Identification of progastrin derived peptides in colorectal carcinoma extracts.

Nemeth, Joe; Taylor, Ben; Pauwels, Stanislas; Varró, Andrea; Dockray, Graham J.

doi:10.1136/gut.34.1.90

Cited by 113 publications

(83 citation statements)

References 17 publications

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“…The successful generation of Fabp-PG mice provided us with the opportunity to examine the effects of paracrine hPG expression within the colonic mucosa; this system mimicked the secretion of the nonamidated gastrins that are produced by colonic tumors. 21,45 Fabp-PG mice exhibited a ϳ4-fold increase in the percentage of proximal colon tumors relative to their wild-type littermates. Proximal colorectal tumors are common in humans, 46,47 which raises the possibility that the pathways mediating proximal colon carcinogenesis in PG-expressing mice are similar to the corresponding pathways in humans.…”

Section: Discussionmentioning

confidence: 96%

“…Azoxymethane (AOM)-induced colonic tumors in rats, as well as a significant percentage of adenomas (Ads) and adenocarcinomas (AdCas) in humans, express the gastrin gene. 5 We now know that autocrine gastrins (primarily PG), which are expressed by colorectal AdCas and by human and murine colon carcinoma cells, 12,21 are required to maintain the growth and tumorigenic potential of gastrin-dependent colon carcinoma cells. [22][23][24] Elevated levels of circulating gastrins (including PG) have been observed in rats 25 and humans 26 -28 with colonic malignancies; however, normal colonic epithelial cells and hyperproliferative (aberrant) colonic crypt cells in mice and rats do not express the gastrin gene.…”

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confidence: 99%

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Intestinal expression of mutant and wild‐type progastrin significantly increases colon carcinogenesis in response to azoxymethane in transgenic mice

Cobb

Wood

Ceci

et al. 2004

Cancer

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Charcot–Marie–Tooth neuropathy type 1C (CMT1C) is an autosomal dominant demyelinating peripheral neuropathy caused by missense mutations in the small integral membrane protein of lysosome/late endosome (SIMPLE) gene. To investigate the prevalence of SIMPLE mutations, we screened a cohort of 152 probands with various types of demyelinating or axonal and pure motor or sensory inherited neuropathies. SIMPLE mutations were found only in CMT1 patients, including one G112S and one W116G missense mutations. A novel I74I polymorphism was identified, yet no splicing defect of SIMPLE is likely. Haplotype analysis of STR markers and intragenic SNPs linked to the gene demonstrated that families with the same mutation are unlikely to be related. The clustering of the G112S, T115N, and W116G mutations within five amino acids suggests this domain may be critical to peripheral nerve myelination. Electrophysiological studies showed that CMT1C patients from six pedigrees (n = 38) had reduced nerve conduction velocities ranging from 7.5 to 27.0m/sec (peroneal). Two patients had temporal dispersion of nerve conduction and irregularity of conduction slowing, which is unusual for CMT1 patients. We report the expression of SIMPLE in various cell types of the sciatic nerve, including Schwann cells, the affected cell type in CMT1C.

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Section: Discussionmentioning

confidence: 96%

mentioning

confidence: 99%

Intestinal expression of mutant and wild‐type progastrin significantly increases colon carcinogenesis in response to azoxymethane in transgenic mice

Cobb

Wood

Ceci

et al. 2004

Cancer

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“…More recently both progastrin and gastrin were detected by immunohistochemistry in more than 80% of the tumour cells in 20/23 colorectal adenocarcinomas, whereas in normal coIonic mucosa only occasional crypt cells stained simultaneously for progastrin and gastrin [22]. An increase in progastrin production in colorectal tumour tissue compared to normal mucosa has also been demonstrated in tissue extracts [14,15]. In contrast to the immunohistochemical results levels of mature gastrin were low, and did not differ between normal and tumour tissue [13][14][15].…”

Section: Role Of Progastrin In Colorectal Carcinoma Growthmentioning

confidence: 99%

“…1 [13][14][15], a candidate receptor for autocrine gastrin should not require an amidated C-terminus for binding. A cell-surface receptor binding glycine-extended gastrin2 17 and capable of stimulating proliferation of the rat pancreatic carcinoma cell line AR4-2J has recently been reported [16].…”

Section: Introductionmentioning

confidence: 99%

Binding of progastrin fragments to the 78 kDa gastrin‐binding protein

Baldwin

1995

FEBS Letters

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The non-selective gastrin/eholeeystokinin receptor antagonists proglumide and benzotript inhibit colon carcinoma cell proliferation by binding to the 78 kDa gastrin-binding protein (GBP) (Baldwin, Proc. Natl. Acad. Sci. USA, 91 (1994) 7593-7597). However, although most colon carcinoma cell lines synthesize progastrin, production of mature amidated gastrin~7 has not been observed. In order to define the structural requirements for the binding of gastrin to the GBP the affinities of various fragments of amidated amd C-terminally extended gastrin~7 for the GBP have been measured. The results indicate that the GBP recognizes both N-and C-termini of gastrin~7. Moreover since C-terminal amidation is not a prerequisite for binding of gastrin to the GBP, the GBP is a potential target for the autocrine effects of progastrin.

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“…Amidated serum gastrin levels were measured by Professor Andrea Varro (Physiology Department, University of Liverpool) using the L2 antiserum, as previously described (Nemeth et al, 1993).…”

Section: In Vivo Treatmentmentioning

confidence: 99%

Potential role of endocrine gastrin in the colonic adenoma carcinoma sequence

et al. 2002

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The role of hyper-gastrinaemia in the incidence of colonic cancer remains to be clarified. The aim of this study was to determine whether cholecystokinin-2 (CCK-2) receptor expression predicts the sensitivity of human colonic adenomas to the proliferative effects of serum hyper-gastrinaemia. Gene expression of the classical (74 kDa) CCK-2 receptor in human colonic adenoma specimens and cell lines, was quantified by real-time PCR. Western blotting, using a CCK-2 receptor antiserum, confirmed protein expression. A transformed human colonic adenoma was grown in SCID mice, with hyper-gastrinaemia induced by protein pump inhibitors. CCK-2 receptor blockade was achieved by using neutralising antiserum. Both human colonic adenoma cell lines and biopsies expressed CCK-2 receptor mRNA at levels comparable with CCK-2 receptor transfected fibroblasts and oxyntic mucosa. Western blotting confirmed immunoreactive CCK-2 receptor bands localised to 45, 74 and 82.5 kDa. Omeprazole and lansoprazole-induced hyper-gastrinaemia (resulting in serum gastrin levels of 34.0 and 153.0 pM, respectively) significantly increased the weight of the human adenoma grafts (43% (P=0.016) and 70% (P=0.014), respectively). The effect of hypergastrinaemia on tumour growth was reversed by use of antiserum directed against the CCK-2 receptor. Hyper-gastrinaemia may promote proliferation of human colonic adenomas that express CCK-2 receptor isoforms.

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Identification of progastrin derived peptides in colorectal carcinoma extracts.

Abstract: The possible production of gastrin by colorectal carcinomas has been studied.

Cited by 113 publications

References 17 publications

Intestinal expression of mutant and wild‐type progastrin significantly increases colon carcinogenesis in response to azoxymethane in transgenic mice

Intestinal expression of mutant and wild‐type progastrin significantly increases colon carcinogenesis in response to azoxymethane in transgenic mice

Binding of progastrin fragments to the 78 kDa gastrin‐binding protein

Potential role of endocrine gastrin in the colonic adenoma carcinoma sequence

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