Cytokine Regulation of the Trefoil Factor Family Binding Protein GKN2 (GDDR/TFIZ1/blottin) in Human Gastrointestinal Epithelial Cells

Baus-Lončar, Mirela; Lubka, Maria; Pusch, Carsten M.; Otto, W; Poulsom, Richard; Blin, Nikolaus

doi:10.1159/000104166

Cited by 34 publications

(38 citation statements)

References 62 publications

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“…At that time, a mouse homologue of GKN2 was characterized (formerly termed blottin) and non-covalent binding to a TFF2 fusion protein was reported [7,8]. GKN2 is one of the most up-regulated genes after Helicobacter pylori eradication [9] and it shows a similar regulation pattern with respect to cytokines as the TFF genes [10].…”

Section: Introductionmentioning

confidence: 99%

Biosynthesis of Gastrokine-2 in the Human Gastric Mucosa: Restricted Spatial Expression along the Antral Gland Axis and Differential Interaction with TFF1, TFF2 and Mucins

Kouznetsova

Laubinger

Kalbacher

et al. 2007

Cell Physiol Biochem

105

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Gastrokine-2 (GKN2) is a secretory peptide of human gastric surface mucous cells (SMCs). It forms disulfide-linked heterodimers with the trefoil factor family (TFF) peptide TFF1. Binding with TFF2 was also reported. Antral SMCs differ from those of the corpus by their TFF3 expression. The aim of this study was to localize GKN2 expression along the antral gland axis, to characterize the continuous regeneration of antral glands, and to investigate the interactions of GKN2 with TFF1, TFF2 and mucins. Methods: The spatial expression of GKN1, GKN2, TFF1-3, MUC5AC and MUC6 was determined using laser microdissection and RT-PCR analysis. Furthermore, antral extracts were separated by gel chromatography and the association of GKN2 with TFF1, TFF2, and mucins was investigated. Results: Differential GKN2 expression was localized along the rostro-caudal axis of the stomach. Laser microdissection revealed characteristic differential expression profiles of GKN1, GKN2, TFF1-3, MUC5AC and MUC6 along the antral gland axis. Both GKN2 and TFF1 were expressed in superficial SMCs. Surprisingly, the TFF1-GKN2 heterodimer did not associate with the mucin fraction; whereas TFF2 showed exclusive association with mucins. Conclusions: Maturation of antral SMCs occurs stepwise via trans-differentiation of TFF3 expressing progenitor cells. The TFF1-GKN2 heterodimer and TFF2 differ characteristically by their binding to gastric mucins. This points to different physiological functions of TFF1 and TFF2, the latter maybe acting as a “link peptide” for stabilization of the gastric mucus.

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Section: Introductionmentioning

confidence: 99%

Biosynthesis of Gastrokine-2 in the Human Gastric Mucosa: Restricted Spatial Expression along the Antral Gland Axis and Differential Interaction with TFF1, TFF2 and Mucins

Kouznetsova

Laubinger

Kalbacher

et al. 2007

Cell Physiol Biochem

105

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“…In view of the similar expression and biological functions, it was reasonable to speculate that there is some possible relationships between TFF1 and GKN1. GKN2 is a downstream gene of GKN1 and belongs to gastroinkase family (23). Recent studies have shown that GKN2 may interact with TFF1 to be a heterodimer.…”

Section: Discussionmentioning

confidence: 99%

“…In other words, GKN1 and TFF1 were similar in both the expressed location and physical functions. GKN2, a number of gastrokine family, also contains a BRICHOS domain and is a downstream gene of GKN1 (23). Several studies found that GKN2 combined with TFF1 as a heterodimer to maintain the stabilization of mucosa (24)(25)(26).…”

Section: Introductionmentioning

confidence: 99%

Role of trefoil factor 1 in gastric cancer and relationship between trefoil factor 1 and gastrokine 1

et al. 2012

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Abstract. Trefoil factor 1 (TFF1) is a small cysteine-rich secreted protein which is principally expressed in the superficial cells of gastric mucosa. In gastric cancer, TFF1 is downregulated and plays an important role. Gastrokine 1 (GKN1) is a secreted protein with similar expression and biological functions to TFF1. This study aimed to determine the expression and biological functions of TFF1 and the relationships between TFF1 and GKN1 in gastric cancer. RT-PCR and immunohistochemistry were performed to detect TFF1 expression in gastric cancer cell lines and tissues. The transfected and co-transfected AGS cells which stably expressed TFF1 or both TFF1 and GKN1 were generated. Phenotypic changes such as cell viability, apoptosis and cell cycle modulation were assayed in the transfected cells. We found that TFF1 expression was significantly downregulated or lost in gastric cancer cell lines, gastric dysplasia and cancer. Restoration of TFF1 expression in AGS cells suppressed tumor cell viability and arrested AGS cells in the G1-S transition phase after olomoucine treatment. However, TFF1 was unable to induce cell apoptosis. In co-transfected cells, we found that TFF1 and GKN1 did not directly interact at the protein level. GKN1 was unable to cooperate with TFF1 on cell viability suppression, cell apoptosis and differentiation. Together, these results indicate that TFF1 expression is significantly downregulated in gastric cancer. TFF1 inhibited cell proliferation by delaying G1-S phase transition but not by inducing apoptosis. TFF1 may not interact or cooperate with GKN1 at the protein and functional level. IntroductionGastric cancer is the second most common cause of cancer mortality worldwide (1-3). Although the molecular mechanisms of gastric cancer are still unclear, some molecular changes in the development of tumor were characterized. In recent studies, TFF1 is a spotlight molecule in gastric cancer. TFF1 is a 60-amino acid, highly conserved protein with a clover leaf-like structure formed by cysteine disulphide bonds and belongs to the trefoil factor family (4-6). TFF1 was found abundantly expressed in normal gastric mucosa. As a secreted protein, TFF1 protein was synthesized and secreted by the gastric epithelial cells and expressed in the upper part of the pits. In ulceration or inflammatory diseases, TFF1 induced epithelial restitution after injury and protects the integrity of the epithelial barrier (7-10). TFF1 was also involved in gastric carcinogenesis. In most gastric adenocarcinomas, the expression of TFF1 was downregulated or absent comparing to abundant in normal gastric mucosa (11,12). A previous study found that the TFF1-deficient mice were dysfunctional and showed severe hyperplasia and dysplasia, and all homozygous mutant mice developed antropyloric adenoma (13). Moreover, TFF1 demonstrated inhibition of cell growth and arrest of cell difference in gastric cancer (14,15). Thus, TFF1 is hypothesized as a tumor suppressor in gastric cancer. TFF1 was also involved in other human cancers such a...

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“…However, PPARγ agonists have been reported to foster ulcer healing [20] and protect against gastric ischemiareperfusion damage [19]. Possibly, the stimulating effect on gastric acid secretion is overridden by the simultaneous stimulating effect on trefoil factor expression [17], which are known to exert protective effects [18].…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, they may induce apoptosis [16]. In gastric tissue, PPARγ agonists stimulate expression of trefoil factors , which in turn exert protective effects [18]. Accordingly, activation of PPARγ by its agonists may protect against gastric ischemia reperfusion damage [19] and foster ulcer healing [20].…”

Section: Introductionmentioning

confidence: 99%

Pioglitazone Induced Gastric Acid Secretion

Rotte

Mack²,

Bhandaru³

et al. 2009

Cell Physiol Biochem

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PPARγ agonists, such as pioglitazone, are widely used in the treatment of diabetes and several further disorders. They enhance transcription of the serum and glucocorticoid inducible kinase SGK1, which could in turn enhance gastric acid secretion by stimulating KCNQ1 K⁺ channels. The present study explored whether pioglitazone upregulates SGK1 protein expression in gastric glands and thus modifies gastric acid secretion. Food containing the PPARγ agonist pioglitazone (approximately 25mg/kg bw/day) was administered to gene-targeted mice lacking SGK1 (sgk1^-/-, n=11) and their wild-type littermates (sgk1^+/+, n=11). Western blotting was employed to analyze SGK1 expression, BCECF-fluorescence to determine acid secretion in isolated gastric glands and immunohistochemistry to elucidate KCNQ1 and H⁺/K⁺-ATPase protein abundance in the parietal cell membrane. Pioglitazone significantly increased SGK1 expression. Cytosolic pH and cellular buffer capacity were not significantly different between sgk1^+/+and sgk1^-/- mice and not significantly modified in either genotype by pioglitazone. Without pioglitazone treatment, Na⁺-independent pH-recovery following an ammonium pulse (ΔpH/min) reflecting H⁺/K⁺-ATPase activity was again similar in sgk1^+/+and sgk1^-/- mice. Pioglitazone significantly increased ΔpH/min (≈3 fold) in sgk1^+/+ but not in sgk1^-/- mice. H⁺/K⁺-ATPase inhibitor omeprazole (100 μM) abolished ΔpH/min in both genotypes irrespective of pioglitazone treatment. Increase in local K⁺ concentrations to 35 mM (replacing Na⁺/NMDG) significantly increased ΔpH/min and abrogated the differences between genotypes. KCNQ1 and H⁺/K⁺-ATPase protein abundance in the parietal cell membrane was enhanced by pioglitazone treatment in sgk1^+/+but not in sgk1^-/- mice. In conclusion, pioglitazone increases gastric acid secretion, an effect at least partially due to stimulation of SGK1 expression and SGK1-dependent upregulation of KCNQ1.

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Cytokine Regulation of the Trefoil Factor Family Binding Protein GKN2 (GDDR/TFIZ1/blottin) in Human Gastrointestinal Epithelial Cells

Cited by 34 publications

References 62 publications

Biosynthesis of Gastrokine-2 in the Human Gastric Mucosa: Restricted Spatial Expression along the Antral Gland Axis and Differential Interaction with TFF1, TFF2 and Mucins

Biosynthesis of Gastrokine-2 in the Human Gastric Mucosa: Restricted Spatial Expression along the Antral Gland Axis and Differential Interaction with TFF1, TFF2 and Mucins

Role of trefoil factor 1 in gastric cancer and relationship between trefoil factor 1 and gastrokine 1

Pioglitazone Induced Gastric Acid Secretion

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