Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated the effects of antagonists of growth hormone-releasing hormone (GHRH) alone and in combination with bombesin/gastrin-releasing peptide (BN/GRP) antagonist RC-3940-II on the growth of H-69 human small cell lung carcinoma (SCLC) xenografted into nude mice. Since the activation of the signaling pathways involving protein kinase C (PKC) and the subsequent steps involving mitogen-activated protein kinase (MAPK) and c-fos and c-jun oncogenes are known to be important mechanisms implicated in cellular growth, we investigated how the blockade of tumoral GHRH receptor splice variants and BN/GRP receptors by these antagonists could interfere with these intracellular signaling pathways. Treatment with GHRH antagonists JV-1-65 or MZ-J-7-110 for 4 weeks significantly (p<0.05) decreased the tumor volume by 22.7+/-3.0% and 36.7 +/- 3.6%, respectively, as compared to controls. A larger decrease in tumor volume of 73.0 +/- 9.5% (p<0.01) was produced by BN/GRP antagonist RC-3940-II and its combination with JV-I-65 caused the greatest tumor reduction of 91.0 +/- 9.8% (p<0.01) vs. controls. H-69 SCLC tumors expressed alpha-, betaII-, delta- and eta-PKC isoforms. Antagonists of GHRH and BN/GRP decreased significantly (p<0.05) the expression of betaII- and delta-, but not of alpha- and eta-PKC isoforms. They also inhibited MAPK levels, the effects being significant (p<0.05) in the groups that received BN/GRP antagonist. In addition, expression of c-fos and c-jun mRNA was reduced after combined treatment with JV-1-65 and RC-3940-II. The proliferation of H-69 SCLC cells "in vitro" was also significantly inhibited after incubation of cells with GHRH antagonist, PKC inhibitors or MAPK inhibitor. These findings suggest that the anti-proliferative effects of antagonists of GHRH and BN/GRP on H69-SCLC involve an inhibition of the signaling pathways of specific PKC isoforms, MAPK and c-fos and c-jun oncogenes.
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PMID:Suppression of growth of H-69 small cell lung carcinoma by antagonists of growth hormone releasing hormone and bombesin is associated with an inhibition of protein kinase C signaling. 1538 37

Although amidated forms of gastrin-releasing peptide (GRP) have been identified as autocrine growth factors in small cell lung cancer, their role in the development and progression of colorectal carcinoma is less clear. In addition, the biological activity of non-amidated gastrin-releasing peptide has not been investigated in colorectal carcinoma cells. We therefore investigated the effect of bombesin (a homologue of gastrin-releasing peptide) on proliferation, migration and inositol phosphate production in the human colorectal carcinoma cell line DLD-1, and determined the ability of gastrin-releasing peptide receptor antagonists to inhibit these effects. We also compared the biological activities of amidated and non-amidated GRP in the same assays. Treatment with either bombesin, or amidated or non-amidated GRP resulted in significant increase in proliferation, and in migration in a wound-healing assay. Both the mitogenic and migratory effects of amidated and non-amidated forms were inhibited by the GRP receptor antagonist [D-Phe(6), Leu-NHet(13), des-Met(14)]-bombesin(6-13). The presence of GRP receptor mRNA and GRP binding sites in three colorectal carcinoma cell lines was demonstrated by RT-PCR and by binding of radiolabelled bombesin, respectively. Transfection of DLD-1 cells with a dominant negative phosphatidylinositol 3-kinase did not affect bombesin-stimulated cell proliferation, but inhibited bombesin-stimulated cell migration. Bombesin and GRPgly activated phospholipase C, mitogen-activated protein kinase and focal adhesion kinase. We conclude that both amidated and non-amidated forms of gastrin-releasing peptide accelerate proliferation and migration of DLD-1 human colorectal carcinoma cells via the gastrin-releasing peptide receptor, but that phosphatidylinositol 3-kinase is only involved in the cell migration signalling pathway. Our results suggest a potential role for gastrin-releasing peptide receptor antagonists in the management of colorectal carcinoma.
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PMID:Stimulation of proliferation and migration of a colorectal cancer cell line by amidated and glycine-extended gastrin-releasing peptide via the same receptor. 1549 3

G protein-coupled receptors (GPCRs) of Gi- or Gq-coupling specificity are effectively linked to activation of the c-Jun N-terminal kinase (JNK) cascade. However, little is known with regard to the regulation of JNK by Gs-coupled receptors. In this report, we used COS-7 cells transfected with the dopamine D1 receptor (D1R) to illustrate the signaling mechanism for Gs-mediated JNK activation. Stimulation of D1R triggered a weak but significant elevation of JNK activity in a time- and dose-dependent manner. This D1R-mediated JNK activation required the participation of Gbetagamma, Src-like kinases, and small GTPases, whereas disruptions of cAMP-, phosphoinositide-3-kinase-, and epidermal growth factor receptor-mediated signaling had no effect. Costimulation of D1R with GPCRs of other coupling specificities resulted in differential activation profiles of JNK. Activation of Gs-coupled D1R weakly potentiated the JNK activation induced by the Gi-coupled opioid receptor-like receptor, but it exhibited a significant inhibitory effect on the kinase activity triggered by the Gq-coupled gastrin-releasing peptide-preferring bombesin receptor (GRPR). Administration of Spadenosine-3',5'-cyclic monophosphorothioate triethylamine (a cAMP analog that mimics the Gs/cAMP signal) also suppressed the JNK activation mediated by Gq-coupled GRPR, as well as the Ca2+-induced kinase activation upon thapsigargin treatment. Moreover, the Ca2+ signal from GRPR synergistically potentiated the D1R-triggered cAMP elevation when the two receptors were stimulated simultaneously. Taken together, our results demonstrated that stimulation of Gs-coupled receptors in COS-7 cells not only enhanced the JNK activity, but also exhibited a "tuning" effect on the kinase activation mediated by GPCRs of other coupling specificities.
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PMID:Gq-mediated activation of c-Jun N-terminal kinase by the gastrin-releasing peptide-preferring bombesin receptor is inhibited upon costimulation of the Gs-coupled dopamine D1 receptor in COS-7 cells. 1606 71

Gastrin-releasing peptide (GRP) has a widespread distribution and multiple stimulating effects on endocrine and exocrine secretions and metabolism. The prohormone for GRP (ProGRP, 125 amino acids) is processed to the amidated, biologically active end products GRP(1-27) and GRP(18-27). Amidated forms of GRP are putative autocrine or paracrine growth factors in a number of cancers including colorectal cancer. However, the potential role and biological activity of proGRP has not been investigated. Using a newly developed antisera directed to the N terminus of human proGRP, proGRP immunoreactivity was detected in all of the endometrial, prostate, and colon cancer cell lines tested and in nine of 10 resected colorectal carcinomas. However, no amidated forms were detected, suggesting an attenuation of processing in tumors. Recombinant proGRP was expressed as a His-tag fusion protein and purified by metal affinity chromatography and HPLC. ProGRP stimulated proliferation of a colon cancer cell line and activated MAPK, but unlike GRP(18-27)amide had no effect on inositol phosphate production. ProGRP did not compete with iodinated bombesin in binding assays on Balb-3T3 cells transfected with the known GRP receptors, GRP-R or BRS-3. We conclude that proGRP is present in a number of cancer cell lines and in resected colorectal tumors and is biologically active. Our results suggest that antagonists to GRP precursors rather than the amidated end products should be developed as a treatment for colorectal and other cancers that express proGRP-derived peptides.
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PMID:Synthesis, expression and biological activity of the prohormone for gastrin releasing peptide (ProGRP). 1622 66

Our previous studies indicate that the activation of mitogen-activated protein kinase (MAPK) pathway is involved in bombesin-induced cell proliferation in prostate cancer cells. Cyclin D1 is a critical regulator involved in cell cycle progression through the G1 phase into the S phase, thereby contributing to cell proliferation. Mostly, mitogen-stimulated expression of cyclin D1 is attributed to the extracellular signal-regulated kinase (ERK) activation. Here, we found that bombesin induced human cyclin D1 expression on both mRNA and protein levels in DU-145 prostate cancer cells. Mutational analyses showed that bombesin-enhanced cyclin D1 transcription required the binding of nuclear proteins to the -143 to -105 region of the human cyclin D1 promoter, which contains binding sites for transcription factors Sp-1 and early growth response protein (Egr-1). Do novo protein synthesis was requisite for bombesin-induced cyclin D1 expression. Further studies showed Egr-1 was induced upon bombesin stimulation. The induction of Egr-1 expression and its binding to the cyclin D1 promoter were essential for bombesin-enhanced cyclin D1 transcription. Inhibition of MAPK pathway with either the MEK1 inhibitor PD98059 or a dominant-negative Ras mutant, RasN17, abolished bombesin-induced cyclin D1 activation. Taken together, bombesin-induced cyclin D1 expression in prostate cancer cells is mediated by Egr-1 activation and the interaction of Egr-1 with the Egr-1/Sp1 motif of the cyclin D1 promoter through the activation of MAPK pathway. These findings represent a novel mechanism of bombesin-dependent stimulation of mitogenesis by regulating directly the cell cycle in prostate cancer.
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PMID:Bombesin regulates cyclin D1 expression through the early growth response protein Egr-1 in prostate cancer cells. 1626 18

Protein kinase C-delta (PKC-delta) becomes activated in pancreatic acini in response to cholecystokinin (CCK) and plays a pivotal role in the exocrine pancreatic secretion. Rottlerin, a polyphenolic compound, has been widely used as a potent and specific PKC-delta inhibitor. However, some recent studies showed that rottlerin was not effective in inhibiting PKCdelta activity in vitro and that may display unspecific effects. The aims of this work were to investigate the specificity of rottlerin as an inhibitor of PKC-delta activity in intact cells and to elucidate the biochemical causes of its unspecificity. Preincubation of pancreatic acini with rottlerin (6 microM) inhibited CCK-stimulated translocation, tyrosine phosphorylation (TyrP) and activation of PKC-delta in pancreatic acini in a time-dependent manner. Rottlerin inhibited amylase secretion stimulated by both PKC-dependent pathways (CCK, bombesin, carbachol, TPA) and also by PKC-independent pathways (secretin, VIP, cAMP analogue). CCK-stimulation of MAPK activation and p125(FAK) TyrP which are mediated by PKC-dependent and -independent pathways were also inhibited by rottlerin. Moreover, rottlerin rapidly depleted ATP content in pancreatic acini in a similar way as the mitochondrial uncouplers CCCP and FCCP. All studied inhibitory effects of rottlerin in pancreatic acini were mimicked by FCCP (agonists-stimulated amylase secretion, p125(FAK) TyrP, MAPK activation and PKC-delta TyrP and translocation). Finally, rottlerin as well as FCCP display a potent inhibitory effect on the activation of other PKC isoforms present in pancreatic acini. Our results suggest that rottlerin effects in pancreatic acini are not due to a specific PKC-delta blockade, but likely due to its negative effect on acini energy resulting in ATP depletion. Therefore, to study the role of PKC-delta in cellular processes using rottlerin it is essential to keep in mind that may deplete ATP levels and inhibit different PKC isoforms. Our results give reasons for a more careful choice of rottlerin for PKC-delta investigation.
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PMID:Rottlerin inhibits stimulated enzymatic secretion and several intracellular signaling transduction pathways in pancreatic acinar cells by a non-PKC-delta-dependent mechanism. 1636 65

Although the gastrin-releasing peptide-preferring bombesin receptor (GRPR) has been implicated in memory formation, the underlying molecular events are poorly understood. In the present study, we examined interactions between the GRPR and cellular signaling pathways in influencing memory consolidation in the hippocampus. Male Wistar rats received bilateral infusions of bombesin (BB) into the dorsal hippocampus immediately after inhibitory avoidance (IA) training. Intermediate doses of BB enhanced, whereas a higher dose impaired, 24-h IA memory retention. The BB-induced memory enhancement was prevented by pretraining infusions of a GRPR antagonist or inhibitors of protein kinase C (PKC), mitogen-activated protein kinase (MAPK) kinase and protein kinase A (PKA), but not by a neuromedin B receptor (NMBR) antagonist. We next further investigated the interactions between the GRPR and the PKA pathway. BB-induced enhancement of consolidation was potentiated by coinfusion of activators of the dopamine D1/D5 receptor (D1R)/cAMP/PKA pathway and prevented by a PKA inhibitor. We conclude that memory modulation by hippocampal GRPRs is mediated by the PKC, MAPK, and PKA pathways. Furthermore, pretraining infusion of BB prevented beta-amyloid peptide (25-35)-induced memory impairment, supporting the view that the GRPR is a target for the development of cognitive enhancers for dementia.
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PMID:Molecular mechanisms mediating gastrin-releasing peptide receptor modulation of memory consolidation in the hippocampus. 1673 43

There are many precedents for the production from a single precursor of multiple peptides, with independent receptors and different bioactivities. Gastrin-releasing peptide (GRP) is initially synthesized as amino acids 1-27 of a 125-residue precursor, proGRP, and is subsequently cleaved and amidated to form GRP18-27. We investigated the hypothesis that C-terminal proGRP peptides are also biologically active. Human proGRP18-125 was expressed in Escherichia coli as a glutathione S-transferase fusion protein. Recombinant proGRP18-125 stimulated proliferation and migration of the human colorectal carcinoma cell line DLD-1. The observations that an antagonist selective for the GRP receptor did not inhibit activity in either proliferation or migration assays and that the recombinant peptide did not bind to either the GRP receptor or orphan receptor BRS-3 indicated that neither activity was mediated by the known GRP receptors. Recombinant human proGRP31-125 and proGRP42-98 were also prepared and shown to stimulate proliferation of DLD-1 cells and the human prostate carcinoma cell line DU145. The synthetic peptides proGRP47-68 and [Tyr79]proGRP80-97 stimulated inositol phosphate production, MAPK kinase activity, and proliferation and migration of DLD-1 cells. Binding sites for both radioiodinated synthetic peptides were demonstrated on DLD-1 cells. Each peptide was able to compete with the other for binding, and a GRP receptor antagonist did not inhibit binding of either peptide. We conclude that peptides derived from the C terminus of proGRP are biologically active and that their activity is mediated by a receptor distinct from the two known GRP receptors.
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PMID:C-terminal fragments of the gastrin-releasing peptide precursor stimulate cell proliferation via a novel receptor. 1712 80

Approximately 15-25% of all primary cancers of the lung are classified histologically as small cell lung carcinoma (SCLC), a subtype characterized by rapid growth and a poor prognosis. Neuropeptide hormones like bombesin/gastrin-releasing peptide, bradykinin or galanin are the principal mitogenic stimuli of this tumour entity. The mitogenic signal is transmitted into the cell via heptahelical neuropeptide hormone receptors, which couple to the heterotrimeric G proteins of the Gq/11 familiy. Subsequent activation of phospholipase Cbeta (PLCbeta) entails the activation of protein kinase C and the elevation of the intracellular calcium concentration. There is mounting evidence to support the notion that calcium mobilization is the key event that initiates different mitogen-activated protein kinase cascades. Neuropeptide-dependent proliferation of SCLC cells relies on parallel activation of the Gq/11/PLCbeta/Ras/extracellular signal-regulated kinase and the c-jun N-terminal kinase pathways, while selective engagement of either signalling cascade alone results in growth arrest and differentiation or apoptotic cell death. Basic experimental research has the potential to identify and validate novel therapeutic targets located at critical points of convergence of different mitogenic signal transduction pathways. In the case of SCLC, targeting the distinct components of the Ca2+ influx pathway as well as critical Ca2+-dependent cellular effectors may be rewarding in this regard.
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PMID:Calcium-dependent growth regulation of small cell lung cancer cells by neuropeptides. 1715 54

Overexpression of cyclooxygenase-2 (COX-2), an inducible enzyme regulating prostaglandin release, is mechanistically linked to the development, growth, and spread of gastrointestinal (GI) cancers. GI peptide bombesin (BBS) was reported to stimulate COX-2 gene expression. Here we show that TGF-beta1 dramatically enhances the BBS-induced expression of COX-2 mRNA and protein, and the release of PGE2 in the model rat intestinal epithelial cell (RIE-1) line. The synergistic increase in COX-2 levels results from a combination of enhanced COX-2 transcription and reduced mRNA degradation. BBS, but not TGF-beta1, stimulated COX-2 promoter activity, and TGF-beta1 enhanced COX-2 mRNA stability through a p38(MAPK)-dependent pathway. The synergistic regulation of COX-2 expression by TGF-beta1 and BBS may contribute to the upregulation of COX-2 in GI cancers.
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PMID:Synergistic regulation of COX-2 expression by bombesin and transforming growth factor-beta. 1809 63


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