Disease relevance of CHGA

• CHGA is a candidate gene for autonomic dysfunction syndromes, including intermediate phenotypes that contribute to human hypertension [1].
• Highly purified human CgA (hCgA) was produced by expression in Escherichia coli and purification using metal affinity chromatography. hCgA was digested with plasmin [2].
• Secretagogin stained 82% (46/56) of benign and 71% (48/68) of prostate adenocarcinomas and co-localized with the NE markers CgA and NSE [3].
• 2.3 kilobases of the upstream regulatory region of the human CgA gene directed efficient transcription of a reporter chloramphenicol acetyltransferase gene in several neuroendocrine cell lines, including human medullary thyroid C-cell tumor, mouse pituitary corticotroph, rat pituitary tumor, and rat pheochromocytoma [4].
• Elevated plasma CgA levels are frequently observed in prostate cancer patients with hormone-refractory disease and correlate with poor prognosis [5].

Psychiatry related information on CHGA

• Human saliva chromogranin A (CgA) is clinically promising as a psychological stress marker [6].
• The immunoreactive patterns of CgA and CgB were investigated in CJD and compared to those observed in Alzheimer's disease [7].
• In cortical and hippocampal plaques in Alzheimer's disease (AD) beta APP colocalized with CgA in a neuritic population largely distinct from the subset of neurites labeled by tau [8].
• CgA was detectable in each sample, but the results in dementia showed substantial overlap with and no significant (p = 0.55) difference from the results in healthy controls [9].
• Several lines of evidence link chromogranin A (CgA), the major soluble protein in catecholamine storage vesicles, with the cholinergic nervous system, abnormalities of which may play a central role in memory deficits in Alzheimer dementia [9].

High impact information on CHGA

• CgA is a 49 kilodalton protein that is present in the secretory granules of most endocrine and many neuroendocrine cells [10].
• CgA is an important new tool for the endocrinologist in the diagnosis and management of patients with endocrine and neuroendocrine tumors [10].
• The secretory prohormone chromogranin A (CHGA) is overexpressed in essential hypertension, a complex trait with genetic predisposition, while its catecholamine release-inhibitory fragment catestatin is diminished, and low catestatin predicts augmented adrenergic pressor responses [11].
• These results suggest a coupled relationship between CHGA-mediated chromaffin granule biogenesis, necessary for catecholamine storage, and catestatin-induced inhibition of cholinergic-stimulated catecholamine release, which regulates autonomic control of blood pressure [12].
• Transgenic expression of human Chga and exogenous injection of human catestatin, a CHGA-derived nicotinic cholinergic antagonist, restored normal blood pressure in these mice [12].

Chemical compound and disease context of CHGA

• We enrolled 19 patients (12 females and 7 males, mean+/-SD age 54.9+/-11.2 yr, age range 34-75 yr) with incidental, non-functioning, benign adrenocortical adenomas, and measured circulating levels of CgA, catecholamines and creatinine before and 2 months after surgery [13].
• We report the first evidence that differential transcriptional regulation of human chromogranin A (CHGA) gene expression occurs during in vitro treatment of tumorigenic neuroblastoma (NB) cells with retinoic acid (5 microM) and/or dibutyryl-cAMP (1 mM) [14].
• In situ hybridization analyses showed that gonadotropin-releasing hormone and pancreastatin treatment led to significant increases in CgB and follicle-stimulating hormone mRNAs in gonadotroph adenomas, whereas CgA mRNA levels did not change significantly [15].
• After treatment with phorbol 12-myristate 13-acetate (10(-7) M) for 7 days, there was an increase in the mRNA for CgB and SgII mRNAs in GH and null cell tumors, while dexamethasone treatment for 7 days increased CgA mRNA in GH and null cell adenomas [16].
• Furthermore, the rise of CgA levels during hypoglycemia lagged 60 minutes behind those of epinephrine [17].

Biological context of CHGA

• Functional variants include both common alleles that quantitatively alter gene expression and rare alleles that qualitatively change the encoded product to alter the signaling potency of CHGA-derived catecholamine release-inhibitory catestatin peptides [1].
• We show that a full-length CgA/EAP chimera is sorted to chromaffin granules for exocytosis [18].
• The single copy human CgA gene was isolated from a human fetal liver gene library [4].
• Functional analysis of Sp1-, Egr-1-, or CREB-specific promoter mutations in transfection studies confirmed the tripartite organization of the CgA -92/-62 element [19].
• The gene for human chromogranin A (CgA) is located on chromosome 14 [20].

Anatomical context of CHGA

• Because the binding-prone property of CgA with secretory proteins may be essential for its targeting to secretory granules, we screened its binding partner proteins using a yeast two-hybrid system [21].
• Localization analysis showed that CgA and SgIII were coexpressed in pituitary and pancreatic endocrine cell lines, whereas SgIII was not expressed in the adrenal glands and PC12 cells [21].
• These results identify plasmin as a protease, present in the local environment of the chromaffin cell, that selectively cleaves CgA to generate a bioactive fragment, hCgA-(360-373), that inhibits nicotinic-mediated catecholamine release [2].
• In the present study, we investigated the expression and localization of CgA in the human submandibular gland (HSG) using various methods [6].
• However, expression of CgA is poorly understood in humans, although salivary gland localization of CgA in other mammals, such as rodents and horses, has been demonstrated [6].

Associations of CHGA with chemical compounds

• RATIONALE: The chromogranin A (CHGA) fragment pancreastatin (human CHGA250-301) impairs glucose metabolism, but the role of human pancreastatin in vivo remains unexplored [22].
• Proteolytic cleavage of chromogranin A (CgA) by plasmin. Selective liberation of a specific bioactive CgA fragment that regulates catecholamine release [2].
• CgA and CgB were sporadically detected in normal cells of the ducts, acini, and luminal secretion [23].
• Chromogranin A (CgA) is an acidic glycoprotein, which is widely expressed in endocrine and neuroendocrine cells [4].
• The effect of bafilomycin A1 on CgA secretion depends on a sorting determinant located within the amino terminus (CgA-(1-115)) but not the C-terminal region of the granin [18].

Physical interactions of CHGA

• We found that CgA bound to secretogranin III (SgIII) by specific interaction both in vitro and in endocrine cells [21].
• Gastrin elevated cellular and nuclear Egr-1 levels in a time-dependent manner and also increased Egr-1 binding to the CgA -92/-73 region [19].

Regulatory relationships of CHGA

• Studies of the mechanism of action showed that CgA inhibits TNF-induced VE-cadherin down-regulation and barrier alteration of cultured endothelial cells, in an indirect manner [24].
• Other effectors, such as thrombin and vascular endothelial growth factor were partially inhibited by CgA N-terminal fragments in in vitro permeability assays [24].
• With multivariate analysis, expression of BRCA1 significantly influenced the expression of CgA (p=0.01), while no factor significantly influenced to the expression of CgB [25].
• These results show that there is a differential distribution of pancreastatin secretion in pituitary adenomas and that the hypothalamic hormone gonadotropin-releasing hormone and the CgA-derived peptide pancreastatin can regulate CgB mRNA in gonadotroph adenomas, suggesting an autocrine effect of pancreastatin on pituitary tumor function [15].
• Immunoreactive pancreastatin and CgA were present diffusely in gonadotroph and null cell adenomas, but only a few prolactin adenoma cells expressed pancreastatin or CgA [15].

Other interactions of CHGA

• Immunoelectron microscopy demonstrated that CgA and SgIII were specifically colocalized in large secretory granules in male rat gonadotropes, which possess large-type and small-type granules [21].
• These results suggest that the plasminogen/plasmin system through its interaction with CgA may play a major role in catecholaminergic function and suggest a specific mechanism as well as a discrete CgA peptide through which this effect is mediated [2].
• In neonatal islets, CgA was localized in the periphery of immature alpha- and beta-cell granules and throughout the matrix of delta-cell granules; CgB was distributed throughout the matrix of these granules [26].
• Thirty-seven carcinoids of the gastrointestinal tract were studied with immunohistochemical staining for chromogranin A (CgA) and Leu-7 (CD57) [27].
• Ectopic Egr-1 overexpression potently stimulated the CgA promoter, whereas coexpression of Egr-1 with Sp1 and/or CREB resulted in additive effects [19].

Analytical, diagnostic and therapeutic context of CHGA

• CgA was consistently localized in serous and ductal cells in HSG, as detected by immunohistochemistry and in situhybridization [6].
• In the patient subset undergoing chemotherapy, median CgA (range) values were 13.3 (3.0-141.0) U/l at baseline, 19.1 (3.0-486.0) U/l after 3 months, 20.8 (3.0-702.0) U/l after 6 months and 39.4 (3.0-414.0) U/l after 9 months (P<0.01) [5].
• The specificity of the antibodies for CgA was demonstrated by immunoassay, immunohistology, and immunoprecipitation of the in vitro translation products of mRNA from CgA-producing tissues [28].
• Plasma CgA was evaluated by immunoradiometric assay [13].
• Selected 5 tumors from this group were studied in detail using confocal laser scanning microscopy (CLSM) and double immunofluorescence staining to disclose the patterns of distribution of CgA and CD57 positive granules within the individual tumor cells [27].

References