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 roles of gastrin and sodium vanadate in proliferation were examined in cultured IEC-6 cells that are mitotically active and derived originally from jejunal crypts of the rat intestine. Incubation of the cells in the presence of gastrin at a concentration of 250 ng/ml or of sodium vanadate at a concentration of 0.2 mM leads to a 60% increase in cell growth in 24 hr. The stimulated growth in both cases was inhibited by genistein, a tyrosine kinase inhibitor. Incubation in the presence of gastrin and sodium vanadate together produced a small, albeit significant, potentiation of growth of the cells. Gastrin as well as sodium vanadate also promoted the phosphorylation on tyrosine of a similar group of proteins with molecular masses of 42, 45, 52, 60, 78, and 120 kDa. The phosphorylations were rapidly occurring as early as 5 min and lasted for only 15 min. Several proteins were detected in normal IEC-6 cells, including GTPase activating protein, raf1 kinase, phospholipase C gamma-1, and phosphoinositide 3-kinase. The results suggest that gastrin and sodium vanadate induce growth of IEC-6 cells by stimulation of tyrosine kinase and/or inhibition of tyrosine phosphatase. The gastrin and sodium vanadate effects also involve the phosphorylation of a number of proteins, the identities of which are not known at present but may include some of the kinases that are frequently associated with cell growth, such as mitogen-activated protein kinase, raf1 kinase, phosphoinositide 3-kinase, and others.
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PMID:Role of tyrosine kinase and phosphotyrosine phosphatase in growth of the intestinal crypt cell (IEC-6) line. 845 7

Gastrin/CCKB G protein-coupled receptors have been shown to mediate proliferative effects of their endogenous ligands. In the present study, we examined the signal transduction mechanisms linked to the G/CCKB receptor occupancy. We report here that gastrin stimulates MAP kinase activation in a dose- and time-dependent manner, a pathway known to play a key role in cell proliferation. We also characterized the molecular events, upstream of p21-Ras, that may link the MAP kinase pathway to G/CCKB receptors. Gastrin induced a rapid and transient increase in tyrosine phosphorylation of several proteins including the 2 isoforms (46 and 52 kDa) of the adaptor protein Shc. Phosphorylated Shc subsequently associated with a complex that includes Grb2 and the p21-Ras activator, Sos. Our results also indicate that Sos becomes phosphorylated in response to gastrin as shown by a reduction in electrophoretic mobility of the protein. Tyrosine phosphorylation of Shc and subsequent complex formation with Grb2 and Sos appear to be a common mechanism by which tyrosine kinase receptors and the G/CCKB G protein-coupled receptor stimulate the Ras-dependent MAP kinase pathway.
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PMID:Gastrin induces tyrosine phosphorylation of Shc proteins and their association with the Grb2/Sos complex. 854 7

The homogenate of MC3T3-E1 cells hydrolysed phosphotyrosine, but not phosphoserine or phosphothreonine at acidic pH. It dephosphorylated lysozyme and Raytide (a gastrin analogue peptide) phosphorylated by tyrosine kinase, but showed little activity toward histones phosphorylated by cyclic AMP-dependent protein kinase. Dephosphorylation of phosphorylated lysozyme and Raytide were inhibited by zinc and vanadate, but were insensitive to okadaic acid. These data suggest that the osteoblastic cell line MC3T3-E1 has a phosphotyrosyl protein phosphatase-like activity that may participate in cellular regulation involving protein tyrosine phosphorylation.
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PMID:Phosphotyrosyl protein phosphatase-like activity of a clonal osteoblastic cell line (MC3T3-E1 cell). 865 86

Stimulation of small cell lung cancer (SCLC) cells with neuropeptides bombesin, bradykinin, gastrin, and neurotensin resulted in increased tyrosine kinase activity and tyrosine phosphorylation of a number of polypeptides including a p120 kDa polypeptide identified by immunoblotting as focal adhesion kinase (p125FAK). The neuropeptides stimulated a rapid, concentration-dependent phosphorylation of p125FAK (EC50 of 1 nM, 5 nM, and 2 nM for bombesin, bradykinin, and gastrin, respectively), which was receptor mediated and inhibited by both specific and broad-spectrum neuropeptide receptor antagonists. Specific inhibition of protein tyrosine kinase activity by tyrphostin-25 inhibited both basal and neuropeptide-stimulated SCLC cell growth. These results identify a novel neuropeptide-stimulated growth signaling event in SCLC cells.
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PMID:Neuropeptides stimulate tyrosine phosphorylation and tyrosine kinase activity in small cell lung cancer cell lines. 880 78

Carcinoid tumours may develop from enterochromaffin cells in the gastrointestinal tract. Benign insulin-producing tumours may develop from islet cells, whereas other islet cell tumours might derive from multipotent stem cells in the pancreatic ducts. The idea that multiple endocrine neoplasia type 1 (MEN-1) tumours in the pancreas originate from multipotent stem cells is supported by our demonstration that CD44 is expressed in exocrine cells, in gastrin-producing endocrine cells only and in some non-functioning islet cell tumours; there are no gastrin-producing cells in the adult pancreas. We have identified phospholipase C beta 3 (PLC beta 3) as the gene implicated in MEN-1. It appears to be a tumour suppressor gene since it is expressed in endocrine pancreatic tumours, some lung carcinoids, and medullary thyroid carcinomas. So neuroendocrine tumours might have a dual growth-regulating system, involving both traditional growth factors through the tyrosine kinase system and also G-protein-mediated growth signals. Deletion of PLC beta 3, which is an important enzyme in the signal transduction pathway of G-protein-mediated signals, might be important in the growth regulation of neuroendocrine tumours. It is proposed that its deletion causes dysregulation of growth control in neuroendocrine cells, with possible distortion of the apoptotic process. In the last stage of the disease, tumour biology is altered and becomes more aggressive. Further, chromogranin A may be both a tumour marker for neuroendocrine tumours and a growth-promoting agent for neuroendocrine tumour cells; it is a very good marker of tumour mass but is also related to poor prognosis of survival. Mutation analyses of PLC beta 3 and studies of the growth-promoting effect of chromogranin are ongoing and should lead to more effective therapies.
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PMID:Biological aspects of neuroendocrine gastro-enteropancreatic tumours. 881 67

We have previously reported that gastrin induces a rapid and transient tyrosine phosphorylation of phospholipase C gamma 1 (PLC gamma 1) in association with inositol 1,4,5-trisphosphate (IP3) formation in rat colonic epithelial cells (34). In this study, we demonstrate that gastrin regulates IP3 formation mainly through PLC gamma 1 isozyme. Immunoblotting analysis revealed the expression of PLC beta 3 and -gamma 1, but not PLC beta 1, -beta 2, or -beta 4 in the rat colonic epitheliums. To explore what PLC isozyme(s) modulates gastrin effect on IP3, immunoneutralizing antibody to PLC beta 1, -beta 3, or -gamma 1 was introduced into the colonic cells using a lipid carrier. The gastrin-stimulated increase in IP3 concentration was specifically prevented by anti-PLC gamma 1 but not by anti-PLC beta 1 or -beta 3 antibody. Immunoprecipitation assays have also revealed that gastrin promoted an increase in tyrosine phosphorylation and co-precipitation of a 60 kDa src kinase with PLC gamma 1. Administration of antibody specific to pp60c-src into the colonic cells prevented the gastrin-stimulated increases in IP3. Tyrosine phosphorylation of PLC gamma 1 may be a major mechanism through which gastrin regulates IP3 level in the colonic cells. Pretreatment of cells with the tyrosine kinase inhibitor genistein abrogated gastrin's effect on IP3, while extended pretreatment with pertussis toxin, a G-protein inhibitor, did not affect the ability of gastrin to stimulate IP3 formation. Colonic cells expressed the G alpha i subunits1-3; however, immunoblotting analysis did not reveal any difference in G alpha i proteins' expression between control and gastrin treated cells. The results provide direct evidence that gastrin regulates IP3 level by a signaling mechanism that involves PLC gamma 1 and pp60c-src kinase.
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PMID:Gastrin induces IP3 formation through phospholipase C gamma 1 and pp60c-src kinase. 943 36

In Fischer 344 rats, induction of gastric mucosal proliferative activity, whether the result of aging or injury or occurring after administration of epidermal growth factor, gastrin, or bombesin, is associated with a rise in tyrosine kinase activity and tyrosine phosphorylation of several mucosal proteins, including a protein with a molecular mass of 53-55 kDa. We hypothesized that this phosphotyrosine membrane protein (referred to as pp55) may play a role in regulating gastric mucosal cell proliferation and differentiation. Purification and subsequent immunoprecipitation studies now show that pp55 is a tyrosine kinase. In addition, the enzyme activity in the gastric mucosa is found to be fourfold higher in aged rats than in young rats. Incubation of gastric mucosal membranes with transforming growth factor-alpha (2 x 10(-8) M) stimulates tyrosine kinase activity of pp55. Immunolocalization studies reveal that pp55 immunoreactivity is predominantly present in mucous cells that are located just above the proliferative zone and spasmolytic peptide-immunoreactive mucous neck cells. Tyrosine kinase activity as well as expression of pp55 are also greatly increased in the gastric mucosa after hypertonic saline-induced injury, a condition that results in stimulation of surface mucosal cell proliferation and differentiation. Our current data suggest that pp55 is a tyrosine kinase, likely localized to pre-surface cells. The presence of pp55 in pre-surface mucous cells and the expression and tyrosine kinase activity of this protein, which can be stimulated during mucosal cell proliferation and differentiation, strongly suggest a role for pp55 in differentiation of gastric surface mucous cells.
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PMID:Localization and significance of pp55, a gastric mucosal membrane protein with tyrosine kinase activity. 961 67

Gastrointestinal (GI) peptides (also referred to as neuropeptides or regulatory peptides), including the mammalian bombesin-like peptides gastrin and CCK, elicit the synthesis of classic second messengers (e.g., Ca2+, diacylglycerol, and cAMP) and the consequent stimulation of serine/threonine protein kinase cascades. An emerging theme in signal transduction is that these agonists also induce rapid and coordinate tyrosine phosphorylation of a set of focal adhesion proteins, including the nonreceptor tyrosine kinase p125fak and the adaptor proteins p130cas and paxillin. GI peptide-mediated induction of tyrosine phosphorylation of these focal adhesion proteins is critically dependent on the integrity of the actin cytoskeleton and on functional Rho. The purpose of this article is to review recent advances in unraveling this novel tyrosine kinase pathway(s), because it appears to play a fundamental role in the mediation of important biological effects induced by GI peptides, including cell migration and proliferation.
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PMID:V. Gastrointestinal peptide signaling through tyrosine phosphorylation of focal adhesion proteins. 968 42

The intracellular events involved in normal pancreatic growth have been extensively investigated in response to cholecystokinin. Recent data indicate that tyrosine kinase, phospholipase D, phosphatidylinositol 3-kinase, and p42/p44 MAPK are stimulated in rat pancreatic acinar cells. Although we begin to understand the intracellular signaling pathways activated in normal pancreas, such information is not yet available in pancreatic cancer cells. This study was undertaken to identify the growth factors and hormones involved in cell proliferation of two human pancreatic cancer cell lines of ductal origin, the MIA PaCa-2, and PANC-1 cells, and to establish the intracellular events involved in the control of their growth. We demonstrated that FGF-2, IGF-1, cerulein, and gastrin but not FGF-1, HGF, secretin, and PACAP, stimulated proliferation of MIA PaCa-2 and PANC-1 cells. Autocrine factors such as gastrin and IGF-1 were also responsible for their proliferation. In response to EGF, FGF-2, IGF-1, cerulein, gastrin and bombesin, tyrosine kinase, and tyrosine phosphatase activities were stimulated in both cell lines. The close relationship established between cell growth and tyrosine kinase activation results from the observation that maximal growth stimulation paralleled with maximal enzyme activation and that genistein, the tyrosine kinase inhibitor, blocked cell growth and enzyme activation. The implication of PLD in growth-stimulated processes is doubtful since all growth factors and hormones tested failed to stimulate an already very active PLD activity. We finally observed a constitutive activity of p44 MAPK in both cell lines and of p42 in MIA PaCa-2 cells. However, p38 and p42 were stimulated in MIA PaCa-2 and PANC-1 cells, respectively, by all growth factors and hormones.
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PMID:Growth effects of regulatory peptides and intracellular signaling routes in human pancreatic cancer cell lines. 986 51

Resveratrol is a phytoalexin with several biological and pharmacological activities including the "French paradox". We investigated the effect of resveratrol on cytolytic activity by oxygen reactive species and on soluble and particulate tyrosine kinases from human placenta and human prostatic adenoma. These effects were compared with those of piceatannol, quercetin, catechin and epicatechin. Fifty percent of erythrocyte lysis due to H2O2-lactoperoxidase-KI incubation, in which I3-, OI- and oxygen singlet are produced, was obtained after 22 +/- 7 (SD) min in the absence of the tested compounds. The 50% lysis was obtained after 66 +/- 15, 129 +/- 35, 196 +/- 21, 240 +/- 63 and 420 +/- 80 min with 40 microM piceatannol, quercetin, resveratrol, epicatechin and catechin respectively. Protection was concentration dependent. The assay of tyrosine kinase activity was performed using two different substrates as follows: substrate A corresponded to the sequence 1-17 of gastrin, and substrate B to sequence 6-20 of cell division kinase p34cdc2. In all experiments, initial velocity was measured. When assayed with both substrates, tyrosine kinase activities from particulate and cytosolic fractions of placenta were more inhibited by piceatannol and quercetin. Resveratrol significantly inhibited the particulate fraction and the cytosolic fraction respectively when substrates A and B were employed: Catechin acted as an inhibitor with substrate A and particulate fraction while in the other experimental conditions it acted as an activator. Resveratrol inhibited the tyrosine kinase of particulate and cytosolic fractions of prostatic adenoma assayed with substrate A and B.
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PMID:Effect of resveratrol and some other natural compounds on tyrosine kinase activity and on cytolysis. 1037 Aug 68


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