Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.24 (mitogen-activated protein kinase)
95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gastrin stimulates transcription of the human histidine decarboxylase (HDC) gene through binding to the G-protein-coupled cholecystokinin-B/gastrin receptor. We have explored the possibility that mitogen-activated protein kinase cascades play a role in mediating the effects of gastrin on transcription in a gastric cancer (AGS-B) cell line. Gastrin and phorbol 12-myristate 13-acetate (PMA) treatment of AGS-B cells was found to increase the phosphorylation of tyrosine residues of extracellular signal-regulated kinases (ERKs) 1 and 2 and increase ERK activity as determined by the in vitro phosphorylation of myelin basic protein. Reporter gene assays also demonstrated that gastrin and PMA stimulated Elk-1- and c-Myc-dependent transactivation, consistent with gastrin- and PMA-induced activation of ERKs. Overexpression of wild type ERK-1 and ERK-2 or activation of endogenous ERKs using activated MEK-1 (mitogen-activated protein kinase kinase or ERK kinase) overexpression stimulated HDC promoter activity in a dose-dependent fashion. Interruption of the ERK-related pathway using expression vectors for kinase-deficient ERKs or an ERK-specific phosphatase (PAC-1) blocked gastrin- and PMA-stimulated HDC promoter activity. In contrast, inhibition of the Jun kinase pathway using an interfering dominant negative SEK-1 (stress-activated protein kinase/ERK-1) mutant did not inhibit HDC promoter activity. Furthermore, whereas gastrin stimulated phosphorylation of Shc proteins and association with Grb2, activation of the HDC promoter was not influenced by expression of dominant negative Ras (N15 or N17) proteins. However, gastrin stimulated Raf-1 kinase activity, and activation of the HDC promoter was blocked by coexpression of a dominant negative Raf-1 construct. Overall, these data demonstrate that gastrin regulates HDC transcription in a Rafdependent, Ras-independent fashion predominantly through activation of the ERK-related pathway.
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PMID:Gastrin and phorbol 12-myristate 13-acetate regulate the human histidine decarboxylase promoter through Raf-dependent activation of extracellular signal-regulated kinase-related signaling pathways in gastric cancer cells. 934 Nov 40

The human histidine decarboxylase gene is regulated by gastrin through a cis-acting element known as the gastrin response element (GAS-RE) that was initially localized to a site (+2 to +24) downstream of the transcriptional start site. Electrophoretic mobility shift assays using sequentially deleted DNA probes and nuclear extracts from AGS-B gastric cancer cells showed that the GAS-RE is actually composed of two overlapping binding sites (GAS-RE1, +1 to +19; and GAS-RE2, +11 to +27) that bind distinct nuclear factors. Reporter gene assays demonstrated that each element alone could confer gastrin responsiveness, but the presence of both elements was required for complete gastrin response. Stimulation of AGS-B cells with gastrin for 10-20 min resulted in a >2-fold increase in factor binding. The binding was inhibited by pretreatment of AGS-B cells with cycloheximide and the MEK1 inhibitor PD98059, indicating a requirement for protein synthesis and also indicating that activation occurs through the MEK/mitogen-activated protein kinase pathway. UV cross-linking and Southwestern blot analysis showed that GAS-RE1 bound a 52-kDa protein, whereas GAS-RE2 bound a 35-kDa protein. Hence, activation of histidine decarboxylase gene promoter activity by gastrin is most likely mediated by two separate nuclear factors.
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PMID:Activation of human histidine decarboxylase gene promoter activity by gastrin is mediated by two distinct nuclear factors. 1040 43

1. Stimulation of the murine macrophage cell line RAW 264.7 with thapsigargin, an endomembrane Ca(2+)-ATPase inhibitor, induced histamine production in a time- and concentration-dependent manner. 2. The protein kinase C activator, 12-O-tetradecanoylphorbol 13-acetate (TPA), also enhanced histamine production. 3. alpha-Fluoromethylhistidine, a suicide substrate of L-histidine decarboxylase (HDC), suppressed the thapsigargin (30 nM)- and TPA (30 nM)-induced histamine production. 4. Both thapsigargin (30 nM) and TPA (30 nM) induced phosphorylation of p44/p42 MAP kinase and p38 MAP kinase. 5. PD98059, a specific inhibitor of MEK-1 which phosphorylates p44/p42 MAP kinase, strongly suppressed both the thapsigargin (30 nM)- and TPA (30 nM)-induced histamine production, whereas SB203580, a specific inhibitor of p38 MAP kinase, inhibited them only partially. 6. The other MEK-1 inhibitor, U-0126, also inhibited both the thapsigargin- and TPA-induced histamine production in a concentration-dependent manner. 7. Thapsigargin (30 nM) and TPA (30 nM) increased the levels of HDC mRNA at 4 h, but PD98059 suppressed both the thapsigargin- and TPA-induced increases in the HDC mRNA level. 8. These findings indicate that thapsigargin and TPA induce histamine production in RAW 264.7 cells by increasing the level of HDC mRNA, and that both the thapsigargin- and TPA-induced histamine production are regulated largely by p44/p42 MAP kinase and partially by p38 MAP kinase.
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PMID:Participation of mitogen-activated protein kinase in thapsigargin- and TPA-induced histamine production in murine macrophage RAW 264.7 cells. 1071 50

Stimulation of RAW 264.7 cells with the Ca(2+)-ATPase inhibitor thapsigargin increased histamine production. Immunoblot analyses revealed that thapsigargin increased the expression of 74-kDa histidine decarboxylase protein although rat mast cell line RBL-2H3 cells express both 74- and 53-kDa histidine decarboxylase proteins. The inhibition of histamine production by the mitogen-activated protein kinase-extracellular signal-regulated kinase kinase (MEK) inhibitors PD98059 (2'-amino-3'-methoxyflavone) and U0126 (1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio)butadiene) and by the p38 mitogen-activated protein (MAP) kinase inhibitor SB203580 (4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole) was correlated with the inhibition of the expression of thapsigargin-induced 74-kDa histidine decarboxylase protein. The synthetic glucocorticoid dexamethasone inhibited thapsigargin-induced histamine production and 74-kDa histidine decarboxylase protein expression. The thapsigargin-induced activation of p42/p44 MAP kinase and p38 MAP kinase was also inhibited by dexamethasone. These findings indicate that the induction of histamine production by thapsigargin in RAW 264.7 cells is due to the increased expression of 74-kDa histidine decarboxylase protein and that dexamethasone inhibits thapsigargin-induced histidine decarboxylase protein expression and histamine production via inhibition of MAP kinase activation.
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PMID:Expression of 74-kDa histidine decarboxylase protein in a macrophage-like cell line RAW 264.7 and inhibition by dexamethasone. 1133 61

Stimulating cells of the mouse macrophage-like cell line RAW 264.7 with the Ca(2+)-ATPase inhibitor thapsigargin increased histamine production. Thapsigargin increased the levels of histidine decarboxylase (HDC) mRNA at 4 h and the expression of 74-kDa HDC protein at 8 h. PD98059, a specific inhibitor of MEK-1 which phosphorylates p44/p42 MAP kinase, strongly suppressed the thapsigargin-induced histamine production, the increase in HDC mRNA level and 74-kDa HDC protein expression. In contrast, SB203580, an inhibitor of p38 MAP kinase, showed only a partial inhibition of histamine production. TPA and LPS also induced histamine production in RAW 264.7 cells, and the histamine production induced by TPA or LPS was also inhibited by PD98059, but the effect of SB203580 was partial. The synthetic glucocorticoid dexamethasone inhibited thapsigargin-induced histamine production, 74-kDa HDC protein expression and the activation of p44/p42 MAP kinases. In conclusion, the increase in histamine production in macrophages stimulated with inflammatory stimulants is due to the increased expression of 74-kDa HDC, which is positively regulated by activated p44/p42 MAP kinases. Dexamethasone inhibits thapsigargin-induced HDC protein expression and histamine production by inhibiting the MAP kinase activation.
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PMID:[Regulation of histamine production in macrophages]. 1149 23

A poorly defined negative feedback loop decreases transcription of the L-histidine decarboxylase (HDC) gene. To help understand this regulation, we have studied the effect of HDC protein expression on HDC gene transcription in transfected AGS-B cells. Expression of the rat HDC protein inhibited HDC promoter activity in a dose-dependent fashion. The region of the HDC promoter mediating this inhibitory effect corresponded to a previously defined gastrin and extracellular signal-related kinase (ERK)-1 response element. Overexpression of the HDC protein reduced nuclear factor binding in this region. Experiments employing specific histamine receptor agonists indicated that the inhibitory effect was not dependent on histamine production, and studies with the HDC inhibitor alpha-fluoromethylhistidine revealed that inhibition was unrelated to enzyme activity. Instead, an enzymatically inactive region at the amino terminal of the HDC enzyme (residues 1-271) was shown to mediate inhibition. Fluorescent chimeras containing this domain were not targeted to the nucleus, arguing against specific inhibition of the HDC transcription machinery. Instead, we found that overexpression of HDC protein decreased ERK protein levels and ERK activity and that the inhibitory effect of HDC protein could be overcome by overexpression of ERK1. These data suggest a novel feedback-inhibitory role for amino terminal sequences of the HDC protein.
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PMID:L-histidine decarboxylase decreases its own transcription through downregulation of ERK activity. 1155 29

Histidine decarboxylase (HDC) is the key enzyme for gastric histamine synthesis, and enhanced HDC expression is critically involved in the pathogenesis of gastric disorders, including gastroduodenal ulcer disease. We characterized the pathogenicity mechanism underlying activation of the HDC promoter in H. pylori-infected gastric epithelial cells and performed a detailed analysis of the participating signaling elements. We found that H. pylori infection of gastric epithelial cells activated the MEK1-2/ERK1-2 cascade through cAMP-dependent stimulation of Rap1 and B-Raf, but not Ras/c-Raf-1, leading to potent transactivation of the human HDC promoter. H. pylori-triggered elevation of adenylate cyclase activity was directed by GalphaS-subunits of heterotrimeric G proteins. Stimulation of this signaling cascade was triggered independent of bacterial-cell contact by a small molecular- weight component(s) (approximately 1 kDa) released by H. pylori and did not require a functional type IV secretion system. Thus, our studies demonstrate for the first time to our knowledge that the GalphaS-->cAMP-->Rap1--->B-Raf-->MEK1/2-->ERK1/2 pathway is critical for H. pylori-dependent epithelial gene regulation, which can be induced via a bioactive component(s) apart from the site of bacterial colonization. These results further elucidate the molecular mechanisms underlying interaction of H. pylori with gastric epithelial cells and help to define potential molecular targets for therapeutic interventions in the context of H. pylori-related gastric diseases.
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PMID:B-Raf/Rap1 signaling, but not c-Raf-1/Ras, induces the histidine decarboxylase promoter in Helicobacter pylori infection. 2703 32

Enterochromaffin-like (ECL) cells are neuroendocrine cells in the gastric epithelium characterized by numerous electron-empty, histamine-containing secretory vesicles. The antral hormone gastrin is the key stimulus of histamine secretion from this cell type, thereby controling acid secretion. Following receptor binding, gastrin activates a biphasic calcium signal in ECL cells that involves activation of inositol triphosphate receptors and calcium entry across the plasma membrane. Dihydropyridines block gastrin-induced histamine secretion. However, no depolarization was observed following stimulation with gastrin. Elevation of intracellular calcium by gastrin is an important prerequisite for exocytosis. In permeabilized ECL cells, addition of calcium results in histamine release, which can be inhibited by tetanus toxin and botulinum neurotoxin A, underlining the functional importance of the synaptosome-associated protein of 25 kDa (SNAP-25) and synaptobrevin. Immunocytochemistry also confirmed the presence of these SNAP receptor (SNARE) proteins, as well as synaptophysin, synaptotagmin, and syntaxin. Following 3-6 h of incubation in isolated cells, several transcription factors are induced by gastrin, such as ERK1/2, Sp1, and CRE. Gastrin thereby directly stimulates transcription of the vesicular monoamine transporter subtype 2 (VMAT-2) and chromogranins. Gene expression of histidine decarboxylase (HDC) appears to be stimulated by a putative "gastrin-responsive" element adjacent to the HDC exon 1 gene. ECL cells thereby share several similarities with adrenal chromaffin cells and neurons, but have their own functional properties. Gastrin coordinates secretion, synthesis, and storage by activating diverging signal transducers, leading to a functional synergy in this cell type.
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PMID:Circle of life of secretory vesicles in gastric enterochromaffin-like cells. 1243 57

4E-BP1 plays a major role in translation by inhibiting cap-dependent translation initiation. Several reports have investigated the regulation of 4E-BP1 phosphorylation, which varies along with cell differentiation and upon various stimulations, but very little is known about the regulation of its expression. In a first part, we show that the expression of 4E-BP1 protein and transcript decreases in hematopoietic cell lines cultivated in the presence of phorbol 12-myristate 13-acetate (PMA). This decrease depends on the activation of the ERK/mitogen-activated protein kinases. 4E-BP1 expression also decreases when the p38/mitogen-activated protein kinase pathway is activated by granulocyte/macrophage colony-stimulating factor but to a lesser extent than with PMA. In a second part, we examine how 4e-bp1 promoter activity is regulated. PMA and granulocyte/macrophage colony-stimulating factor induce Egr-1 expression through ERK and p38 activation, respectively. Using a dominant negative mutant of Egr, ZnEgr, we show that this transcription factor is responsible for the inhibition of 4e-bp1 promoter activity. In a third part we show that histidine decarboxylase, whose activity and expression are inversely correlated with 4E-BP1 expression, is a potential target for the translational machinery. These data (i) are the first evidence of a new role of ERK and p38 on the translational machinery and (ii) demonstrate that 4E-BP1 is a new target for Egr-1.
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PMID:ERK and p38 inhibit the expression of 4E-BP1 repressor of translation through induction of Egr-1. 1261 31

Roles of mitogen-activated protein (MAP) kinases in lipopolysaccharide (LPS)-induced production of histamine in the mouse macrophage-like cell line RAW 264 were analyzed. Incubation of RAW 264 cells in the presence of LPS increased histamine levels in the conditioned medium in a concentration- and time-dependent manner. The levels of histidine decarboxylase (HDC) mRNA and the 74-kDa HDC protein were also increased at 4 to 8 h and 8 to 12 h, respectively. LPS elicited the phosphorylation of p44/42 MAP kinase, p38 MAP kinase, and c-Jun N-terminal kinase (JNK). The MAP kinase-Erk kinase 1 inhibitor U0126 (0.1-10 microM) suppressed the LPS-induced phosphorylation of p44/42 MAP kinase, and inhibited the LPS-induced production of histamine and expression of the HDC mRNA and 74-kDa HDC protein in a concentration-dependent manner. The JNK inhibitor SP600125 (3-30 microM) suppressed the LPS-induced phosphorylation of c-Jun, and inhibited the LPS-induced production of histamine and expression of the HDC mRNA and 74-kDa protein in a concentration-dependent manner. Combined treatment with U0126 (0.3 microM) and SP600125 (10 microM) inhibited the LPS-induced production of histamine additively. The p38 MAP kinase inhibitor SB203580 (0.1-10 microM) partially inhibited the LPS-induced production of histamine. These findings suggest that LPS increases histamine production in RAW 264 cells by inducing the expression of the 74-kDa HDC protein, and that the LPS-induced expression of HDC is up-regulated at the transcriptional level by MAP kinases, especially p44 MAP kinase and JNK.
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PMID:Involvement of MAP kinases in lipopolysaccharide-induced histamine production in RAW 264 cells. 1697 63


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