Regenerating gene protein may mediate gastric mucosal proliferation induced by hypergastrinemia in rats

Fukui, Hirokazu; Kinoshita, Yoshikazu; Maekawa, Toru; Okada, Akihiko; Waki, Shinya; Hassan, Sazzad; Okamoto, Hiroshi; Chiba, Tsutomu

doi:10.1016/s0016-5085(98)70027-7

Cited by 168 publications

(155 citation statements)

References 30 publications

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“…*p Ͻ 0.05 compared with both the control and single-dose groups. for RegI in cellular proliferation is well demonstrated in pancreas (Francis et al, 1992;Miyaura et al, 1991;Watanabe et al, 1994), and RegI has also been implicated as exerting trophic effects on the gastric epithelium (Asahara et al, 1996;Fukui et al, 1998;Higham et al, 1999;Kawanami et al, 1997;Kazumori et al, 2000). Moreover, our results show clear evidence of concordantly increased expression of RegI and PCNA in both damaged and healing gastric epithelium.…”

Section: Alderman Et Alsupporting

confidence: 74%

Insights into the Mechanisms of Gastric Adaptation to Aspirin-Induced Injury: A Role for Regenerating Protein but Not Trefoil Peptides

Alderman

Ulaganathan

Judd

et al. 2003

Laboratory Investigation

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SUMMARY:The phenomenon of reduced gastric mucosal injury despite repeated doses of a damaging agent is termed adaptation. Adaptation to nonsteroidal anti-inflammatory drug-induced injury has been clearly demonstrated in both humans and experimental animals; however, the precise mechanisms remain unclear. We hypothesized that mediators of adaptation might be the regenerating protein (RegI) and the trefoil peptides TFF1 and TFF2, because these proteins play pivotal roles in gastric mucosal protection and repair. The gene expression and the protein levels of these proteins were measured and compared in normal, aspirin-injured, and aspirin-adapted rat stomachs. TFF gene and protein expression levels were similar in all three groups, whereas RegI gene expression and protein levels in adapted stomach were increased. A time course analysis of RegI expression during the onset and offset of adaptation showed that mucosal RegI increased during the development of adaptation, was maintained during subsequent aspirin dosing, and returned to baseline levels once dosing had ceased and adaptation was lost-indicative of a causal role in the adaptation process. Colocalization of increased RegI with gastric epithelial areas showing increased proliferation also suggests that RegI may be an important mediator of the resolution of mucosal injury that is characteristic of gastric adaptation to aspirin. (Lab Invest 2003, 83:1415-1425.

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Section: Alderman Et Alsupporting

confidence: 74%

Insights into the Mechanisms of Gastric Adaptation to Aspirin-Induced Injury: A Role for Regenerating Protein but Not Trefoil Peptides

Alderman

Ulaganathan

Judd

et al. 2003

Laboratory Investigation

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“…In addition to the role of Reg I in the pancreas, we have demonstrated that Reg I functions as a growth factor in gastric cells and is involved in gastric mucosal regeneration (Asahara et al, 1996;Fukui et al, 1998;Kazumori et al, 2000). Recently, we generated Reg I-transgenic mice, which showed that Reg I is a key regulatory molecule for the maintenance of the growth axis of the gastric glands (Miyaoka et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Reg I-knockout mice reveal its role in regulation of cell growth that is required in generation and maintenance of the villous structure of small intestine

et al. 2006

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Reg I (regenerating gene product I) is a growth factor that plays a central role in the generation and regeneration of the gastric mucosal architecture. On the other hand, mouse Reg I mRNA is expressed at the highest levels in the small intestine among the gastrointestinal tissues. In the current study, with the aim to clarify the role of Reg I protein in the small intestine, the temporal and spatial pattern of Reg I expression and the phenotype of Reg I-knockout mice in the tissue were examined. In the wild-type mice, immunohistochemistry localized Reg I protein expression in absorptive cells located in the lower half of the intestinal villi. Reg I expression was undetectable until embryonic day 13 (E13), when the fetal intestine still lacks villous structure; however, it dramatically increased at E17 along with the formation and maturation of the fetal intestinal villi. In the small intestine of the adult Reg I-knockout mice, less densely packed, round-shaped aberrant morphology of the absorptive cells was observed light microscopically, and electron microscopical examination revealed a strikingly loose connection of these cells to the basement membrane. Antiproliferating cell nuclear antigen staining and anti-Ki67 staining demonstrated the marked decrease in the number of proliferating cells in the small intestinal mucosa of the knockout mice. The cell migration speed visualized by one shot labeling of 5-bromodeoxyuridine was significantly slower in the knockout mice. These phenotypes of Reg I-knockout mice emerged, in accordance with the temporal pattern of Reg I expression described above, from E17. Reg I was considered to be a regulator of cell growth that is required to generate and maintain the villous structure of the small intestine.

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“…1 Thereafter, its human homologue REG Ia protein was suggested to be involved in the pathophysiology of gastrointestinal inflammation and its associated cancer. [2][3][4][5][6] Indeed, we previously reported that REG Ia protein behaves as a trophic and/or an anti-apoptotic factor in the development of colitis-or gastritis-associated cancer. 5,6 To clarify the regulatory mechanism of REG Ia gene expression, we initially screened major cytokines and showed that interleukin (IL)-6 and IFN-g are possible stimulators of REG Ia gene expression under inflammatory conditions.…”

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confidence: 99%

Involvement of the IL-22/REG Iα axis in ulcerative colitis

Sekikawa

Fukui

Suzuki

et al. 2010

Laboratory Investigation

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The Regenerating gene (REG) Ia protein, a trophic and/or anti-apoptotic factor, is important in the pathophysiology of gastrointestinal inflammation. Interleukin (IL)-22 is a recently identified cytokine that is suggested to have pivotal roles in inflammatory bowel diseases. We therefore investigated the involvement of the IL-22/REG Ia axis and examined the mechanism of regulation of REG Ia expression by IL-22 stimulation in ulcerative colitis (UC) mucosa. Expression of IL-22, IL-22 receptor 1 (IL-22R1), and REG Ia in UC mucosa was analyzed by real-time RT-PCR and immunohistochemistry. The effects of IL-22 on REG Ia protein expression were examined using a small-interfering RNA for STAT3, an MAPK inhibitor or a PI3K inhibitor. The element responsible for IL-22-induced REG Ia promoter activation was determined by a promoter deletion and electrophoretic mobility shift assay. The expression of IL-22 was enhanced in infiltrating inflammatory cells, and that of IL-22R1 and REG Ia was concurrently enhanced in the inflamed epithelium in UC mucosa. The levels of REG Ia and IL-22 mRNA expression were strongly correlated, and the distributions of REG Ia-and IL-22R1-positive epithelial cells were very similar. IL-22 simulation enhanced the expression of REG Ia protein through STAT3 tyrosine phosphorylation in colon cancer cells. The IL-22-responsive element was located between À142 and À134 in the REG Ia promoter region. REG Ia protein may have a pathophysiological role as a biological mediator for immune cell-derived IL-22 in the UC mucosa.

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Regenerating gene protein may mediate gastric mucosal proliferation induced by hypergastrinemia in rats

Abstract: Gastrin stimulates the production of Reg protein in gastric ECL cells, which may be involved in the gastrin-induced gastric mucosal cell growth.

Cited by 168 publications

References 30 publications

Insights into the Mechanisms of Gastric Adaptation to Aspirin-Induced Injury: A Role for Regenerating Protein but Not Trefoil Peptides

Insights into the Mechanisms of Gastric Adaptation to Aspirin-Induced Injury: A Role for Regenerating Protein but Not Trefoil Peptides

Reg I-knockout mice reveal its role in regulation of cell growth that is required in generation and maintenance of the villous structure of small intestine

Involvement of the IL-22/REG Iα axis in ulcerative colitis

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