Multiple Protein Kinase Pathways Are Involved in Gastrin-releasing Peptide Receptor-regulated Secretion

Hellmich, Mark R.; Ives, Kirk L.; Udupi, Vidyavathi; Soloff, Melvyn S.; Greeley, George H.; Christensen, Burgess N.; Townsend, Courtney M.

doi:10.1074/jbc.274.34.23901

Cited by 60 publications

(54 citation statements)

References 46 publications

(39 reference statements)

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“…Involvement of Ca 2 þ /Cn signaling pathway in BBS-mediated upregulation of Cox-2 expression Agonist binding to GRP-R results in the rapid release of Ca 2 þ from inositol 1,4,5-triphosphate-sensitive stores (Hellmich et al, 1999). To test whether BBS induced an increase in [Ca 2 þ ] i , Caco-2 cells were loaded with the Ca 2 þ indicator dye Fura-2/AM and stimulated with BBS (100 nM) in the presence or absence of the BBS antagonist RC-3940-II.…”

Section: Resultsmentioning

confidence: 99%

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Bombesin induces cyclooxygenase-2 expression through the activation of the nuclear factor of activated T cells and enhances cell migration in Caco-2 colon carcinoma cells

et al. 2006

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Cyclooxygenase-2 (Cox-2), the gastrin-release peptide (GRP) and its cognate receptor (GRP-R) are overexpressed in a significant percentage of colorectal carcinomas and are associated with cell growth, invasiveness and tumor progression. However, a molecular link between all of them in adenocarcinomas has not been established. Here, we show that bombesin (BBS), a GRP homolog, stimulates the expression of Cox-2 mRNA and protein in human colon adenocarcinoma Caco-2 cells, resulting in enhanced release of prostaglandin E 2 . These effects were markedly inhibited by the specific BBS antagonist RC-3940-II. BBS promotes the activation of the nuclear factor of activated T cells (NFAT) through a Ca 2 þ /calcineurin (Cn)-linked pathway. Upon BBS stimulation, the NFATc1 isoform translocates into the nucleus with a concomitant increase in NFATc1 binding to two specific recognition sites in the promoter region of the Cox-2 gene. Furthermore, inhibition of Cn activity by the immunosuppressive drug cyclosporin A impaired NFAT activation and diminished Cox-2 expression in BBSstimulated cells. Interestingly, BBS pretreatment strongly enhances the invasive capacity of carcinoma cells, effect which was inhibited by a Cox-2-specific inhibitor. These findings provide the first evidence for the involvement of the Ca 2 þ /Cn/NFAT pathway in BBS-mediated induction of genes involved in colon carcinoma invasiveness such as Cox-2. Oncogene (2007) 26, 958-969.

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Section: Resultsmentioning

confidence: 99%

“…Agonist-induced changes in [Ca 2 þ ] i were detected using the Ca 2 þ -sensitive dye Fura-2/AM as described by Hellmich et al (1999). Briefly, cell monolayers at 80% confluence were trypsinized, washed and then loaded with 1 mM Fura-2/AM under continuous stirring for 30 min at 371C.…”

Section: Intracellular Calcium Measurementsmentioning

confidence: 99%

Bombesin induces cyclooxygenase-2 expression through the activation of the nuclear factor of activated T cells and enhances cell migration in Caco-2 colon carcinoma cells

et al. 2006

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“…When a cell is activated either by membrane depolarization or through a ligand-activated cell surface receptor such as CCK 2 of adenylyl cyclase and phospholipases (9,10). Several studies have documented the dependence of specific gene expression, secretion, and cell proliferation on the amplitude, duration, and spacial pattern of change in [Ca 2ϩ ] i (11,13,41). Dolmetsch and co-workers demonstrated the differential activation of the proinflammatory transcriptional regulator nuclear factor-B, c-Jun N-terminal kinase, and nuclear factor of activated T-cells in B lymphocytes when the amplitude and duration of change in [Ca 2ϩ ] i was manipulated with ionomycin and Ca 2ϩ chelator EGTA (11).…”

Section: Discussionmentioning

confidence: 99%

“…Small differences in the amplitude, duration, and/or temporal pattern of change in [Ca 2ϩ ] i can have profound effects on cell physiology, altering programs of gene expression (11,12), secretory activity (13), cell proliferation, and survival (14 -16). Calcium is an essential signaling molecule in G17-stimulated cell proliferation.…”

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confidence: 99%

Epidermal Growth Factor Potentiates Cholecystokinin/Gastrin Receptor-mediated Ca2+ Release by Activation of Mitogen-activated Protein Kinases

Olszewska-Pazdrak

Ives

Park

et al. 2004

Journal of Biological Chemistry

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2؉ ] i in the absence of G17. These data demonstrate that the activation state of the MEK1,2/ERK1,2 pathway can modulate the amplitude of the CCK 2 R-mediated Ca 2؉ release response and identify a novel mechanism for cross-talk between EGF receptor-and CCK 2 Rregulated signaling pathways.The gastrointestinal peptide hormone gastrin-(1-17) (G17) 1 plays an essential role in the regulation of digestion by stimulating gastric acid secretion, histamine synthesis and release, and proliferation of the gastric epithelium and endocrine pancreas (1, 2). In cancers of the stomach, pancreas, and colon, G17 promotes tumor cell proliferation, motility, and invasion (3-5). The biological effects of G17 are mediated by the cholecystokinin-2 (CCK 2 )/G17 receptor (CCK 2 R) (previously named CCK-B receptor), a member of the G protein-coupled receptor superfamily. Three splice variants of the CCK 2 R have been identified (6 -8) that bind the structurally related peptides cholecystokinin (CCK) and G17 with high affinities. An early event following agonist activation of CCK 2 R is the phospholipase C␤-mediated elaboration of inositol 1,4,5-triphosphate (6) from membrane phospholipids and the subsequent release of calcium (Ca 2ϩ ) from inositol 1,4,5-triphosphate-sensitive intracellular Ca 2ϩ stores.Calcium is an essential intracellular signal involved in many biological processes including fertilization, secretion, contraction, proliferation, differentiation, and apoptosis (9, 10). Small differences in the amplitude, duration, and/or temporal pattern of change in [Ca 2ϩ ] i can have profound effects on cell physiology, altering programs of gene expression (11, 12), secretory activity (13), cell proliferation, and survival (14 -16). Calcium is an essential signaling molecule in G17-stimulated cell proliferation. In Chinese hamster ovary cells expressing recombinant CCK 2 R, an agonist-induced increase in mitogen-activated protein kinase (MAPK) activity and [ 3 H]thymidine incorporation into DNA requires a slow oscillatory increase in [Ca 2ϩ ] i (17). In the rat pancreatic cancer cell line AR4-2J, a CCK 2 Rmediated increase in [Ca 2ϩ ] i is required for formation of the Shc-Grb2-Sos protein complex and subsequent activation of MAPK (18). Defining the molecular mechanisms involved in CCK 2 R regulation of [Ca 2ϩ ] i is necessary to understand the proliferative effects of G17 on normal and neoplastic cells.Like G17, epidermal growth factor (EGF) also stimulates the proliferation of gastric epithelial cells (19,20), and recently, the G17-related peptide CCK has been shown to synergize with EGF to stimulate DNA synthesis ([ 3 H]thymidine incorporation), cyclin-D3 expression, and retinoblastoma protein phosphorylation in cells expressing both CCK 2 R and EGF receptors (21). EGF and the related growth factors transforming growth factor-␣ and amphiregulin bind to a family of receptors known as type I receptor tyrosine kinases. This family is composed of four related receptors: the EGF receptor (EGFR/ErbB1/HER1), ErbB2 (HER2/neu), ErbB3 ...

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“…Moreover, we [22] found that the addition of 1-oleoyllysophosphatidic acid to rat ascites hepatoma cells resulted in an instantaneous increase in intracellular calcium, but when these cells were pretreated with the antimetastatic agent, ginsenoside Rg3, the intracellular calcium spike induced by 1-oleoyl-lysophosphatidic acid was completely abolished. Hellmich et al [23] found that bombesin induced either intracellular calcium oscillations or biphasic elevation in intracellular calcium, and that the activation of mitogen-activated protein kinase (MAPK) kinase (MEK) was important for maintaining the elevated intracellular calcium levels induced by bombesin. The MAPK-MEK cascade was closely related to the tumor cell invasion [24].…”

Section: Discussionmentioning

confidence: 99%

Induction by bombesin of peritoneal metastasis of gastric cancers induced by N -methyl- N ?-nitro- N -nitrosoguanidine in Wistar rats

et al. 2001

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Multiple Protein Kinase Pathways Are Involved in Gastrin-releasing Peptide Receptor-regulated Secretion

Abstract: Gastrin-releasing peptide (GRP) and its

Cited by 60 publications

References 46 publications

Bombesin induces cyclooxygenase-2 expression through the activation of the nuclear factor of activated T cells and enhances cell migration in Caco-2 colon carcinoma cells

Bombesin induces cyclooxygenase-2 expression through the activation of the nuclear factor of activated T cells and enhances cell migration in Caco-2 colon carcinoma cells

Epidermal Growth Factor Potentiates Cholecystokinin/Gastrin Receptor-mediated Ca2+ Release by Activation of Mitogen-activated Protein Kinases

Induction by bombesin of peritoneal metastasis of gastric cancers induced by N -methyl- N ?-nitro- N -nitrosoguanidine in Wistar rats

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