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

An important role for beta-catenin pathways in colorectal carcinogenesis was first suggested by the protein's association with adenomatous polyposis coli (APC) protein, and by evidence of dysregulation of beta-catenin protein expression at all stages of the adenoma-carcinoma sequence. Recent studies have, however, shown that yet more components of colorectal carcinogenesis are linked to beta-catenin pathways. Pro-oncogenic factors that also release beta-catenin from the adherens complex and/or encourage translocation to the nucleus include ras, epidermal growth factor (EGF), c-erbB-2, PKC-betaII, MUC1, and PPAR-gamma, whereas anti-oncogenic factors that also inhibit nuclear beta-catenin signaling include transforming growth factor (TGF)-beta, retinoic acid, and vitamin D. Association of nuclear beta-catenin with the T cell factor (TCF)/lymphoid enhancer factor (LEF) family of transcription factors promotes the expression of several compounds that have important roles in the development and progression of colorectal carcinoma, namely: c-myc, cyclin D1, gastrin, cyclooxygenase (COX)-2, matrix metalloproteinase (MMP)-7, urokinase-type plasminogen activator receptor (aPAR), CD44 proteins, and P-glycoprotein. Finally, genetic aberrations of several components of the beta-catenin pathways, eg, Frizzled (Frz), AXIN, and TCF-4, may potentially contribute to colorectal carcinogenesis. In discussing the above interactions, this review demonstrates that beta-catenin represents a key molecule in the development of colorectal carcinoma.
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PMID:Beta-catenin--a linchpin in colorectal carcinogenesis? 1183 57

In the accompanying study, we show how retroviral tropism can be redirected by insertion of short peptide ligands at multiple locations in envelope. Here we use this approach to selectively target and destroy human cancer cells. Many cancer cells overexpress specific cell surface receptors. We have generated Moloney murine leukemia virus (MLV) envelope derivatives bearing short peptide ligands for gastrin-releasing protein (GRP) and human epidermal growth factor receptors. Pseudotyped viruses containing these chimeric envelope derivatives selectively transduce human cancer cell lines that overexpress the cognate receptor. A retrovirus targeting the GRP receptor can deliver the thymidine kinase gene to human melanoma and breast cancer cells, which are killed by the subsequent addition of ganciclovir. Collectively, our results demonstrate that short peptide ligands inserted at appropriate locations in MLV envelope can selectively target retroviruses to human cancer cells and deliver a therapeutically relevant gene.
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PMID:Selective targeting and inducible destruction of human cancer cells by retroviruses with envelope proteins bearing short peptide ligands. 1188 81

The exocrine pancreatic cell line AR42J is also known to display some neuroendocrine (NE) features. We have extended this fact by showing that AR42J cells express mRNA of chromogranin A (CgA), display immunoreactivity (IR) to CgA, and secrete its cleavage product pancreastatin. A sparse occurrence of typical NE secretion granules, together with only a faint IR to conventional NE markers, indicates that the NE cells are of a poorly differentiated type. CgA promoter reporter plasmid experiments showed that gastrin, epidermal growth factor, and phorbol 12-myristate 13-acetate, induce upregulation of CgA after 24 h. By RT-PCR, it was found that AR42J expresses all of the five subtypes of the somatostatin (SST) receptor (SSTR) family, except SSTR4. The existence of functional SSTRs was confirmed by showing that the SST analog octreotide could inhibit gastrin-induced proliferation. Thus, the AR42J cell line may function as a valuable experimental model to study the regulation of CgA and SSTRs in poorly differentiated NE tumor cells.
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PMID:Expression of chromogranin A and somatostatin receptors in pancreatic AR42J cells. 1224 39

The conjugation of doxorubicin with [D-Lys6] Luteinizing Hormone-Releasing Hormone (LH-RH), yields AN-152, a cytotoxic analog that can be targeted to tumor cells expressing LH-RH receptors. This conjugate is more potent against LH-RH receptor positive cancer cells and has less peripheral toxicity than free doxorubicin. The proliferation of MCF-7 human breast cancer cells in vitro is inhibited by AN-152 and this effect can be augmented by the up-regulation of LH-RH receptor expression through stimulation of tyrosine phosphorylation with epidermal growth factor (EGF). Bombesin and gastrin releasing peptide increase tyrosine phosphorylation and can act synergistically with EGF, as well as independently. The aim of this study was to demonstrate that bombesin enhances cytotoxic sensitivity of MCF-7 cells to AN-152 and that a significantly higher efficacy of the drug can be achieved in cells exposed to both bombesin and EGF. The cells were pretreated with bombesin and/or EGF, and then exposed to 0-10 micro M AN-152 for 96 h for determination of cytotoxicity. In addition, cells pretreated with bombesin and/or EGF were exposed for 1 h to 0.6 micro M AN-152 labeled with a two-photon fluorophore (AN-152:C625) for fluorescent imaging of drug entry. Bombesin as well as EGF increased the uptake and cytotoxicity of AN-152 in MCF-7 cells. The exposure of the cells to both EGF and bombesin produces a synergistic effect and results in increased cellular entry and cytotoxicity of AN-152. These results suggest that the activation of LH-RH receptors by compounds that increase tyrosine phosphorylation could further improve the response to targeted chemotherapy with AN-152.
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PMID:Bombesin and epidermal growth factor potentiate the effect of cytotoxic LH-RH analog AN-152 in vitro. 1242 84

Small differences in amplitude, duration, and temporal patterns of change in the concentration of free intracellular Ca2+ ([Ca2+](i)) can profoundly affect cell physiology, altering programs of gene expression, cell proliferation, secretory activity, and cell survival. We report a novel mechanism for amplitude modulation of [Ca2+](i) that involves mitogen-activated protein kinase (MAPK). We show that epidermal growth factor (EGF) potentiates gastrin-(1-17) (G17)-stimulated Ca2+ release from intracellular Ca2+ stores through a MAPK-dependent pathway. G17 activation of the cholecystokinin/gastrin receptor (CCK(2)R), a G protein-coupled receptor, stimulates release of Ca2+ from inositol 1,4,5-triphosphate-sensitive Ca2+ stores. Pretreating rat intestinal epithelial cells expressing CCK(2)R with EGF increased the level of G17-stimulated Ca2+ release from intracellular stores. The stimulatory effect of EGF on CCK(2)R-mediated Ca2+ release requires activation of the MAPK kinase (MEK)1,2/extracellular signal-regulated kinase (ERK)1,2 pathway. Inhibition of the MEK1,2/ERK1,2 pathway by either serum starvation or treatment with selective MEK1,2 inhibitors PD98059 and U0126 or expression of a dominant-negative mutant form of MEK1 decreased the amplitude of the G17-stimulated Ca2+ release response. Activation of the MEK1,2/ERK1,2 pathway either by pretreating cells with EGF or by expression of constitutively active K-ras (K-rasV12G) or MEK1 (MEK1*) increased the amplitude of G17-stimulated Ca2+ release. Although EGF, MEK1*, and K-rasV12G activated the MEK1,2/ERK1,2 pathway, they did not increase [Ca2+](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 Ca2+ release response and identify a novel mechanism for cross-talk between EGF receptor- and CCK(2)R-regulated signaling pathways.
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PMID:Epidermal growth factor potentiates cholecystokinin/gastrin receptor-mediated Ca2+ release by activation of mitogen-activated protein kinases. 1460 17

At the turn of XIX and XX century, the principal concept explaining the mechanism of secretory activity of the digestive glands was nervism proposed by I. P. Pavlov at Russian physiological school in St Petersburg, and this dogma was widely recognized for several years in other countries. The discovery of secretin in 1902 by W.B. Bayliss and E.H. Starling, and then of gastrin in 1906 by J.S. Edkins, emphasized the hormonal regulation of pancreatic and gastric secretion, respectively. In 1943, A.C. Ivy and E. Olberg discovered a hormone, which contracts the gallbladder - cholecystokinin (CCK), while A. Harper and H.S. Raper described another hormone, pancreozymin, which stimulated pancreatic enzymes. It required over twenty years, however, for these and many other hormones to be identified, purified and synthesized due to the extensive work of several teams including R. Gregory, G. Dockray and Kenner of the UK; J. Rehfeld of Denmark and E. Wunsch of Germany for their work on gastrin; E. Jorpes and V. Mutt of Sweden and N. Yahaihara of Japan for their work on secretin and other GI hormones including, CCK, vasoactive intestinal peptide (VIP), gastric inhibitory peptide (GIP), motilin, gastrin-releasing peptide (GRP) and others peptides. CCK and pancreaozymin were found by E. Jorpes and V. Mutt to represent structurally a common messenger for pancreatico-biliary secretion. This rapid development of GI endocrinology in the 1960s and 1970s could be attributed to the application of peptide biochemistry in characterizing various peptide hormones. The technique of radioimmunoassay by S.A. Berson and R.S. Yalow in 1959 measured minute amounts of hormones in the circulation and tissue, and the technique of immunocytochemistry detected the cellular origin of these hormones. Further progress in molecular biology led to sequencing GI hormones and their prohormones, and opened a new area of investigation for the physiological role of these hormones in the mechanism of digestive gland secretion, motility of gastrointestinal tract, visceral blood flow, tissue growth and integrity in health, as well as in various digestive diseases. Overall, apparent divergent concepts, the nervous control (Pavlov) and hormonal control (Bayliss and Starling), greatly facilitated the elucidation of the interacting neurohormones during the cephalic, gastric, and intestinal phases of gastric and pancreatic secretion in health and digestive diseases. Although Polish contributions in the early phase of GI endocrinology concerned mostly gastric inhibitory hormones such as enterogastrone and urogastrone, major Polish traces can be detected in the elucidation of origin and physiological role and pathological involvement of gastrin, CCK, secretin, motilin, gastric inhibitory peptide and the most recent additions of enterohormones such as epidermal growth factor, somatostatin, leptin or ghrelin. Major achievements have been obtained in gastric and colorectal cancerogenesis involving gastrin and its precursor, progastrin.
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PMID:The history of gastrointestinal hormones and the Polish contribution to elucidation of their biology and relation to nervous system. 1507 66

Cancers of the stomach, colon and exocrine pancreas are major international health problems and result in more than a million deaths worldwide each year. The therapies for these malignancies must be improved. The effects of gastrointestinal (GI) hormonal peptides and endogenous growth factors on these cancers were reviewed. Some GI peptides, including gastrin and gastrin-releasing peptide (GRP) (mammalian bombesin), appear to be involved in the growth of neoplasms of the GI tract. Certain growth factors such as insulin-like growth factor (IGF)-I, IGF-II and epidermal growth factor and their receptors that regulate cell proliferation are also implicated in the development and progression of GI cancers. Experimental investigations on gastric, colorectal and pancreatic cancers with analogs of somatostatin, antagonists of bombesin/GRP, antagonists of growth hormone-releasing hormone as well as cytotoxic peptides that can be targeted to peptide receptors on tumors were summarized. Clinical trials on peptide analogs in patients with gastric, colorectal and pancreatic cancers were reviewed and analyzed. It may be possible to develop new approaches to hormonal therapy of GI malignancies based on various peptide analogs.
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PMID:New approaches to therapy of cancers of the stomach, colon and pancreas based on peptide analogs. 1511 52

The hormone gastrin stimulates proliferation of the gastric mucosa. Inflammation of the stomach is also associated with increased proliferation. The proliferative response is important in the reparative response to injury but can be deleterious by predisposing to the development of cancer. Parietal cells, but not the cells in the proliferative zone of the gastric glands, express the appropriate gastrin receptor. Parietal cells may mediate the trophic effects of gastrin by secreting other growth factors. The role of parietal cells in the proliferative responses has been examined in this study. Rabbit parietal cells were cultured with gastrin or the cytokine interleukin-1beta for 18 hours. The conditioned medium from gastrin or IL-1beta stimulated parietal cells increased proliferation of HeLa cells in an epidermal growth factor-receptor dependant manner. Gastrin and IL-1beta stimulated the secretion of heparin-binding epidermal growth factor and amphiregulin but not transforming growth factor-alpha from parietal cells. Combinations of gastrin and IL-1beta on growth factor secretion were synergistic. The protein kinase C inhibitor staurosporine abolished these stimulatory effects of gastrin and IL-1beta. Divergent effects on histamine-stimulated acid secretion were observed; 18 hours pre-treatment with gastrin enhanced acid secretion by 50% but IL-1beta inhibited acid secretion in both control and gastrin pre-treated parietal cells. The acid-secreting parietal cell plays a central role in the regulation of mucosal proliferation in gastric inflammation. Secretion of paracrine growth factors by parietal cells may be an important point of integration between the endocrine and inflammatory stimuli in determining mucosal responses to injury and inflammation.
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PMID:Gastrin and interleukin-1beta stimulate growth factor secretion from cultured rabbit gastric parietal cells. 1547 51

Pancreatic islet transplantation is a viable treatment for type 1 diabetes, but is limited by human donor tissue availability. The combination of epidermal growth factor (EGF) and gastrin induces islet beta-cell neogenesis from pancreatic exocrine duct cells in rodents. In this study we investigated whether EGF and gastrin could expand the beta-cell mass in adult human isolated islets that contain duct as well as endocrine cells. Human islet cells were cultured for 4 wk in serum-free medium (control) or in medium with EGF (0.3 mug/ml), gastrin (1.0 mug/ml), or the combination of EGF and gastrin. beta-Cell numbers were increased in cultures with EGF plus gastrin (+118%) and with EGF (+81%), but not in cultures with gastrin (-3%) or control medium (-62%). After withdrawal of EGF and gastrin and an additional 4 wk in control medium, beta-cell numbers continued to increase only in cultures previously incubated with both EGF and gastrin (+232%). EGF plus gastrin also significantly increased cytokeratin 19-positive duct cells (+678%) in the cultures. Gastrin, alone or in combination with EGF, but not EGF alone, increased the expression of pancreatic and duodenal homeobox factor-1 as well as insulin and C peptide in the cytokeratin 19-positive duct cells. Also, EGF plus gastrin significantly increased beta-cells and insulin content in human islets implanted in immunodeficient nonobese diabetic-severe combined immune deficiency mice as well as insulin secretory responses of the human islet grafts to glucose challenge. In conclusion, combination therapy with EGF and gastrin increases beta-cell mass in adult human pancreatic islets in vitro and in vivo, and this appears to result from the induction of beta-cell neogenesis from pancreatic exocrine duct cells.
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PMID:Combination therapy with epidermal growth factor and gastrin induces neogenesis of human islet {beta}-cells from pancreatic duct cells and an increase in functional {beta}-cell mass. 1576 77

Targeting growth-regulatory pathways is a promising approach in cancer treatment. A prerequisite to the development of such therapies is characterisation of tumour growth regulation in the particular tumour cell type of interest. In order to gain insight into molecular mechanisms underlying proliferative responses in neuroendocrine (NE) gastrointestinal (GI) tumours, we investigated gene expression in human carcinoid BON cells after exposure to gastrin, hepatocyte growth factor (HGF), pituitary adenylate cyclase-activating polypeptide or epidermal growth factor. We particularly focused on gastrin- and HGF-induced gene expression, and identified 95 gastrin- and 101 HGF-responsive genes. The majority of these genes are known mediators of processes central in tumour biology, and a number of them have been associated with poor prognosis and metastasis in cancer patients. Furthermore, we identified 12 genes that were regulated by all four factors, indicating that they may be universally regulated during NE GI tumour cell proliferation. Our findings provide useful hypotheses for further studies aimed to search for new therapeutic targets as well as tumour markers in NE GI tumours.
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PMID:Identification of novel growth factor-responsive genes in neuroendocrine gastrointestinal tumour cells. 1584


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