New insights into granin-derived peptides: evolution and endocrine roles.
ABSTRACT The granin protein family is composed of two chromogranin and five secretogranin members that are acidic, heat-stable proteins in secretory granules in cells of the nervous and endocrine systems. We report that there is little evidence for evolutionary relationships among the granins except for the chromogranin group. The main granin members, including chromogranin A and B, and secretogranin II are moderately conserved in the vertebrates. Several small bioactive peptides can be generated by proteolysis from those homologous domains existing within the granin precursors, reflecting the conservation of biological activities in different vertebrates. In this context, we focus on reviewing the distribution and function of the major granin-derived peptides, including vasostatin, bovine CgB(1-41) and secretoneurin in vertebrate endocrine systems, especially those associated with growth, glucose metabolism and reproduction.
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ABSTRACT: Granins and their derived peptides are valuable circulating biological markers of neuroendocrine tumors. The aim of the present study was to investigate the tumoral chromogranin A (CgA)-derived peptide WE-14 and the potential advantage to combine plasma WE-14 detection with the EM66 assay and the existing current CgA assay for the diagnosis of pheochromocytoma. Compared to healthy volunteers, plasma WE-14 levels were 5.4-fold higher in patients with pheochromocytoma, but returned to normal values after surgical resection of the tumor. Determination of plasma CgA and EM66 concentrations in the same group of patients revealed that the test assays for these markers had an overall 84% diagnostic sensitivity, which is identical to that determined for WE-14. However, we found that WE-14 measurement improved the diagnostic sensitivity when combined with the results of CgA or EM66 assays. By combining the results of the three assays, the sensitivity for the diagnosis of pheochromocytoma was increased to 95%. In fact, the combination of WE-14 with either CgA or EM66 test assays achieved 100% sensitivity for the diagnosis of paragangliomas and sporadic or malignant pheochromocytomas if taken separately to account for the heterogeneity of the tumor. These data indicate that WE-14 is produced in pheochromocytoma and secreted into the general circulation, and that elevated plasma WE-14 levels are correlated with the occurrence of this chromaffin cell tumor. In addition, in association with other biological markers, such as CgA and/or EM66, WE-14 measurement systematically improves the diagnostic sensitivity for pheochromocytoma. These findings support the notion that granin-processing products may represent complementary tools for the diagnosis of neuroendocrine tumors.PLoS ONE 02/2014; 9(2):e88698. DOI:10.1371/journal.pone.0088698 · 3.53 Impact Factor
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ABSTRACT: This review focuses on gastrointestinal neuroendocrine tumours, excluding pancreatic endocrine tumours. Neuroendocrine tumours are rare ubiquitous neoplasms. Nevertheless, epidemiological studies have detected a significant increased in prevalence during the last 35 years. Most tumours have an indolent course and many patients have developed metastatic disease at the time of diagnosis, a stage for which there is no available curative treatment. Novel diagnostic, prognostic and predictive markers are needed for the early detection and follow-up of disease progression; and identification of critical signalling pathways is needed to identify targets for effective treatment of these tumours. The complex nature of neuroendocrine cell function and the limited access to biopsy material has restricted elucidation of the tumour biology. The molecular pathology responsible for early tumourigenesis and metastatic processes are still largely unknown. However, it is currently the subject of major investigations and the field has progressed during recent years. This recent progress will be discussed in this review.Diagnostic Histopathology 05/2010; 16(5):243-250. DOI:10.1016/j.mpdhp.2010.03.005
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ABSTRACT: Pancreastatin (PST) is a regulatory peptide containing 49 amino acids, first isolated from porcine pancreas. Intracellular and extracellular processing of the prohormone, Chromogranin A (Chga) results various bioactive peptides of which PST has dysglycemic activity. PST regulates glucose, lipid and protein metabolism in liver and adipose tissue. It also regulates the secretion of leptin and expression of leptin and uncoupling protein 2 in adipose tissue. In Chga knockout mice, PST induces gluconeogenesis in the liver. PST reduces glucose uptake in mice hepatocytes and adipocytes. In rat hepatocytes, PST induces glycogenolysis and glycolysis and inhibits glycogen synthesis. In rat adipocytes, PST inhibits lactate production and lipogenesis. These metabolic effects are confirmed in humans. In the dual signaling mechanism of PST receptor, mostly PST activates Gαq/11 protein leads to the activation of phospholipase C β3 isoform, and therefore increasing cytoplasmic free calcium and stimulating protein kinase C. PST inhibits the cell growth in rat HTC hepatoma cells, mediated by nitric oxide (NO) and cylic GMP (cGMP) production. Elevated levels of PST correlating with catecholamines have been found in gestational diabetes and essential hypertension. The rise in blood PST level in type 2 diabetes suggests that PST is a negative regulator of insulin sensitivity and glucose homeostasis.Physiological Genomics 09/2013; 45(22). DOI:10.1152/physiolgenomics.00131.2013 · 2.81 Impact Factor