerance. 991 30

Nerve growth factor differentiates precursor cells into sympathetic neurons. Does acquisition of a "neuronal" phenotype after nerve growth factor involve biosynthesis of chromogranin A, the major soluble protein in chromaffin granule cores? Nerve growth factor activated chromogranin A gene expression 7.6-fold in PC12 pheochromocytoma cells, and similarly activated PC12-transfected mouse, rat or human chromogranin A promoter/reporter constructs. Chromogranin A promoter 5'-deletions narrowed the nerve growth factor response element to a region from - 77 to - 61 bp upstream of the cap site, a region containing the chromogranin A cyclic AMP response element (TGACGTAA). Three different site-directed mutations of the cyclic AMP response element each reduced the nerve growth factor effect by >90%. Transfer of the cyclic AMP response element to a heterologous (thymidine kinase) promoter activated that promoter approximately 5-fold after nerve growth factor, while transfer of a cyclic AMP response element point-gap mutant (TGA-GTAA) to a heterologous promoter abolished the nerve growth factor effect. These findings indicate that the cyclic AMP response element in cis is, at least in part, both necessary and sufficient to activate the chromogranin A gene. Chemical blockade of the nerve growth factor receptor TrkA or the mitogen-activated protein kinase pathway component MEK substantially diminished nerve growth factor-induced expression of chromogranin A. By contrast, the response of chromogranin A to nerve growth factor was not impaired after blockade of phospholipase C-gamma or phosphoinositide-3 kinase. Chemical blockade of TrkA, Ras, MEK or mitogen-activated protein kinase similarly inhibited nerve growth factor activation of chromogranin A. Expression of constitutively activated Ras, Raf or MEK mutants increased chromogranin A promoter activity. Expression of dominant negative (inhibitory) mutants of Sos, Ha-Ras, Rafl, mitogen-activated protein kinase, ribosomal protein S6 serine kinase II (CREB kinase) or CREB (KCREB) each inhibited the nerve growth factor-induced increase in chromogranin A promoter activity. Thus, each component of the mitogen-activated protein kinase pathway is crucially involved in relaying the nerve growth factor signal in trans to the chromogranin A gene, in the following proposed sequence: nerve growth factor --> TrkA --> Shc/Grb2/Sos --> Ras --> Raf --> MEK --> mitogen-activated protein kinase --> ribosomal protein S6 serine kinase II --> CREB cyclic AMP response element.
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PMID:Neurotrophin activation of catecholamine storage vesicle protein gene expression: signaling to chromogranin a biosynthesis. 1019 63


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