Progastrin expression in mammalian pancreas.

Abstract

Expression and processing of progastrin were examined in fetal, neonatal, and adult pancreatic tissue from five mammalian species (cat, dog, man, pig, and rat). A library of sensitive, sequence-specific immunoassays for progastrin and its products was used to monitor extractions and chromatography before and after cleavage with processing-like enzymes. The results showed that progastrin and its products are expressed in the pancreas of all species in total concentrations varying from 0.3 to 58.9 pmol/g of tissue (medians). The degree of processing was age-and species-dependent. In comparison with adult pancreatic tissue the fetal or neonatal pancreas processed a higher fraction to bioactive, C-terminally amidated gastrin. Nevertheless, the pancreatic processing was always less complete than that of the adult antral mucosa. The moderate level of expression and the attenuated processing in the adult pancreas contribute to explain previous failures to detect gastrin in normal pancreatic tissue. Our results indicate that gastrin-producing tumors in the pancreas are not ectopic, but arise from cells that normally express the gastrin gene.Gastrin stimulates the secretion of gastric acid and growth of the fundic mucosa (1). Accordingly, gastrin-producing tumors (gastrinomas) induce hypersecretion of acid with ensuing duodenal ulcer disease and fundic mucosal hypertrophy, i.e., the Zollinger-Ellison syndrome. By far most gastrinomas originate in the pancreas, although gastrin normally is synthesized in the antroduodenal mucosa. Gastrinomas are nevertheless a frequent type of endocrine tumor in the human pancreas (2, 3) and have been found also in dogs (4, 5).The pancreatic origin of gastrinomas has been an enigma. Insulinomas, glucagonomas, somatostatinomas, pancreaticpolypeptide tumors (PPomas), and vasoactive intestinal polypeptide tumors (VIPomas) all have cellular counterparts that express the corresponding hormone in the normal pancreas. In contrast, attempts to detect gastrin in the normal pancreas have so far either failed (6-10) or resulted in the misidentification of somatostatin cells as gastrin cells (11)(12)(13). The only reproducible exception has been the apparently transient gastrin synthesis in the fetal and neonatal rat pancreas (14)(15)(16)(17)(18).Deduction of the sequence of mammalian preprogastrins (19)(20)(21) has paved the way for development of radioimmunoassays for progastrin and its processing intermediates (22-25). Such radioimmunoassays have proved useful for studies ofgastrin biosynthesis in tissues known to express the gastrin gene (24-29). The observation of expression but attenuated processing of progastrin in the normal pituitary (29) suggested that progastrin might be expressed also in the normal pancreas, and hence explain the gastrinoma enigma (30). This hypothesis has now been examined. NOMENCLATUREMammalian preprogastrins comprise 101-104 amino acid residues (19-21). They have an N-terminal signal sequence, a spacer sequence, the sequence containing the major bioactive form...

Sonic hedgehog and pancreatic-duodenal homeobox 1 expression distinguish between duodenal and pancreatic gastrinomas

“…After proving the existence of gastrin expression in adult pancreatic tissue, it became clear that pancreatic gastrinomas do not develop by ectopic dedifferentiation of transcription mechanisms, but rather by acceleration of already existing translational and post-translational processing mechanisms (Bardram et al 1990). Sporadic duodenal gastrinomas usually arise from the first part of the duodenum and are located in the submucosa (Guz et al 1995).…”

“…Attempts to detect gastrin in the normal pancreas had so far either failed or resulted in the misidentification of somatostatin cells as gastrin cells (Brand & Fuller 1988). Bardram et al (1990) showed for the first time that human pancreatic tissue contained progastrin. Thus, gastrinomas illustrate a phenotypic characteristic of neoplasia; namely, the expression of genes which are only transiently active during fetal development.…”

Molecular structure and genetic mapping of the mouse gastrin gene

“…3B). Thus, the sites and relative abundance of gastrin mRNA in mice are similar to those of other mammalian species, where stomach and the duodenum are the main sites of gastrin synthesis [1] and low amounts of gastrin are found in normal ovaries [4], pancreas [27], and certain regions of the brain [6,28,29]. Further studies are needed to identify the specific cell types expressing gastrin, and to determine to what extent the mRNA is translated to progastrin in the mouse.…”

Essential Interaction of Egr-1 at an Islet-specific Response Element for Basal and Gastrin-dependent Glucagon Gene Transactivation in Pancreatic α-Cells

“…Indeed, because of the presence of responsive elements that account for islet expression on its gene promoter, the major site of expression of amidated gastrin is the pancreas of mammals during fetal life (7,8). After birth, gastrin ceases to be expressed in the pancreas, supporting a specific role played in this organ during the fetal period (9).…”