Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01350 (gastrin)
 9,683 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

With regard to the structural analogies between the C-terminal tetrapeptide of gastrin, gastrin receptor antagonists and anticancer derivatives of glutamine, it is plausible to propose that the mechanism of the anticancer activity may be related to interaction with the gastrin receptor. Dietary glutamine intake and glutamine metabolites may also influence the activity of gastrin receptors.
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PMID:Glutamine derivatives as novel anticancer agents acting via gastrin binding sites. 237 92

Intestinal adaptation, in terms of increasing intestinal length and weight, usually occurs rapidly after small-bowel resection. However, this response depends on provision of enteral nutrients. If total parenteral nutrition without enteral feeding is prolonged, hypoplasia of the intestinal mucosa results. Adaptation is probably mediated through the presence of luminal nutrients, particularly glutamine, which is preferentially used by the intestine. However, systemic hormonal factors, possibly gastrin, cholecystokinin, and glucagon, also influence intestinal adaptation. Thus, in the management of short-bowel syndromes, enteral nutrition should be added to total parenteral nutrition as soon as possible.
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PMID:Changes in the gastrointestinal tract during enteral or parenteral feeding. 250 20

This study evaluated the dose-related trophic effects of glutamine, gastrin, and somatostatin on the in vitro growth of human gastric cancer cells and normal human gastric mucosal cells. Quadruplicate cell cultures were seeded into growth medium with or without glutamine, gastrin, or somatostatin. After 72 hours' incubation, cells were counted and their numbers compared with those of controls. Glutamine and gastrin stimulated the growth of both normal and malignant gastric mucosal cells. Compared with normal cells, the malignant cells responded to these growth factors at lower concentrations. Somatostatin enhanced growth of gastric cancer cells at all concentrations and inhibited growth of normal cells at high concentrations. Further studies on the responsiveness of gastric adenocarcinoma to gastrointestinal tract hormones may elucidate mechanisms of oncogenesis and suggest new therapeutic avenues for patients with gastric cancer.
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PMID:Effects of gastrin, glutamine, and somatostatin on the in vitro growth of normal and malignant human gastric mucosal cells. 286 4

The heptadecapeptide form the rabbit gastrin was extracted from 16 rabbit antra and purified by a combination of DEAE Sephadex, C-18 SEP PAK cartridges, fast performance liquid chromatography (FPLC) and reverse phase high pressure liquid chromatography (HPLC) steps. After the HPLC purification, a sharp, single peak of gastrin-like immunoreactivity was detected that had the same absorption to immunoreactivity ratio as human gastrin. An amino terminal pyrrolidone carboxylic acid blocking group was removed by incubation with pyrrolidone carboxylic peptidase. The amino acid analysis, microsequence analysis and mass spectrometry all confirmed the structure of rabbit gastrin being pQGPWLQEEEEAYGWMDFamide. This sequence is identical to human gastrin-17 except for glutamine in position 6 which replaces glutamate in human gastrin. Both sulfated and unsulfated rabbit gastrin-17 were characterized by mass spectrometry.
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PMID:Isolation and characterization of rabbit gastrin. 322 52

The gene structure of human cholecystokinin (CCK) is known and the cDNA structures are known for pig and rat. However, the molecular forms of CCK produced, stored and released from neural or endocrine cells cannot be predicted from the known structures of preprocholecystokinin derived from cDNA. It is well recognized that gastrin and CCK share carboxyl-terminal homology and similar processing to form the biologic active peptides. Comparisons of the structures of preprogastrin and preprocholecystokinin reveal a similar degree of homology in the midregion of the precursors (the structure of preprogastrin 55-59 and preprocholecystokinin 39-42 is His-Arg-Arg-Gln-Leu). Gastrin-34 (whose amino terminus corresponds to position 58 of preprogastrin) is formed by cyclization of glutamine to pyrrolidone carboxylic acid subsequent to cleavage at the double basis site. Identical posttranslational processing in this region would yield CCK-61. However, CCK-58 is the largest biologically active peptide so far isolated and chemically characterized. CCK can be found in high concentrations in gut and brain but the molecular forms differ in the two tissues. Thus, the most abundant forms in the intestine are CCK-58, followed by CCK-39, CCK-33, and CCK-8, whereas in the brain CCK-8 is the most abundant form, followed by CCK-58 and CCK-5. The brain contains in contrast to the intestine little or no CCK-39 and CCK-33. Therefore differences in posttranslational processing between gut and brain are assumed. The predominant small CCK forms in the brain act presumably as neurotransmitters. Large and small molecular forms are released from the endocrine cell of the gut and act as circulating hormones. Several problems have hindered the characterization and quantitation of CCK forms in tissue and blood. The large forms (CCK-58, CCK-39, CCK-33) are easily lost because they are more basic and bind to glass and plastic surfaces. In addition to recovery problems, CCK-58 can be readily degraded into smaller forms at neutral or basic pH in tissue extracts and in blood or plasma. When special care is taken to prevent these problems, we have shown that, in the dog, CCK-58 is not only the most abundant molecular form in the intestinal mucosa but also in the circulating blood. The physiology and pathophysiology of circulating CCK (regulation of pancreatic secretion, of the motility of the gallbladder and the bowel, and involvement in satiety mechanisms) has to be studied further.
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PMID:Cholecystokinin--gene structure, and molecular forms in tissue and blood. 378 30

Twenty-six peptides, analogs of bombesin (BNa) and gastrin releasing peptide (GRP), have been synthesized by the solid phase method. The synthetic peptides were purified by ion exchange and partition chromatography and shown to be homogenous under various conditions on RP-HPLC. They were further characterized by TLC, amino acid analysis and optical rotation. These peptides have been administered IC to rats and their effects on thermoregulation and glucoregulation have been compared to those of the two natural peptides: frog skin bombesin (BNa) and GRP. Their structure activity relationship is also discussed. The minimum essential residues required for full potency of bombesin-like effects is represented by an acetylated C-terminal 8-peptide fragment, where in position 7 of this peptide an L-amino acid such as alanine, histidine or glutamine, or the D-glutamine residue can be introduced. Modification of the tryptophan [8] and histidine [12] residues by alanine abolished the biological potency of those peptides. Analogs with a free N-terminus were found to express little, but significant, activity, thus indicating that blocked N-terminus is necessary for maximal response. [Ac-Ala7, DAla11]-bombesin (7--14) and [Ac-DGln7 DAla11]-bombesin (7--14) were found to be more potent than bombesin, whereas [Ac-DAla7, DAla11]-bombesin or [Ac-DAla7, DAla11] bombesin N-methylamide were found to have 10 and 1% of bombesin potency, respectively.
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PMID:Bombesin analogs: effects on thermoregulation and glucose metabolism. 734 58

Elements that confer identity to a tRNA in the cellular environment, where all aminoacyl-tRNA synthetases are competing for substrates, may be delineated by in vivo experiments using suppressor tRNAs. Here we describe the selection of active Escherichia coli tRNAAsp amber mutants and analyze their identity. Starting from a library containing randomly mutated tRNA(CUA)Asp genes, we isolated four amber suppressors presenting either lysine, alanine, or glutamine activity. Two of them, presenting mainly alanine or lysine activity, were further submitted to a second round of mutagenesis selection in order to improve their efficiency of suppression. Eleven suppressors were isolated, each containing two or three mutations. Ten presented identities of the two parental mutants, whereas one had switched from lysine to arginine identity. Analysis of the different mutants revealed (or confirmed for some nucleotides) their role as positive and/or negative determinants in AlaRS, LysRS, and ArgRS recognition. More generally, it appears that tRNAAsp presents identity characteristics closely related to those of tRNALys, as well as a structural basis for acquiring alanine or arginine identity upon moderate mutational changes; these consist of addition or suppression of the corresponding positive or negative determinants, as well as tertiary interactions. Failure to isolate aspartic acid-inserting suppressors is probably due to elimination of the important G34 identity element and its replacement by an antideterminant when changing the anticodon of the tRNAAsp to the CUA triplet.
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PMID:Selection of tRNA(Asp) amber suppressor mutants having alanine, arginine, glutamine, and lysine identity. 880 18

Glutaminyl cyclases (QC) catalyze the intramolecular cyclization of N-terminal glutamine residues of peptides and proteins. For a comparison of the substrate specificity of human and papaya QC enzymes, a novel continuous assay was established by adapting an existing discontinuous method. Specificity constants (kcat/Km) of dipeptides and dipeptide surrogates were higher for plant QC, whereas the selectivity for oligopeptides was similar for both enzymes. However, only the specificity constants of mammalian QC were dependent on size and composition of the substrates. Specificity constants of both enzymes were equally pH-dependent in the acidic pH-region, revealing a pKa value identical to the pKa of the substrate, suggesting similarities in the substrate conversion mode. Accordingly, both QCs converted the L-beta homoglutaminyl residue in the peptide H-beta homoGln-Phe-Lys-Arg-Leu-Ala-NH2 and the glutaminyl residues of the branched peptide H-Gln-Lys(Gln)-Arg-Leu-Ala-NH2 as well as the partially cyclized peptide H-Gln-cyclo(N epsilon-Lys-Arg-Pro-Ala-Gly-Phe). In contrast, only QC from C. papaya was able to cyclize a methylated glutamine residue, while this compound did not even inhibit human QC-catalysis, suggesting distinct substrate recognition pattern. The conversion of the potential physiological substrates [Gln1]-gastrin, [Gln1]-neurotensin and [Gln1]-fertilization promoting peptide indicates that human QC may play a key role in posttranslational modification of most if not all pGlu-containing hormones.
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PMID:Substrate specificity of glutaminyl cyclases from plants and animals. 1471

The expression of members of the Reg family of secreted lectin-like proteins is increased in response to stress, inflammation and damage in many tissues. In the stomach, Reg is located in enterochromaffin-like cells, where its expression is stimulated by the gastric hormone gastrin. We have examined the mechanisms by which gastrin stimulates expression of Reg-1. Deletional mutations of 2.1 to 0.1 kb of the rat Reg-1 promoter in a luciferase reporter vector were transiently transfected into gastric cancer AGS-G(R) cells. All promoter fragments tested showed similar relative increases in luciferase expression in response to gastrin (1 nM). The response to gastrin of the smallest (104 bp) construct was 4.2+/-0.4-fold over basal. These responses were reduced by Ro-32-0432, a protein kinase C inhibitor, by C3-transferase, a Clostridium botulinum toxin and a selective inhibitor of the Rho family GTPase RhoA, and by co-transfection with a dominant negative form of RhoA. Co-transfection with a constitutively active form of RhoA stimulated expression 11.6+/-1.7-fold over basal. Mutations through the 104 bp construct identified a C-rich element (C-79CCCTCCC-72) required for responses to gastrin, PKC (protein kinase C) and L63RhoA (the constitutively active form of human RhoA protein containing a glutamine-to-leucine substitution at position 63). EMSAs (electrophoretic-mobility-shift assays) using nuclear extracts of control and gastrin-stimulated AGS-G(R) cells and a probe spanning -86 to -64 bp revealed multiple binding proteins. There was no effect of gastrin on the pattern of binding. Supershift assays indicated that transcription factors Sp1 and Sp3 bound the C-rich sequence. We conclude that gastrin stimulates Reg expression via activation of PKC and RhoA, that a C-rich region (-79 to -72) is critical for the response and that Sp-family transcription factors bind to this region of the promoter.
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PMID:Control of expression of the lectin-like protein Reg-1 by gastrin: role of the Rho family GTPase RhoA and a C-rich promoter element. 1510 6

The development of metabolically stable radiolabeled gastrin analogues with suitable pharmacokinetics is a topic of recent research activity. These imaging vectors are of interest because the gastrin/CCK2 receptor is highly overexpressed in different tumors such as medullary thyroid cancer, neuroendocrine tumors, and SCLC. The drawback of current targeting agents is either their metabolic instability or their high kidney uptake. We present the synthesis and in vitro and in vivo evaluation of 11 (111)In-labeled DOTA-conjugated peptides that differ by their spacer between the peptide and the chelate. We introduced uncharged but hydrophilic spacers such as oligoethyleneglycol, serine, and glutamine. The affinity of all radiopeptides was high with IC(50) values between 0.5 and 4.8 nM. The improvement of human serum stability is 500-fold within this series of compounds. In addition the kidney uptake could be lowered distinctly and the tumor-to-kidney ratio improved almost 60-fold if compared with radiotracers having charged spacers such as glutamic acid.
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PMID:Highly improved metabolic stability and pharmacokinetics of indium-111-DOTA-gastrin conjugates for targeting of the gastrin receptor. 2145 1


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