Gastrin and cancer.
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Amino Acid Sequence↗
Biomedical subjects
L Hilsted
Publications and source records attributed to L Hilsted.
Ontogeny of gastric function in the pig: acid secretion and the synthesis and secretion of gastrin.
Gastric acid secretion, gastrin-releasing peptide (GRP)-stimulated gastrin secretion and concentrations of somatostatin in gastric tissues were studied in sucking pigs (n = 48). In addition, gastrin concentrations in plasma and antral tissue were measured in fetal and sucking pigs (n = 66) from 22 days before birth (93 days gestation) to 36 days of age. From 3 days of age littermate pairs were treated twice a day with either saline (n = 20) or adrenocorticotropin [ACTH (1-24); n = 20]. Pentagastrin-stimulated acid secretion per unit stomach weight was 39 +/- 7 mumol H+/g/h at 0-1 day, increased to 194 +/- 15 mumol H+/g/h at 5-7 days and plateaued. Antral gastrin concentration was 0.14 nmol/g 10 days before birth and increased to 2.7 nmol/g at 5 weeks of age. Plasma gastrin was 25 +/- 2 pmol/l at 22 days before birth, increased to 102 +/- 14 pmol/l at birth and decreased during the postnatal period. Somatostatin concentrations were higher in antral than fundic tissues (p < 0.05) and remained constant during the postnatal period. Increased levels of glucocorticoids in plasma following ACTH treatment had no effect on the studied parameters except that it reduced basal (p < 0.07) and GRP-stimulated (p < 0.05) plasma gastrin concentrations at 6-7 days of age. Development of acid secretion and its gastric regulatory peptides in the pig is different from that in the rat in that it occurs at an earlier age and does not appear to be greatly influenced by elevated glucocorticoid levels from 3 days after birth.
Adrenocorticotropic Hormone↗
Glycine-extended gastrin precursors.
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Amino Acid Sequence↗
Ontogeny of procholecystokinin processing in rat hypothalamus.
The concentration of procholecystokinin (pro-CCK) in the fetal hypothalamus was 126 +/- 41 pmol/g (mean +/- SEM; n = 20), 22 +/- 9 pmol/g at day 7 postpartum and 3 +/- 2 pmol/g in the adult. In contrast, the concentration of bioactive carboxyamidated CCK rose from 6 +/- 2 pmol/g in the fetal hypothalamus to 52 +/- 10 pmol/g in the adult. The concentration of glycine-extended processing intermediates first decreased from 21 +/- 5 pmol/g in the fetus to 5 +/- 1 pmol/g at day 21 postpartum. Subsequently, the concentration rose to 21 +/- 4 pmol/g in the adult. The results show that the CCK gene is well expressed in the fetal hypothalamus. However, only a small fraction of pro-CCK reaches maturation before weaning. We conclude that expression of the CCK gene in the hypothalamus as bioactive peptide to a large degree is regulated at the posttranslational level.
Amino Acid Sequence↗
The expression of peptide hormones in normal cells and tumour cells.
Insight in the mechanisms of peptide hormone expression has grown explosively by elucidation of gene, mRNA and preprohormone structures for most hormone systems during the 1980s. In addition, information about the structure and substrate specificity of many prohormone processing enzymes is rapidly accumulating in these years. The preprohormones vary considerably in size and organization from poly- to monoprotein structures. According to the structural organization and sequence homology the hormones are grouped in families. The prohormones are processed to bioactive peptides by multiple enzymatic modifications during the intracellular transport from the rough endoplasmatic reticulum to the mature secretory granules. The modifications comprise different proteolytic cleavages and amino acid derivatizations. The same prohormone may be expressed in several different cell types that process the precursor in entirely different ways. Awareness of such cell-specific processing patterns is important for the understanding of ectopic synthesis in neuroendocrine tumours.
Gene Expression Regulation↗
Alpha-amidation of gastrin is impaired by diethyldithiocarbamate.
The influence of gastrin alpha-amidation of the heavy-metal chelator diethyldithiocarbamate and disulfiram, its disulfide dimer, was studied in rat gastric antrum. Sensitive, sequence-specific immunoassays for glycine-extended and amidated gastrin were used to monitor extractions and chromatography. The results showed that intraperitoneal diethyldithiocarbamate administration (1000 mg/kg body weight) for two days caused a decrease in amidated gastrin from 2.6 +/- 0.4 to 1.4 +/- 0.3 nmol/g tissue (n = 11) with a simultaneous increase in glycine-extended gastrin from 0.84 +/- 0.15 to 2.4 +/- 0.3 nmol/g. Peroral administration of disulfiram (4 mg/kg body weight) for nine days did not change alpha-amidation significantly. The results of the present study demonstrate that the heavy-metal chelating agent diethyldithiocarbamate inhibits alpha-amidation of gastrin in vivo, in agreement with the inhibition of amidating activity observed in vitro. These results are in accordance with the previous observations that the presence of copper ions is necessary for the alpha-amidation to take place.
Amides↗
Procholecystokinin processing in rat cerebral cortex during development.
Using a library of radioimmunoassays for essential sequences of procholecystokinin (proCCK), we have examined the post-translational processing in the rat cerebral cortex from fetal to adult state. The concentration of proCCK in the fetal cerebral cortex was 43 +/- 7 pmol/g tissue (wet weight; mean +/- S.E.M. (n = 20)). It remained constant until day 21 post partum, after which it decreased to undetectable levels. In contrast, the concentration of fully processed, bioactive CCK peptides (i.e. alpha-carboxyamidated CCK) rose from 2 +/- 1 pmol/g in the fetal cortex to 122 +/- 21 pmol/g in the adult. A particularly steep increase occurred from day 7 post partum (13 +/- 2 pmol/g) to day 21 (108 +/- 11 pmol/g). The concentration of glycine-extended intermediates rose gradually from 8 +/- 1 pmol/g in the fetal brain to 55 +/- 6 pmol/g in the adult. Gel chromatography of cortical extracts from day 7, 21 and 100 confirmed the variable processing at the C-terminal amidation site. The results show that the CCK gene is expressed as proCCK already in the fetal brain. However, the covalent modifications of proCCK follow different time courses so that only a small fraction reaches maturation until the first week post partum. We conclude that expression of transmitter-active CCK peptides in the brain is largely regulated at the post-translational rather than at the transcriptional level.
Aging↗
Progastrin expression in mammalian pancreas.
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.
Aging↗
Screening for multiple endocrine neoplasia type 1 in patients with recognized pituitary adenoma.
A total of 79 consecutive patients with pituitary tumours were screened for multiple endocrine neoplasia type 1 (MEN-1). The 79 patients included 21 patients with acromegaly, nine with Cushing's disease, 18 with prolactinomas, three with mixed pituitary adenomas (GH and PRL), and 28 patients with no detectable hypersecretion of hormones. The screening consisted of: (1) a family history, (2) a uniform medical history of the patient using a standard questionnaire, and (3) hormonal evaluation including measurements of the serum levels of insulin, gastrin, glucagon, somatostatin, vasoactive intestinal polypeptide and pancreatic polypeptide. Ionized calcium and glucose concentration in serum were also measured. We found no patients with the MEN-1 syndrome. In one patient, we found a transient elevation of serum concentrations of pancreatic polypeptide for which we have no explanation. In another patient, the serum gastrin concentration was elevated secondary to achlorhydria. No other endocrine disorders were found, and no patients had relatives with recognized endocrine pancreatic tumours, primary hyperparathyroidism (HPT), or pituitary adenomas.
Adenoma↗
Gastrin in human bronchogenic carcinomas: constant expression but variable processing of progastrin.
Using a library of radioimmunoassays against essential sequences of human progastrin and procholecystokinin, we have examined the occurrence of gastrin, cholecystokinin, and their precursors in bronchogenic adenocarcinomas, large-cell, small-cell, and squamous-cell carcinomas (n = 17). Progastrin and some of its bioactive (i.e., alpha-carboxyamidated) products were present in all tumors, irrespective of histological classification. The concentration of progastrin varied from 0.2 to 21.9 pmol/g tissue; glycine-extended intermediates constituted less than 0.1 to 0.5 pmol/g; and bioactive, carboxyamidated gastrin ranged from less than 0.1 to 6.1 pmol/g. Chromatography showed that the bioactive gastrins were exclusively gastrin-17 peptides, half of which were tyrosine O-sulfated. Neither procholecystokinin nor its processing products were found in the tumor extracts. Six samples of nonneoplastic human lung tissue contained traces of progastrin (range, less than 0.1-0.8 pmol/g), but neither bioactive gastrins nor any cholecystokinin. The results show that the gastrin gene is expressed in all classes of bronchogenic carcinomas. Due to incomplete posttranslational processing measurement of progastrin may be necessary to detect such expression.
Base Sequence↗
Progastrin processing during antral G-cell hypersecretion in humans.
Using radioimmunoassays specific for essential processing sites of human progastrin in combination with chromatography before and after cleavage with trypsin and carboxypeptidase B, we have examined antral biopsy specimens and serum from 10 hypergastrinemic patients with fundic atrophic gastritis and 7 normal control subjects. Four types of processing were studied: N-terminal proteolysis (at the N-terminus of component I, gastrin 34, and gastrin 17); C-terminal proteolysis (at the C-terminus of the amide donor, glycine93 in preprogastrin); alpha-carboxyamidation (of phenylalanine92); and O-sulfation (of tyrosine87). The results show that progastrin during permanent G-cell hypersecretion is less completely processed with respect to C-terminal proteolysis, alpha-amidation, and tyrosine-sulfation. In contrast, the degree of N-terminal proteolysis is normal. Thus, the processing of progastrin adjacent to the active site of gastrin is more restrictively controlled than N-terminal processing during G-cell hypersecretion associated with pernicious anemia.
Carboxypeptidase B↗
Cholecystokinin, gastrin and their precursors in pheochromocytomas.
Using sequence-specific radioimmunoassays before and after cleavage with trypsin and carboxypeptidase B, we have examined the occurrence and molecular nature of cholecystokinin (CCK) and gastrin peptides in bioactive (i.e. alpha-carboxyamidated) as well as non-amidated precursor forms in extracts from 13 human pheochromocytomas. All but one tumour contained amidated CCK, but only in moderate amounts (less than or equal to 20 pmol/g tissue). In contrast to the complete sulphation in tissues which normally produce CCK (the brain and small intestine), the amidated adrenal CCK peptides were poorly sulphated (less than or equal to 17%). Four pheochromocytomas, including the one without amidated CCK, contained between 28 and 0.2 pmol amidated gastrin/g, mainly in the form of sulphated gastrin-17. In addition, all tumours contained biosynthetic precursors of both CCK and gastrin. In most extracts there was more precursor than bioactive peptide(s), the progastrin concentration ranging up to 338 pmol/g. The results show that pheochromocytomas synthesize CCK and gastrin. The posttranslational processing differs, however, markedly from that of the principal CCK and gastrin producing tissues, with respect to both proteolytic cleavages and amino acid derivatization. This emphasizes that accurate quantitation in tumours requires assays which measure the translation products irrespective of their degree of processing.
Adrenal Gland Neoplasms↗
Peptide hormone expression and precursor processing.
Insight in the mechanisms of peptide hormone expression has grown explosively by elucidation of gene, mRNA and preprohormone structures for most hormone systems during the 1980s. The preprohormones vary considerably in size and organization from poly- to mono-protein structures. According to the structural organization and sequence homology the hormones are grouped in families. The prohormones are processed to bioactive peptides by multiple enzymatic modifications during the intracellular transport from the rough endoplasmatic reticulum to the mature secretory granules. The modifications comprise different proteolytic cleavages and amino acid derivatizations. The same prohormone may be expressed in several different cell-types that process the precursor in entirely different ways. Awareness of such cell-specific processing patterns is important for the understanding of ectopic synthesis in neuroendocrine tumours.
Animals↗
The unique specificity of antibodies in modern radioimmunochemistry--an essay on assays.
The gradual recognition and exploitation of the specificity of antibodies in peptide radioimmunoassays (RIA) during the last three decades are reviewed. From the old fashioned RIA techniques of the sixties through sequence-specific RIA libraries of the seventies to residue-specific immunoassays of the eighties, the RIA technique has to an increasing degree been based on the ability to select strictly monospecific antibodies in high-titered polyclonal antisera. High-avidity monospecific antibodies from polyclonal antisera provide the RIA technology of to-day with unrivalled specificity. This specificity again has increased the utility of RIA as a tool in basic as well as clinical biochemistry.
Amino Acid Sequence↗
The effect of ACTH-treatment on gastric acid secretion and gastric regulatory peptides in young pigs.
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Adrenocorticotropic Hormone↗
Progastrin maturation during ontogenesis. Accumulation of glycine-extended gastrins in rat antrum at weaning.
The post-translational maturation of antral progastrin was studied in the developing rat. While N-terminal proteolysis remained unchanged and tyrosine O-sulphation varied only slightly during ontogenesis, major changes were observed in the degree of alpha-carboxyamidation. In the third week of life the immediate precursor of amidated gastrin, glycine-extended gastrin, accumulated, and at weaning (day 21) the concentrations exceeded those of amidated gastrin. Our results confirm that weaning is accompanied by an increased synthesis of gastrin and imply that alpha-carboxyamidation is the rate-limiting step during the biosynthetic maturation of gastrin.
Amides↗
Effect of low-dose exogenous secretin on pentagastrin- and meal-stimulated gastric acid secretion in humans.
Intravenous infusion of secretin in a dose of 0.05 CU/kg/hr inhibited pentagastrin-stimulated (100 ng/kg/hr) acid secretion by 42% (P less than 0.05) abd meal-stimulated (10% peptone, pH 5.5) acid secretion by 33% (P less than 0.05) in 10 healthy subjects. Median serum gastrin concentration during peptone stimulation was reduced by 24% (P less than 0.05) during secretin infusion. Median plasma secretin concentrations were 6.0 and 5.2 pmol/liter, respectively. Since these secretin concentrations are of the same magnitude as those seen after duodenal acidification, it is concluded that secretin may participate in the physiological inhibition of gastric acid secretion.
Adult↗
Neither glycine-extended gastrin nor the 1-13 fragment of gastrin 17 influences gastric acid secretion in humans.
The effect on gastric acid secretion of two gastrin 17-related peptides without the carboxyamide, i.e., the glycine-extended 5-17 fragment and the 1-13 fragment of human gastrin 17, was examined in normal subjects. Acid secretion was stimulated by an intravenous infusion of 21 pmol/kg.h of gastrin 17 or by intragastric instillation of peptone; gastric acid output during simultaneous infusion of 325 pmol/kg.h of the glycine-extended 5-17 fragment or 319 pmol/kg.h of the 1-13 fragment was then compared with acid output during infusion of saline. Neither the glycine-extended 5-17 fragment nor the 1-13 fragment of gastrin 17 influenced gastric acid secretion. By gel and ion-exchange chromatography of serum drawn during infusion, the infused peptide was recovered at the position of the intact synthetic peptide. The disappearance curve of circulating glycine-extended gastrin could be described by two components with half-lives of 3.6 and 48 min. As the glycine-extended fragment was stable in serum or plasma in vitro for 1 h at 37 degrees C, the rapid elimination observed in vivo cannot be ascribed to circulating plasma enzymes.
Adult↗