Functional Localization of Proprotein-convertase Furin and its Substrate TGFβ in EGF Receptor-expressing Gastric Chief Cells

Fujisawa, Tomomi; Kamimura, Hitoshi; Hosaka, Masahiro; Torii, Seiji; Izumi, Tetsuro; Kuwano, Hiroyuki; Takeuchi, Toshiyuki

doi:10.1080/0897719042000201659

Cited by 8 publications

(7 citation statements)

References 28 publications

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“…We (39) have previously suggested that SPEM cells arise from the transdifferentiation of chief cells, based on the observation of cells expressing both intrinsic factor and SP/TFF2 at the bases of the fundic glands after a single dose of DMP-777 in gastrin-deficient mice. Although a previous investigation (36) has suggested that EGF receptors are enriched in human parietal cells, it is important to note that several investigators have reported that EGF receptors are enriched in rodent chief cells (19,26). Thus alterations in EGF receptor ligands might have particular influence on the differentiation and function of chief cells.…”

Section: Discussionmentioning

confidence: 96%

“…Therefore, to examine the possible influence of SP/TFF2 as an autocrine growth factor of metaplasia, we studied lineage changes after DMP-777 administration in SP/TFF2-deficient mice. Additionally, previous investigations have noted that EGF receptors are strongly enriched in chief cells (19,26). Thus, given the important role of EGF receptor ligands in regulating epithelial mucosal cell differentiation (24), we also evaluated the role of the EGF receptor signaling pathway by treating waved-2 mice, which carry a point mutation that reduces tyrosine kinase activity in the EGF receptor (35).…”

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confidence: 99%

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Altered metaplastic response ofwaved-2EGF receptor mutant mice to acute oxyntic atrophy

Ogawa¹,

Nomura²,

Varró³

et al. 2006

American Journal of Physiology-Gastrointestinal and Liver Physi

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Metaplastic cell lineages are putative precursors for the development of gastric adenocarcinoma. The loss of parietal cells (oxyntic atrophy) is the initiating step in the evolution of gastric fundic mucosal lineage changes including metaplasia and hyperplasia. However, the intrinsic mucosal factors that promote and modulate the emergence of metaplastic phenotypes remain obscure. Over the past several years, we have studied pharmacologically induced, reversible oxyntic atrophy in rodents treated with DMP-777, a drug that acts as a parietal cell secretory membrane protonophore. DMP-777 elicits a rapid loss of parietal cells followed by the emergence of foveolar hyperplasia and spasmolytic polypeptide (SP)-expressing metaplasia (SPEM). The objective of the present study was to provide further insights into the intrinsic mucosal factors regulating the emergence of SPEM in the setting of oxyntic atrophy. We therefore studied the effects of DMP-777 administration on both SP/trefoil factor (TFF)2-deficient mice, which lack SP/TFF2, a marker of SPEM, and waved-2 mice, which harbor a point mutation in the EGF receptor that attenuates its tyrosine kinase activity. As in wild-type mice, treatment with DMP-777 for 7 days did elicit SPEM in SP/TFF2-deficient mice. These results suggest that SP/TFF2 does not impact on the development of metaplasia after the induction of parietal cell loss. In contrast, waved-2 homozygous mice displayed accelerated SPEM development by 3 days of treatment with DMP-777. These findings indicate that attenuation of EGF receptor signaling in waved-2 mice does elicit a more rapid emergence of SPEM. The results support a role for EGF receptor ligands in the regulation of gastric metaplasia.

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Section: Discussionmentioning

confidence: 96%

mentioning

confidence: 99%

Altered metaplastic response ofwaved-2EGF receptor mutant mice to acute oxyntic atrophy

Ogawa¹,

Nomura²,

Varró³

et al. 2006

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…Another striking feature of the IL-11-treated fundus was the loss of chief cells; this was accompanied by reduced expression of active protease products of chief cells54 55; trypsin 4/10, amylase 2, pancreatic lipase-related protein 1 and furin, whereas pepsinogen C expression and localisation of the intrinsic factor were unchanged. It is unclear from the present study whether chief cell loss was secondary to a reduction in parietal cells, or whether IL-11 acts directly on the chief cell.…”

Section: Discussionmentioning

confidence: 99%

IL-11 is a parietal cell cytokine that induces atrophic gastritis

Howlett

Chalinor

Buzzelli

et al. 2011

Gut

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Background and Aims IL-is important in gastric damage, mucosal repair and gastric cancer progression. We analysed IL-11 expression in H.pylori infected mouse stomach, the site of gastric IL-11 expression in mice and humans, and the effect of exogenous IL-11 on gastric mucosal homeostasis. Methods IL-11 protein was localised in mouse and human stomach. The impact of chronic, exogenous IL-11 on normal mouse stomach was examined Histologically and transcriptionally by microarray, confirmed by mRNA and protein analysis. Functional impact of IL-11 on gastric acid secretion was determined. Results In mice infected with H.pylori, IL-11 was increased in fundic mucosa with temporal expression similar to IL-1b. IL-11 protein was localised predominantly to parietal cells in mouse and human stomach. Application of exogenous IL-11 to resulted in fundic parietal and chief cell loss, hyperplasia, mucous cell metaplasia and inflammation. Coincident with cellular changes were an increased gastric pH, altered parietal cell ultrastructure and altered gene expression, particularly genes involved in immune response and ion transport which could result in compromised acid secretion. We confirmed that a single dose of IL-11 effectively ablated the gastric response to histamine. Conclusions IL-11 is a parietal cell cytokine that blocks gastric acid secretion, likely via reducing expression of parietal cell ion transport genes, CCKb and histamine H2 receptors. IL-11 expression is increased in H. pylori infected mouse stomach and treatment of wild type mice with IL-11 induced changes in the gastric fundic mucosa reminiscent of chronic atrophic gastritis, a precursor to gastric cancer.

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“…In the gastrointestinal tract, TGFβ isoforms regulate epithelial renewal through effects on cell proliferation [3]–[7], differentiation [8], [9], epithelial mesenchymal transition [10], [11], migration [12], and apoptosis [13]. TGFβ has been detected in human and murine milk [14], [15] and after suckling and oral administration, signaling is activated in gastric epithelial cells through receptors (TβRI and TβRII) and Smads central cascade [6], [15]–[17].…”

Section: Introductionmentioning

confidence: 99%

Transforming Growth Factor β1 Increases p27 Levels via Synthesis and Degradation Mechanisms in the Hyperproliferative Gastric Epithelium in Rats

2014

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Throughout postnatal development, the gastric epithelium expresses Transforming Growth Factor beta1 (TGFβ1), but it is also exposed to luminal peptides that are part of milk. During suckling period, fasting promotes the withdrawal of milk-born molecules while it stimulates gastric epithelial cell proliferation. Such response can be reversed by exogenous TGFβ1, as it directly affects cell cycle through the regulation of p27 levels. We used fasting condition to induce the hyperproliferation of gastric epithelial cells in 14-day-old Wistar rats, and evaluated the effects of TGFβ1 gavage on p27 expression, phosphorylation at threonine 187 (phospho-p27Thr187) and degradation. p27 protein level was reduced during fasting when compared to suckling counterparts, while phospho-p27Thr187/p27 ratio was increased. TGFβ1 gavage reversed this response, which was confirmed through immunostaining. By using a neutralizing antibody against TGFβ1, we found that it restored the p27 and phosphorylation levels detected during fasting, indicating the specific role of the growth factor. We noted that neither fasting nor TGFβ1 changed p27 expression, but after cycloheximide administration, we observed that protein synthesis was influenced by TGFβ1. Next, we evaluated the capacity of the gastric mucosa to degrade p27 and we recorded a higher concentration of the remaining protein in pups treated with TGFβ1, suggesting augmented stability under this condition. Thus, we showed for the first time that luminal TGFβ1 increased p27 levels in the rat gastric mucosa by up- regulating translation and reducing protein degradation. We concluded that such mechanisms might be used by rapidly proliferating cells to respond to milk-born TGFβ1 and food restriction.

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Functional Localization of Proprotein-convertase Furin and its Substrate TGFβ in EGF Receptor-expressing Gastric Chief Cells

Cited by 8 publications

References 28 publications

Altered metaplastic response ofwaved-2EGF receptor mutant mice to acute oxyntic atrophy

Altered metaplastic response ofwaved-2EGF receptor mutant mice to acute oxyntic atrophy

IL-11 is a parietal cell cytokine that induces atrophic gastritis

Transforming Growth Factor β1 Increases p27 Levels via Synthesis and Degradation Mechanisms in the Hyperproliferative Gastric Epithelium in Rats

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