Gastrin regulates the heparin-binding epidermal-like growth factor promoter via a PKC/EGFR-dependent mechanism

Sinclair, Natalie; Ai, Wandong; Raychowdhury, Raktima; Bi, Meixia; Wang, Yichen; Koh, Theodore J.; McLaughlin, John

doi:10.1152/ajpgi.00206.2002

Cited by 39 publications

(37 citation statements)

References 30 publications

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“…It has been previously reported that H. pylori can induce an up-regulation in both HB-EGF gene expression and ectodomain shedding in human gastric cells (35,36). In addition, it has been shown that gastrin stimulation results in the up-regulation of the HB-EGF gene in gastric cells transfected with CCK-2R (37). We speculated that the presence of CCK-2R might render gastric cells more susceptible to H. pylori-induced HB-EGF gene and protein up-regulation.…”

Section: Resultsmentioning

confidence: 97%

Helicobacter pylori Can Induce Heparin-Binding Epidermal Growth Factor Expression via Gastrin and Its Receptor

Dickson¹,

Grabowska²,

El–Zaatari³

et al. 2006

Cancer Research

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Both gastrin and Helicobacter pylori have been shown capable of up-regulating gene expression and protein shedding of heparin-binding epidermal growth factor (HB-EGF). Furthermore, the bacteria have previously been shown to induce serum hypergastrinemia in infected individuals. The aim of this work was to assess the extent to which the ability of H. pylori to upregulate expression of HB-EGF can be attributed to its effect on gastrin. Gastric cells, transfected with either gastrin small interfering RNA or antisense plasmid or the gastrin/cholecystokinin-2 receptor (CCK-2R), were cultured for 24 hours with H. pylori +/À , a CCK-2R antagonist. Gene expression levels were measured using reverse transcription-PCR, whereas protein changes were measured using ELISA, Western blotting, and immunofluorescence. H. pylori induced significantly higher levels of HB-EGF gene expression and ectodomain shedding in the CCK-2R-transfected cells than the vector control (P < 0.01). Addition of the CCK-2R inhibitor significantly decreased gene and shedding up-regulation. Gastrin down-regulation reduced the effect of the bacteria on HB-EGF gene and protein expression levels. Endogenous gastrin and CCK-2R expression were also found to be significantly up-regulated in all cell lines as a result of exposure to H. pylori (P < 0.02). Gastric mucosal tissue from H. pylori-infected individuals had significantly higher CCK-2R expression levels than noninfected (P < 0.003), and in hypergastrinemic mice, there was an increase in HB-EGF-expressing cells in the gastric mucosa and colocalization of HB-EGF with CCK-2R-positive enterochromaffin-like cells. In conclusion, gastrin and the CCK-2R play significant roles in the induction of HB-EGF gene and protein expression and ectodomain shedding by H. pylori. (Cancer Res 2006; 66(15): 7524-31)

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Section: Resultsmentioning

confidence: 97%

Helicobacter pylori Can Induce Heparin-Binding Epidermal Growth Factor Expression via Gastrin and Its Receptor

Dickson¹,

Grabowska²,

El–Zaatari³

et al. 2006

Cancer Research

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“…This mechanism involves transactivation of the epidermal growth factor (EGF) receptor. In gastric epithelial cells, gastrin induces the expression and processing of proHB-EGF leading to the release of HB-EGF, tyrosine phosphorylation of EGF receptors and the subsequent activation of downstream signaling pathways (327,475). In contrast, gastrin induces EGF receptor transactivation in intestinal cells via an intracellular signaling pathway mediated by Src family kinases (191).…”

Section: Mitogen-activated Kinase Cascadesmentioning

confidence: 99%

“…In these cells, the mechanism by which CCK2R induces HB-EGF gene transcription involves activation of PKCs and the EGF receptor and requires a GC-rich region of the promoter (475).…”

Section: Target Genes Of Cholecystokinin Receptors a Gastrin-depementioning

confidence: 99%

Cholecystokinin and Gastrin Receptors

Dufresne

Seva²,

Fourmy³

2006

Physiological Reviews

417

418

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Cholecystokinin and gastrin receptors (CCK1R and CCK2R) are G protein-coupled receptors that have been the subject of intensive research in the last 10 years with corresponding advances in the understanding of their functioning and physiology. In this review, we first describe general properties of the receptors, such as the different signaling pathways used to exert short- and long-term effects and the structural data that explain their binding properties, activation, and regulation. We then focus on peripheral cholecystokinin receptors by describing their tissue distribution and physiological actions. Finally, pathophysiological peripheral actions of cholecystokinin receptors and their relevance in clinical disorders are reviewed.

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“…Importantly, much emphasis has been placed on the ability of gastrin to both up-regulate ligands of the epidermal growth factor (EGF) receptor, in particular amphiregulin and heparin-binding EGF-like growth factor (HB-EGF; refs. [16][17][18]. The effect of gastrin on both the shedding of EGF receptor growth factors and related downstream signaling pathways has received particular attention.…”

Section: Introductionmentioning

confidence: 99%

Gastrin Enhances the Angiogenic Potential of Endothelial Cells via Modulation of Heparin-Binding Epidermal-Like Growth Factor

et al. 2006

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This study examined whether gastrin modulates endothelial cell activity via heparin-binding epidermal growth factor-like growth factor (HB-EGF) expression. Human umbilical vascular endothelial cells (HUVEC) were assessed for tubule formation in the presence of amidated gastrin-17 (G17) and glycineextended gastrin-17 (GlyG17) peptides. HB-EGF gene and protein expressions were measured by quantitative reverse transcription-PCR, immunocytochemistry, and Western blotting, and HB-EGF shedding by ELISA. Matrix metalloproteinases MMP-2, MMP-3, and MMP-9 were assessed by Western blotting. Chick chorioallantoic membrane studies measured the in vivo angiogenic potential of gastrin and microvessel density (MVD) was assessed in large intestinal premalignant lesions of hypergastrinaemic APC Min mice. MVD was also examined in human colorectal tumor and resection margin normals and correlated with serum-amidated gastrin levels (via RIA) and HB-EGF protein expression (via immunohistochemistry). HUVEC cells showed increased tubule and node formation in response to G17 (186%, P < 0.0005) and GlyG17 (194%, P < 0.0005). This was blockaded by the cholecystokinin-2 receptor (CCK-2R) antagonists JB95008 and JMV1155 and by antiserum to gastrin and HB-EGF. Gastrin peptides increased HB-EGF gene expression/protein secretion in HUVEC and microvessel-derived endothelial cells and the levels of MMP-2, MMP-3, and MMP-9. G17 promoted angiogenesis in a chorioallantoic membrane assay, and MVD was significantly elevated in premalignant large intestinal tissue from hypergastrinaemic APC Min mice. In terms of the clinical situation, MVD in the normal mucosa surrounding colorectal adenocarcinomas correlated with patient serum gastrin levels and HB-EGF expression. Gastrin peptides, acting through the CCK-2R, enhance endothelial cell activity in models of angiogenesis. This may be mediated through enhanced expression and shedding of HB-EGF, possibly resulting from increased activity of matrix metalloproteinases. This proangiogenic effect translates to the in vivo and human situations and may add to the tumorigenic properties attributable to gastrin peptides in malignancy. (Cancer Res 2006; 66(7): 3504-12)

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Gastrin regulates the heparin-binding epidermal-like growth factor promoter via a PKC/EGFR-dependent mechanism

Cited by 39 publications

References 30 publications

Helicobacter pylori Can Induce Heparin-Binding Epidermal Growth Factor Expression via Gastrin and Its Receptor

Helicobacter pylori Can Induce Heparin-Binding Epidermal Growth Factor Expression via Gastrin and Its Receptor

Cholecystokinin and Gastrin Receptors

Gastrin Enhances the Angiogenic Potential of Endothelial Cells via Modulation of Heparin-Binding Epidermal-Like Growth Factor

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