Glycine-extended post-translational processing intermediates of gastrin and cholecystokinin in the gut

Marino, Lucyndia R; Muglia, B. H.; Dickinson, Chris J.

doi:10.1016/0167-0115(94)90193-7

Cited by 14 publications

(6 citation statements)

References 36 publications

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“…The results reported here suggest that longer term exposure of D-cells to gastrin and G-Gly also stimulates a further negative feedback loop by enhancing subsequent somatostatin release thus providing a means to restrain acid hypersecretion caused by hypergastrinaemia and control longer term acid secretion. Several studies have confirmed that G-Gly is produced in gastric antral G-cells 22– 25 and this study adds further support to the suggestion that these peptide processing intermediates may have a role in the normal physiological control of the gastric secretions.…”

Section: Discussionsupporting

confidence: 80%

Glycine-extended gastrin enhances somatostatin release from cultured rabbit fundic D-cells

Beales

2013

F1000Res

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The role of the peptide hormone gastrin in stimulating gastric acid secretion is well established. Mature amidated gastrin is processed from larger peptide precursor forms. Increasingly these processing intermediates, such as glycine-extended gastrin (G-Gly) and progastrin, have been shown to have biological activities of their own, often separate and complementary to gastrin. Although G-Gly is synthesized and secreted by gastric antral G-cells, the physiological functions of this putative mediator are unclear. Gastrin and cholecystokinin (CCK) stimulate the secretion of somatostatin from gastric D-cells as part of the feedback control of gastric acid. In this study the effect of G-Gly and gastrin on the release of somatostatin from rabbit fundic D-cells was examined. D-cells were obtained by collagenase-EDTA digestion and elutriation and cultured for 48 hours. With a 2 hour exposure to the peptides, gastrin but not G-Gly stimulated somatostatin release. Treatment of D-cells for 24 hours with gastrin or G-Gly individually, significantly enhanced subsequent basal as well as CCK- and GLP-1-stimulated somatostatin release. Twenty four hours exposure to gastrin combined with G-Gly synergistically enhanced basal and agonist-stimulated somatostatin release and cellular somatostatin content. Gastrin and G-Gly may be important in the longer term regulation of D-cell function.

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Section: Discussionsupporting

confidence: 80%

Glycine-extended gastrin enhances somatostatin release from cultured rabbit fundic D-cells

Beales

2013

F1000Res

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“…The authors were uncertain of the sequence of this third component but speculated that it could be an additional processed form of GIP (16). Differential posttranslational processing resulting in multiple products has been described for other peptides such as somatostatin, gastrin, and cholecystokinin (CCK) (4,23). In addition, the uneven distribution of varying forms of gastrin and CCK throughout the small intestine supports the notion of a nonuniform expression of posttranslational processing enzymes in the gut (11,23).…”

Section: Discussionmentioning

confidence: 75%

“…Furthermore, although the PC2 cleavage site in pro-GIP is highly conserved in mammalian species, the expression of processing enzymes may differ among species resulting in different proportions of the GIP isoforms. Species-dependent expression of peptide isoforms has been described for other gut peptides, such as CCK (23).…”

Section: Discussionmentioning

confidence: 99%

“…Differential posttranslational processing resulting in multiple products has been described for other peptides such as somatostatin, gastrin, and cholecystokinin (CCK) (4,23). In addition, the uneven distribution of varying forms of gastrin and CCK throughout the small intestine supports the notion of a nonuniform expression of posttranslational processing enzymes in the gut (11,23). Our findings of increased expression of the COOH-terminal truncated form of GIP in the distal gut relative to proximal regions also suggests a nonuniform expression of the enzymes involved in pro-GIP processing.…”

Section: Discussionmentioning

confidence: 99%

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Differential processing of pro-glucose-dependent insulinotropic polypeptide in gut

Fujita

Asadi

Yang

et al. 2010

American Journal of Physiology-Gastrointestinal and Liver Physi

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Glucose-dependent insulinotropic polypeptide (GIP) is a hormone released from enteroendocrine K cells in response to meals. Posttranslational processing of the precursor protein pro-GIP at residue 65 by proprotein convertase subtilisin/kexin type 1 (PC1/3) in gut K cells gives rise to the established 42-amino-acid form of GIP (GIP1–42). However, the pro-GIP peptide sequence contains a consensus cleavage site for PC2 at residues 52–55 and we identified PC2 immunoreactivity in a subset of K cells, suggesting the potential existence of a COOH-terminal truncated GIP isoform, GIP1–30. Indeed a subset of mouse and human K cells display GIP immunoreactivity with GIP antibodies directed to the mid portion of the peptide, but not with a COOH-terminal-directed GIP antibody, indicative of the presence of a truncated form of GIP. This population of cells represents ∼5–15% of the total GIP-immunoreactive cells in mice, depending on the region of intestine, and is virtually absent in mice lacking PC2. Amidated GIP1–30 and GIP1–42 have comparable potency at stimulating somatostatin release in the perfused mouse stomach. Therefore, GIP1–30 represents a naturally occurring, biologically active form of GIP.

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“…Progastrin is expressed in several normal tissues, such as pituitary gland, cerebellum, antrum, vagal neurons and duodenum (Rehfeld, 1986(Rehfeld, , 1991Marino et al, 1994). The tissue concentration of progastrin and processing intermediates is in the same range as that of the mature a-amidated peptide (Sugano et al, 1987).…”

mentioning

confidence: 99%

Autocrine stimulation of AR4-2J rat pancreatic tumor cell growth by glycine-extended gastrin

et al. 1996

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Glycine-extended gastrin (gastrin-Gly) stimulates proliferation of AR4-2) pancreatic tumor cell line through a specific receptor, different from the gastrin-cholecystokinin B receptor. Our purpose was to determine whether AR4-2) cells produced gastrin-Gly and then whether the peptide was involved in an autocrine loop. First, proliferation of AR4-2) cells in serum-free medium was inhibited by a gastrin anti-sense oligodeoxynucleotide phosphorothioate and by antibodies specific for gastrinGly. In contrast, antibodies specific for a-amidated gastrin were without effect. By using RT-PCR, we have shown that AR4-2J cells expressed gastrin mRNA. The presence of gastrin-Gly, but not a-amidated gastrin, in serum-free media was detected by radioimmunoanalysis. Gel chromatography revealed that the predominant molecular forms secreted were glycine-extended gastrin-34 and gastrin-17. Furthermore, epidermal growth factor (EGF), a stimulator of gastrin gene transcription, modulates gastrin-Gly secretion by AR4-2J. These data together suggest that gastrin-Gly is an autocrine growth factor for AR4-2) cells and that it participates with EGF in the regulation of AR4-2)-cell proliferation.o 1996 Wiley-Liss, Inc.The major physiological role of the gastrointestinal hormone, gastrin, is to stimulate gastric-acid secretion. Gastrin can also promote growth effects on normal gastric mucosa, on colorectal tumors in vivo (Winsett et al., 1986), and on colonic (Kuzyk et al., 1986), broncogenic (Sethi and Rozengurt, 1992) and pancreatic cell lines (Seva et al., 1990). Bioactivity of gastrin and several other regulatory peptides requires Cterminal a-amidation using glycine as amide donor (Hiked and Rehfeld, 1986). Carboxyamidation is the final step in the maturation to a bioactive gastrin, which is able to bind its CCK-B gastrin (RCCK-B) receptor with high affinity.Progastrin is expressed in several normal tissues, such as pituitary gland, cerebellum, antrum, vagal neurons and duodenum (Rehfeld, 1986(Rehfeld, , 1991Marino et al., 1994). The tissue concentration of progastrin and processing intermediates is in the same range as that of the mature a-amidated peptide (Sugano et al., 1987). It has been demonstrated that the immediate precursor of amidated gastrin, glycine-extended gastrin (gastrin-Gly), possesses specific biological functions. Thus, like a-amidated gastrin, gastrin-Gly stimulates proliferation of a tumor-derived pancreatic cell line (AR4-2J), through a specific receptor, different from the CCK-B receptor (Seva et al., 1994). Moreover, colorectal (Singh et al., 1994), gastric (Van Solinge and Rehfeld, 1992) and broncogenic tumors (Rehfeld et aL, 1989) contain glycine-extended gastrins, and occasionally at concentrations higher than that of amidated gastrin.A possible mechanism by which tumor cells show unrestricted growth is a response to the growth factors that they produce. An autocrine role for a "gastrin-like" peptide in human colonic tumor cells has already been suggested (Hoosein et al., 1990). More recently, immunologica...

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Glycine-extended post-translational processing intermediates of gastrin and cholecystokinin in the gut

Cited by 14 publications

References 36 publications

Glycine-extended gastrin enhances somatostatin release from cultured rabbit fundic D-cells

Glycine-extended gastrin enhances somatostatin release from cultured rabbit fundic D-cells

Differential processing of pro-glucose-dependent insulinotropic polypeptide in gut

Autocrine stimulation of AR4-2J rat pancreatic tumor cell growth by glycine-extended gastrin

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