Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01350 (gastrin)
 9,683 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of self-phosphorylation on the protein-tyrosine kinase activity of the epidermal growth factor receptor has been investigated using immunoaffinity-purified protein. Enzyme was first incubated for various times with excess ATP to phosphorylate it to differing extents; the ability of the enzyme to phosphorylate exogenous peptide substrates was then measured as a function of its self-phosphorylation state. Increasing self-phosphorylation to 1.3-1.8 mol of phosphate mol-1 of epidermal growth factor receptor enhanced protein-tyrosine kinase activity 2-3-fold. Comparison of the kinetics of protein-tyrosine kinase activity at different ATP concentrations revealed significant differences between unphosphorylated and phosphorylated enzyme. At low levels of ATP, a double reciprocal plot of the protein-tyrosine kinase activity of the unphosphorylated enzyme was hyperbolic, suggesting that ATP may act as an activator of the enzyme. At higher ATP concentrations, where greater levels of self-phosphorylation occurred during the reaction, the kinetics appeared linear and similar to those of the phosphorylated enzyme. Dose-response studies using three different peptide substrates (angiotensin II, gastrin, and a synthetic peptide corresponding to the self-phosphorylation site in p60v-src) showed that exogenous substrates inhibit receptor self-phosphorylation. In each case, half-maximal inhibition was observed at a peptide concentration approximately equal to the substrate's Km. A kinetic analysis comparing peptide phosphorylation using unphosphorylated and prephosphorylated enzyme indicated that the self-phosphorylation site can act as a competitive inhibitor (alternate substrate) versus peptide substrates. These results suggest that self-phosphorylation of the epidermal growth factor receptor removes a competitive constraint so that exogenous substrates can be more readily phosphorylated.
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PMID:Self-phosphorylation enhances the protein-tyrosine kinase activity of the epidermal growth factor receptor. 299 17

Gastrin is transcriptionally responsive to EGF stimulation (Merchant et al., 1991, Mol. Cell. Biol., 11:2686-2696). Consequently, we hypothesized that previously recognized gastrin autocrine loops (Hoosein et al., 1990, Exp. Cell. Res., 186:15-21), might be controlled by autocrine TGF alpha in human colon carcinoma cells. Therefore, we examined the interaction between these two autocrine growth factors in two colon carcinoma cell lines which utilize TGF alpha. The FET cell line requires exogenous TGF alpha/EGF for optimal growth and has a classical TGF alpha autocrine loop which is disrupted by TGF alpha or epidermal growth factor receptor (EGFr) antibodies. The HCT 116 cell line is not dependent on exogenous TGF alpha/EGF and exhibits a nonclassical TGF alpha autocrine loop which is not disrupted by neutralizing antibodies to either TGF alpha itself or the EGFr. Basal gastrin mRNA production is significantly higher in HCT 116 than FET as measured by RNase protection assay. In the FET cells, exogenous EGF stimulates gastrin mRNA production but not in HCT 116. When the TGF alpha autocrine loop in HCT 116 is disrupted by constitutive expression of antisense TGF alpha mRNA, the gastrin mRNA level is significantly repressed. In xenografts derived from these antisense clones, TGF alpha reverted to high expression, and the gastrin mRNA level was again increased. This interaction between the strong TGF alpha loop in HCT 116 and the gastrin autocrine loop may confer a growth advantage to these colon cells. Such interactions between growth factors may promote enhanced tumorigenicity to transformed cells with these strong, nonclassical autocrine loops.
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PMID:Regulation of autocrine gastrin expression by the TGF alpha autocrine loop. 782 34

This study was designed to localize transforming growth factor alpha (TGF-alpha) and epidermal growth factor receptor (EGFR) expression in the developing human gastrointestinal tract and pancreas. Immunohistochemical techniques using specific antibodies against human TGF-alpha and EGFR were performed on digestive tissues of fetuses from 9 to 10 to 24 weeks of gestation, children and adults. In fetuses, TGF-alpha and EGFR proteins were expressed in all epithelial tissues studied with a good correlation and from an age as early as 9 to 10 weeks of gestation, except for TGF-alpha in the esophagus. The strongest TGF-alpha immunostaining was noted in the stomach and the proximal colon. Unexpectedly, immunoreactive gut endocrine cells were observed with the two antibodies used. Relatively numerous in fetuses, they decreased in number with age and were rare in adults particularly along the colon. Enteroglucagonsecreting cells were shown to express TGF-alpha, while some gastrin, somatostatin and pancreatic glucagon cells were immunostained with EGFR antibodies. The presence of TGF-alpha and its receptor in digestive tract epithelium and pancreatic tissues early in fetal life suggests a functional role for TGF-alpha during the developmental process of the digestive system. We demonstrate that TGF-alpha is also produced by endocrine cells and might have an additional mode of action other than paracrine, at least during fetal life.
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PMID:Developmental expression of transforming growth factor-alpha and epidermal growth factor receptor proteins in the human pancreas and digestive tract. 785 Aug 55

Transforming growth factor-alpha (TGF-alpha), a potent growth factor belonging to the epidermal growth factor family, exerts its role in the proliferation and differentiation of normal and neoplastic cells by binding to epidermal growth factor receptor (EGFR). Coexpression of TGF-alpha and EGFR in carcinomas is believed to confer growth advantage to tumor cells. To evaluate their role in such indolent tumors as gastrointestinal (GI) carcinoids, we investigated the immunohistochemical expression of TGF-alpha and EGFR in 25 GI carcinoids (nine foregut, 13 midgut, and three hindgut) and studied the correlation of their expression with the secretory and clinicopathologic profiles of these tumors. TGF-alpha was expressed in 18 (72%) of these tumors, and whereas 16 of 17 tumors showed immunopositivity for the extracellular domain of EGFR, none expressed its intracellular domain. Ten TGF-alpha-positive tumors were positive for serotonin, seven for somatostatin, three for calcitonin, and one tumor each for gastrin, glucagon, pancreatic polypeptide, vasoactive intestinal peptide, and growth hormone-releasing factor, respectively. Seven TGF-alpha-positive tumors were multihormonal, eight were monohormonal, and three were completely nonreactive for the regulatory substances studied. Except for its correlation with 5-hydroxytryptamine (serotonin) expression by the tumor cells, expression of TGF-alpha showed no significant association with other pathologic attributes, for example, the site of origin, size, depth of intramural penetration, metastases, and the secretory profiles of the tumors. These findings indicate that although TGF-alpha is expressed by a high proportion of GI carcinoids, the absence of its intact receptor molecule (EGFR) on the tumor cells renders it functionally ineffective as a growth factor. Thus, unlike in carcinomas of the GI tract, TGF-alpha appears to play no role in the growth and progression of GI carcinoids, which perhaps explains the indolent behavior and slow biological progression of GI carcinoids.
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PMID:Immunohistochemical expression of transforming growth factor alpha and epidermal growth factor receptor in gastrointestinal carcinoids. 906 Jun 3

Oxidant stress is thought to play a role in the pathogenesis of many gastric disorders. We have recently reported that histidine decarboxylase (HDC) promoter activity is stimulated by gastrin through a protein kinase C- and extracellular signal-regulating kinase (ERK)-dependent pathway in gastric cancer (AGS-B) cells, and this transcriptional response is mediated by a downstream cis-acting element, the gastrin response element (GAS-RE). To study the mechanism through which oxidant stress affects gastric cells, we examined the effects of hydrogen peroxide (H2O2) on HDC promoter activity and intracellular signaling in AGS-B cells. H2O2 (10 mM) specifically activated the HDC promoter 10-12-fold, and this activation was blocked by both mannitol and N-acetylcysteine. Hydrogen peroxide treatment of AGS-B cells increased the phosphorylation and kinase activity of ERK-1 and ERK-2, but did not affect Jun kinase tyrosine phosphorylation or kinase activity. In addition, treatment of AGS-B cells with H2O2 resulted in increased c-fos/c-jun mRNA expression and AP-1 activity, and also led to increased phosphorylation of epidermal growth factor receptor (EGFR) and Shc. H2O2-dependent stimulation of HDC promoter activity was completely inhibited by kinase-deficient ERKs, dominant-negative (N17 and N15) Ras, and dominant-negative Raf, and partially blocked by a dominant-negative EGFR mutant. In contrast, protein kinase C blockade did not inhibit H2O2-dependent induction of the HDC promoter. Finally, deletion analysis demonstrated that the H2O2 response element could be mapped to the GAS-RE (nucleotides 2 to 24) of the basal HDC promoter. Overall, these studies suggest that oxidant stress activates the HDC promoter through the GAS-RE, and through an Ras-, Raf-, and ERK-dependent pathway at least partially involving the EGFR.
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PMID:Oxidative stress activates the human histidine decarboxylase promoter in AGS gastric cancer cells. 972 30

Enterochromaffin-like (ECL) cells are histamine-containing endocrine cells in the gastric epithelium that show increased density during chronic atrophic gastritis. The current study determined cell number and apoptosis of isolated rat ECL cells in response to several growth factors. Isolated ECL cells from fundic mucosa (enrichment >90%) were grown in serum-free medium over 2-5 days. Cell number was determined by mitochondrial formazan production; apoptosis was measured by Tdt-mediated dUTP nick end labeling reaction and DNA fragmentation-based enzyme-linked immunosorbent assay. Immunocytochemistry and RT-PCR demonstrated the presence of epidermal growth factor receptor, neuronal growth factor receptor (type 1), and fibroblast growth factor (FGF) receptor (type 1). Gastrin (EC50, approximately 2 pM), transforming growth factor-alpha (TGF alpha; 10-30 ng/ml), and basic FGF (bFGF; 1-10 ng/ml) increased the total number of cultured ECL cells. bFGF augmented the gastrin (1 pM)-induced response. Beta-neuronal growth factor (10 ng/ml) and bFGF (2 ng/ml) decreased the programed death of ECL cells. Interleukin-1beta (100 pg/ml, 24 h) stimulated apoptosis 2- to 3-fold in ECL cells, and simultaneous incubation with TGF alpha (20 ng/ml) or bFGF (2 ng/ml) significantly inhibited this effect. ECL cells express specific receptors for gastrin, epidermal growth factor, neuronal growth factor, and FGF. bFGF prolonged ECL cell survival by inhibiting spontaneous apoptosis. Our data further indicate that TGF alpha and bFGF increase ECL cell number by inhibiting cytokine-induced programed cell death.
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PMID:Growth factor effects on apoptosis of rat gastric enterochromaffin-like cells. 975 22

Gastrin is a hormone produced by G-cells in the normal gastric antrum. However, colorectal carcinoma cells may aberrantly produce gastrin and exhibit increased expression of cholecystokinin B (CCK-B)/gastrin receptors. Gastrin is trophic for the normal gastric oxyntic mucosa and exerts a growth-promoting action on gastrointestinal malignancy. Thus, gastrin may act as an autocrine/paracrine or endocrine factor in the initiation and progression of colorectal carcinoma. The molecular mechanisms involved have not been elucidated. Hypergastrinemia induced by Helicobacter pylori infection is associated with increased cyclooxygenase-2 (COX-2) expression in gastric and colorectal tissues, suggesting the possibility that gastrin up-regulates COX-2 expression in these tissues; this has not been confirmed. We report here that gastrin significantly increases the expression of COX-2 mRNA and protein, the activity of the COX-2 promoter, and the release of prostaglandin E(2) from a rat intestinal epithelial cell line transfected with the CCK-B receptor. These actions were dependent upon the activation of multiple MAPK signal pathways, including ERK5 kinase; transactivation of the epidermal growth factor receptor; and the increased expression and activities of transcription factors ELK-1, activating transcription factor-2, c-Fos, c-Jun, activator protein-1, and myocyte enhancer factor-2. Thus, our findings identify the signaling pathways coupling the CCK-B receptor with up-regulation of COX-2 expression. This effect may contribute to this hormone-dependent gastrointestinal carcinogenesis, especially in the colon.
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PMID:Gastrin stimulates cyclooxygenase-2 expression in intestinal epithelial cells through multiple signaling pathways. Evidence for involvement of ERK5 kinase and transactivation of the epidermal growth factor receptor. 1223 23

Gastrointestinal peptides including mammalian bombesin-like peptides, cholecystokinin (CCK), gastrin, and neurotensin stimulate DNA synthesis and cell proliferation in cultured cells and are implicated as growth factors in a number of fundamental processes including development, inflammation, tissue regeneration, and neoplastic transformation. These agonists bind to G protein-coupled receptors (GPCRs) that promote Galpha q-mediated activation of beta isoforms of phospholipase C to produce two second messengers: Inositol (1,4,5) trisphosphate {Ins (1, 4, 5) P3} that mobilises Ca2+ from internal stores, and diacylglycerol that activates the classic and new isoforms of the protein kinase C (PKC) family. PKCs play a critical part in transducing bombesin/gastrin releasing peptide (GRP) receptor signals into activation of protein kinase cascades. Protein kinase D (PKD), a serine/threonine protein kinase with distinct structural and enzymological properties, is activated by phosphorylation in living cells through a new PKC-dependent signal transduction pathway. GPCR agonists including bombesin/GRP induce a rapid and striking activation of PKD by PKC. These results indicate that PKD functions downstream from PKCs and identify a new phosphorylation cascade that is activated by gastrointestinal peptide agonists. The bombesin/GRP GPCR also promotes rapid Rho-dependent assembly of focal adhesions, formation of actin stress fibres and tyrosine phosphorylation of multiple cellular proteins. We identified p125 focal adhesion kinase (FAK), p130 Crk-associated substrate (CAS) and paxillin as prominent targets of gastrointestinal peptide-stimulated tyrosine phosphorylation and developed a model that envisages a G12/Rho-dependent pathway connecting GPCR activation to the tyrosine phosphorylation of these focal adhesion proteins. Separate pathways mediate gastrointestinal peptide stimulation of additional tyrosine kinase pathways including transactivation of Src and epidermal growth factor receptor (EGFR). Tyrosine phosphorylation has a critical role in gastrointestinal peptide-induced cellular migration and cooperates with Gq-stimulated events to promote mitogenesis. The growth-promoting effects of neuropeptides and the elucidation of the signalling pathways that mediate their effects assume an added importance because these agonists and their receptors are increasingly implicated in sustaining the proliferation of clinically aggressive solid tumours including those from lung, pancreas, and colon.
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PMID:Gastrointestinal peptide signalling in health and disease. 1614 98

The immunoglobulin molecule contains structural features that make it a powerful tool for cancer therapy (eg, an extremely high specificity and binding affinity for the target molecule that results in low toxicity). Several approaches have been used: monoclonal antibodies targeting a ligand (eg, bevacizumab, anti-vascular endothelial growth factor), monoclonal antibodies targeting a receptor (eg, cetuximab, anti-epidermal growth factor receptor), vaccines targeting a ligand (eg, G17DT, anti-gastrin), or a cell surface antigen (eg, carcinoembryonic antigen-TRIad of COstimulatory Molecules, anti-CEA). Another approach attempts to harness the cellular arm of the immune response (ie, cytotoxic T cells, natural killer cells) for specific killing of tumor cells. The putative underlying mechanism of antibody strategy is the inhibition of intracellular signaling pathways and induction of apoptosis. Clinical evidence suggests that while most of these antibodies achieve limited antitumor activity as monotherapy, they are significantly more efficacious than single agents when combined with chemotherapy. Future use of these agents will include optimized combination chemotherapy/immunotherapy regimens as well as monoclonal antibodies conjugated to cytotoxic molecules and radionuclides.
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PMID:Vaccines and monoclonal antibodies. 1639 39

Peroxisome proliferators-activated receptor gamma (PPARgamma) has been shown to suppress cell proliferation and tumorigenesis, whereas the gastrointestinal regulatory peptide gastrin stimulates the growth of neoplastic cells. The present studies were directed to determine whether changes in PPARgamma expression might mediate the effects of gastrin on the proliferation of colorectal cancer (CRC). Initially, using growth assays, we determined that the human CRC cell line DLD-1 expressed both functional PPARgamma and gastrin receptors. Amidated gastrin (G-17) attenuated the growth suppressing effects of PPARgamma by decreasing PPARgamma activity and total protein expression, in part through an increase in the rate of proteasomal degradation. G-17-induced degradation of PPARgamma appeared to be mediated through phosphorylation of PPARgamma at serine 84 by a process involving the biphasic phosphorylation of ERK1/2 and activation of the epidermal growth factor receptor (EGFR). These results were confirmed through the use of EGFR antagonist AG1478 and MEK1 inhibitor PD98059. Furthermore, mutation of PPARgamma at serine 84 reduced the effects of G-17, as evident by inability of G-17 to attenuate PPARgamma promoter activity, degrade PPARgamma, or inhibit the growth suppressing effects of PPARgamma. The results of these studies demonstrate that the trophic properties of gastrin in CRC may be mediated in part by transactivation of the EGFR and phosphorylation of ERK1/2, leading to degradation of PPARgamma protein and a decrease in PPARgamma activation.
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PMID:Attenuation of peroxisome proliferator-activated receptor gamma (PPARgamma) mediates gastrin-stimulated colorectal cancer cell proliferation. 1657 47


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