Peptide fragments of AMP-18, a novel secreted gastric antrum mucosal protein, are mitogenic and motogenic

Toback, F. Gary; Walsh-Reitz, Margaret M.; Musch, Mark W.; Chang, Eugene B.; Valle, John Del; Ren, Hao; Huang, Erick; Martin, Terence E.

doi:10.1152/ajpgi.00455.2002

Cited by 74 publications

(121 citation statements)

References 30 publications

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“…Wound assays were performed as previously described (21,22). Briefly, confluent monolayers of cells grown in 6-well plates were incubated overnight in serum-free medium and then wounded using a blue pipette tip.…”

Section: Methodsmentioning

confidence: 99%

REG4 acts as a mitogenic, motility and pro-invasive factor for colon cancer cells

Rafa

Dessein²,

Devisme³

et al. 2010

Int J Oncol

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Abstract. REG4, the latest member of the regenerating gene family, is overexpressed in inflammatory bowel diseases and gastrointestinal carcinomas. To date, its pathophysiologic role has not been well established. Using HT-29 models, we previously identified REG4 as being overexpressed in colorectal tumor cells displaying a drug-resistance phenotype; some also displayed invasive properties. Thus, we investigated the potential functions of REG4 in biological processes involved in colorectal tumor progression such as cell proliferation, migration and invasion. Colon cancer cells secreting REG4 (HT29-5M21, HT29-5F7 and HT29/REG4-8) or not (HT-29, HT29/CT1 and Caco-2/TC7) were used to analyze the autocrine and paracrine effects of REG4. REG4 was continuously secreted into the culture medium of colon cancer cells. REG4 stimulated cell growth in a paracrine manner after 24 h of treatment. Notably, REG4 promoted migration and invasion of tumor cells in both an autocrine and paracrine manner, and these effects were significantly decreased by concomitant treatment with an anti-REG4 antibody. Using pharmacological inhibitors, we showed that PI3K/Akt, PKAs, PKCs and Rho-like GTPases, but not MAPK, are involved in REG4 invasion signals. In addition, REG4 expression was found to be increased in tissues harboring proliferation and migration properties such as the developing intestine and tissues from inflammatory bowel disease, hyperplastic polyps, adenoma and colorectal cancers. In various situations, REG4 expression was not confined to proliferating cells, regenerating cells or cells of the invasive front of metastatic tumors, suggesting that extracellular REG4 may act on epithelial cells in a paracrine manner. Altogether, our results indicate that REG4 is a multifunctional secreted protein which acts on colorectal cancer cells in an autocrine and paracrine manner. According to its biological functions and tissue expression, REG4 may play an important role in the development and progression of colorectal cancer, as well as in intestinal morphogenesis and epithelium restitution.

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Section: Methodsmentioning

confidence: 99%

REG4 acts as a mitogenic, motility and pro-invasive factor for colon cancer cells

Rafa

Dessein²,

Devisme³

et al. 2010

Int J Oncol

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“…GKN1 is a novel autocrine/paracrine protein that is specifically expressed in gastric mucosa (1,2). Toback and colleagues reported that GKN1 protects the antral mucosa and promotes healing by facilitating restitution and proliferation after injury (3). Interestingly, GKN1 is downregulated in Helicobacter pylori-infected gastric epithelial cells, and the loss of GKN1 expression is detected in gastric cancer tissues and precancerous lesions such as intestinal metaplasia (4,5).…”

Section: Introductionmentioning

confidence: 99%

GKN1–miR-185–DNMT1 Axis Suppresses Gastric Carcinogenesis through Regulation of Epigenetic Alteration and Cell Cycle

Yoon

Choi

et al. 2013

Clinical Cancer Research

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Purpose: Gastrokine 1 (GKN1) functions to protect the gastric antral mucosa and promotes healing by facilitating restoration and proliferation after injury. GKN1 is downregulated in Helicobacter pylori-infected gastric epithelial cells and loss of GKN1 expression is closely associated with gastric carcinogenesis, but underlying mechanisms of the tumor-suppressing effects of GKN1 remain largely unknown.Experimental Design: AGS, MKN1, MKN28 gastric cancer cells and HFE-145 immortalized nonneoplastic gastric mucosal cells were transfected with GKN1 or shGKN1. We conducted molecular and functional studies of GKN1 and miR-185 and investigated the mechanisms of alteration. We also analyzed epigenetic alterations in 80 gastric cancer tissues.Results: Restoration of GKN1 protein suppressed gastric cancer cell growth by inducing endogenous miR-185 that directly targets epigenetic effectors DNMT1 and EZH2 in gastric cancer cells. In addition, ectopic expression of GKN1 upregulated Tip60 and downregulated HDAC1 in an miR-185-independent manner, thereby inducing cell-cycle arrest by regulating cell-cycle proteins in gastric cancer cells. Notably, GKN1 expression was inversely correlated with DNMT1 and EZH2 expression in a subset of 80 gastric cancer tissues and various gastric cancer cell lines. Interestingly, it was found that GKN1 exerted a synergistic anticancerous effect with 5-fluorouracil on tumor cell growth, which suggests a possible therapeutic intervention method for gastric cancer.Conclusion: Our results show that GKN1 has an miR-185-dependent and -independent mechanism for chromatic and DNA epigenetic modification, thereby regulating the cell cycle. Thus, the loss of GKN1 function contributes to malignant transformation and proliferation of gastric epithelial cells in gastric carcinogenesis.

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“…Beside the important role in gastric mucosal protection 1,4,5 , the biological reason for the antiamyloidogenic properties of human GKN1 and for its role in APP processing in gastric tissues is unclear. One explanation might be assigned to the BRICHOS domain acting in general as a chaperon toward peptides with a tendency to asssume β-strand structure.…”

Section: Gkn1 and Its Role In App Processingmentioning

confidence: 99%

“…Gastrokine1 (GKN1), a 18 kDa protein also known as antrum mucosal protein (AMP-18) 1 , is highly expressed in the gastric mucosa of many mammals species 1,2 . The gene coding GKN1 (CA11), located on the chromosome 2p13 (accession number: BK0017373), is about 6 kb long and contains 6 exons.…”

Section: Introductionmentioning

confidence: 99%

Human Gastrokine 1 and its anti-amyloidogenic properties

Stadio¹,

Altieri²,

Minopoli³

et al. 2017

J Neurol Neuromedicine

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Gastrokine 1 (GKN1) is a 18 kDa stomach protein highly expressed in normal gastric tissue but absent in gastric cancer. GKN1 plays its major role in maintaining gastric mucosal integrity. Because of the presence in its central region of a BRICHOS domain, GKN1 is characterized by multifunctional properties since it interacts and regulates the activity of several proteins. The BRICHOS domain consists of about 100 amino acids and has been found in protein families often associated with major human diseases like familial British and Danish dementia (BRI2) or respiratory distress syndrome (surfactant protein C) (SP-C), both associated with amyloid formation. It has been shown that BRICHOS is a chaperon domain that has the property of binding precursor protein regions with high β-sheet tendencies, thereby preventing them from amyloid formation. Like the BRICHOS domains from BRI2 and SP-C precursor (proSP-C), also GKN1 is able to prevent fibrils formation of amyloidbeta peptide (Aβ) and to interact with the C-terminal region of APP thus hindering the γ-secretase proteolytic sites. Indeed, amyloid is of great medical importance since it originates in several major fatal diseases such as Alzheimer, Parkinson and diabetes mellitus. The results collected until now on the BRICHOS properties of GKN1 and those from other BRICHOS suggest that the different amyloids recognized by BRICHOS should contain similar structural elements therefore, the BRICHOS domain represents a potential powerfull tool for therapeutic approaches against amyloid associated diseases.

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Peptide fragments of AMP-18, a novel secreted gastric antrum mucosal protein, are mitogenic and motogenic

Cited by 74 publications

References 30 publications

REG4 acts as a mitogenic, motility and pro-invasive factor for colon cancer cells

REG4 acts as a mitogenic, motility and pro-invasive factor for colon cancer cells

GKN1–miR-185–DNMT1 Axis Suppresses Gastric Carcinogenesis through Regulation of Epigenetic Alteration and Cell Cycle

Human Gastrokine 1 and its anti-amyloidogenic properties

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