Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.12.2 (MEK)
 18,161 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Helicobacter pylori infection of the gastric mucosa is accompanied by an activated histamine metabolism. Histamine plays a central role in the regulation of gastric acid secretion and is involved in the pathogenesis of gastroduodenal ulcerations. Histidine decarboxylase (HDC) is the rate-limiting enzyme for histamine production, and its activity is regulated through transcriptional mechanisms. The present study investigated the effect of H. pylori infection on the transcriptional activity of the human HDC (hHDC) promoter in a gastric epithelial cell line (AGS) and analyzed the underlying molecular mechanisms. Our studies demonstrate that H. pylori infection potently transactivated the hHDC promoter. The H. pylori-responsive element of the hHDC gene was mapped to the sequence +1 to +27 base pairs, which shows no homology to known cis-acting elements and also functions as a gastrin-responsive element. H. pylori regulates the activity of this element via a Raf-1/MEK/ERK pathway, which was activated in a Ras-independent manner. Furthermore, we found that H. pylori-induced transactivation of the hHDC promoter was independent of the cag pathogenicity island and the vacuolating cytotoxin A gene and therefore may be exerted through (a) new virulence factor(s). A better understanding of H. pylori-directed hHDC transcription can provide novel insights into the molecular mechanisms of H. pylori-dependent gene regulation in gastric epithelial cells and may lead to new therapeutic approaches.
 ...
PMID:Helicobacter pylori activates the histidine decarboxylase promoter through a mitogen-activated protein kinase pathway independent of pathogenicity island-encoded virulence factors. 1065 59

Helicobacter pylori infection elicits persistent neutrophil infiltration in gastric mucosa. The expression of cyclooxygenase (COX) -2 by the neutrophils results in prostaglandin (PG) E2 synthesis, which may account for alterations in tissue homeostasis. In this study, we found that COX-2 mRNA was up-regulated in the neutrophils when stimulated with both H. pylori water extract (HPWE) and live H. pylori in a transwell model and determined by quantitative RT-PCR. PGE2 synthesis was also enhanced in the neutrophils activated by both the HPWE and live H. pylori. A specific COX-2 inhibitor (NS-398) blocked PGE2 synthesis, and an anti-ulcer agent (rebamipide) suppressed it dose dependently. An NF-kappaB inhibitor (pyrrolidine dithiocarbamate), a MAP kinase (MEK) inhibitor (PD98059), and a p38 MAP kinase inhibitor (SB203580) significantly suppressed the COX-2 gene transcription and PGE2 synthesis in the neutrophils. In conclusion, H. pylori water-soluble proteins may enhance the COX-2 expression, and this action could be mediated through the NF-kappaB and MAP kinase signaling pathways. The increased section of PGE2 by the neutrophils may play a proinflammatory role in the gastric mucosal response to H. pylori.
 ...
PMID:Expression of cyclooxygenase-2 in human neutrophils activated by Helicobacter pylori water-soluble proteins: possible involvement of NF-kappaB and MAP kinase signaling pathway. 1168 Jun 8

Epidemiological studies have demonstrated a strong association between Helicobacter pylori infection and gastric cancer. However, there have been few detailed studies on the mechanism of cellular proliferation by H. pylori. Thus, we examined activation of the proto-oncogene c-fos to elucidate the underlying mechanism of cell proliferation caused by H. pylori. Activation of c-fos was evaluated in human gastric cancer cells (TMK1) by Northern blot and reporter assays with deletion analysis of the c-fos transcriptional control region. c-fos promoter activation and transcription were enhanced when cocultured with cag-positive strains. H. pylori-mediated c-fos promoter activation was inhibited by MEK1/2 inhibitor (U0126). The deletion analysis indicated that serum response element (SRE) was required for the activation of c-fos by H. pylori. In conclusion, c-fos promoter activation and transcription were enhanced through the activation of extracellular signal-regulated kinases (ERK)/mitogen-activated protein kinase (MAPK) cascade in gastric cancer cells when cocultured with H. pylori possessing intact cag PAI. SRE is required for the activation of c-fos by H. pylori. These results suggest a direct involvement of H. pylori infection in cellular proliferation, which may play a role in neoplastic transformation.
 ...
PMID:Helicobacter pylori activates the proto-oncogene c-fos through SRE transactivation. 1186 45

Cyclooxygenase-2 (COX-2) represents the inducible key enzyme of arachidonic acid metabolism and contributes to the pathogenesis of gastroduodenal ulcers and gastric cancer. Helicobacter pylori infection is associated with elevated gastric COX-2 levels, but the mechanisms underlying H. pylori-dependent cox-2 gene expression are unclear. H. pylori stimulated cox-2 mRNA and protein abundance in gastric epithelial cells in vitro and in vivo, and functional analysis of the cox-2 gene promoter mapped its H. pylori-responsive region to a proximal CRE/Ebox element at -56 to -48. Moreover, USF1/-2 and CREB transcription factors binding to this site were identified to transmit H. pylori-dependent cox-2 transcription. Activation of MEK/ERK1/-2 signalling by bacterial virulence factors located outside the H. pylori cag pathogenicity island (cagPAI) was found to mediate bacterial effects on the cox-2 promoter. Our study provides a detailed description of the molecular pathways underlying H. pylori-dependent cox-2 gene expression in gastric epithelial cells, and may thus contribute to a better understanding of mechanisms underlying H. pylori pathogenicity.
 ...
PMID:Helicobacter pylori stimulates host cyclooxygenase-2 gene transcription: critical importance of MEK/ERK-dependent activation of USF1/-2 and CREB transcription factors. 1453 97

Helicobacter pylori infection results in peptic ulceration and chronic gastritis through mechanisms which are not fully elucidated. Live H. pylori activate the pro-inflammatory transcription factor NF-kappaB in gastric epithelial cells. Patients may have peptic ulcer disease in the absence of H. pylori infection; therefore other factors contribute to the inflammatory process. Maximal acid output in patients with H. pylori infection and duodenal ulceration is significantly increased indicating a role for acid in the pathogenesis of mucosal ulceration. The effect of low pH on NF-kappaB activation in gastric epithelial cells has not been studied. Human gastric epithelial cells (AGS) were exposed to a range of pH changes in the presence or absence of H. pylori. NF-kappaB DNA-binding and cytosolic IkappaB-alpha were measured using electrophoretic mobility shift assay and Western blotting. NF-kappaB DNA-binding in gastric epithelial cells dramatically increased when the pH of the culture medium decreased. Increases in NF-kappaB nuclear binding were paralleled by decreasing amounts of cytosolic IkappaB-alpha. These findings were similar but less potent than those observed when cells were exposed to H. pylori. Low pH resulted in enhancement of H. pylori-induced NF-kappaB nuclear binding. DNA binding of NF-kappaB activation secondary to low pH was attenuated by PD98059 but not by SB203580. Similar to H. pylori, low pH potently and independently augments NF-kappaB nuclear binding in AGS cells and such activation appears to be mediated through MEK1-dependant signaling pathways.
 ...
PMID:Low pH and Helicobacter pylori increase nuclear factor kappa B binding in gastric epithelial cells: a common pathway for epithelial cell injury? 1608 59

Helicobacter pylori infection increases the risk of hyperplastic polyps and gastric cancer, but the mechanisms remain to be elucidated. H. pylori was recently shown to transactivate epidermal growth factor receptor (EGFR) through metalloprotease stimulation. The present study was designed to investigate the effect of interleukin-8 (IL-8) induced by H. pylori infection on EGFR transactivation and epithelial cell growth. H. pylori Sydney strain 1 (SS1) having wild-type cag(+)A was used. Phospho-EGFR assay was performed by immunoprecipitation using anti-human EGFR and anti-phosphotyrosine antibodies. DNA synthesis was evaluated by [3H]thymidine uptake using the human gastric cancer cell line, KATO III. H. pylori induced EGFR phosphorylation, and a disintegrin and metalloproteinase (ADAM) inhibitor, KB-R7785, completely suppressed EGFR phosphorylation. IL-8 also induced EGFR phosphorylation, while anti-IL-8 and anti-IL-8 receptor (CXCR1) neutralizing antibodies suppressed EGFR phosphorylation. [(3)H]Thymidine uptake analysis demonstrated that H. pylori increased DNA synthesis in gastric epithelial cells, and tyrosine kinase inhibitor, MEK inhibitor, and ADAM inhibitor suppressed the DNA synthesis induced by H. pylori. H. pylori-stimulated IL-8 accelerates processing of EGFR ligands through ADAM activation, and cleaved EGFR ligands bind and stimulate EGFR in paracrine and autocrine manners to induce cell proliferation. This may be one of the mechanisms of hyperplastic polyp and gastric cancer development in H. pylori-infected gastric mucosa.
 ...
PMID:Helicobacter pylori-stimulated interleukin-8 (IL-8) promotes cell proliferation through transactivation of epidermal growth factor receptor (EGFR) by disintegrin and metalloproteinase (ADAM) activation. 1624 Feb 19

Helicobacter pylori infection is recognized as the major cause of gastritis and gastric cancer; however, its role in the development of gastroesophageal reflux disease and Barrett's adenocarcinoma is unclear. The expression of NF-kappaB, AP-1, and COX-2 may be important in inflammation and tumorigenesis in the esophagus. The aim of this study was to examine the effect of live H pylori or H pylori extract (HPE) on these factors in the esophageal epithelial cell lines SKGT-4 and OE33. NF-kappaB and AP-1 activity were assessed by gel shift assay and COX-2 by Western blotting. Coculture of SKGT-4 and OE33 with live H pylori and HPE induced NF-kappaB and AP-1 DNA-binding activity, and also decreased IkappaB-alpha levels. Treatment with the specific MEK1/2 MAPK inhibitor PD98059, but not the p38 MAPK inhibitor SB203580, inhibited NF-kappaB and AP-1 activity. The antioxidant vitamin C inhibited H pylori-induced NF-kappaB activation, but increased AP-1 expression. Moreover, HPE induced COX-2 expression and IL-8 production, and PD98059 inhibited COX-2 expression, ERK1/2 phosphorylation, and IL-8 production. These data demonstrate that both live H pylori and HPE induce NF-kappaB and AP-1 expression in esophageal epithelial cells. The induction of such transcription factors may play a role in the specific immune response within Barrett's mucosa and may indirectly cause inflammation of the gastric cardia and the distal esophagus.
 ...
PMID:Helicobacter pylori extract induces nuclear factor-kappa B, activator protein-1, and cyclooxygenase-2 in esophageal epithelial cells. 1662 21

Helicobacter pylori infection of the human gastric body induces hypochlorhydria by perturbing acid secretion. H. pylori inhibits parietal cell H,K-ATPase alpha-subunit (HKalpha) gene and protein expression, providing a mechanistic basis for clinical hypochlorhydria. Given that H. pylori infection increases gastric mucosal IL-1beta, an acid secretory inhibitor, we investigated the role of IL-1beta in H. pylori-mediated inhibition of HKalpha transcription. Human gastric adenocarcinoma (AGS) cells were transfected with promoter-reporter constructs containing human HKalpha 5'-flanking sequence deletions. IL-1beta (10 ng/ml) had no effect on the transcriptional activity of six progressively shorter deletion constructs of the HKalpha promoter (HKalpha2179-HKalpha340) and significantly stimulated the activity of HKalpha206, HKalpha177, HKalpha165, and HKalpha102 deletion constructs (80%, 100%, 46%, and 35%, respectively). H. pylori inhibited the transcriptional activity of HKalpha2179, HKalpha206, HKalpha177, and HKalpha165; IL-1beta relieved the H. pylori inhibition of HKalpha2179 and HKalpha206 activity but not HKalpha177 and HKalpha165 activity. AGS cell pretreatment with a MEK1/2 inhibitor prevented the IL-1beta-mediated stimulation, but p38 and JNK pathway inhibitors did not. IL-1beta mRNA levels in AGS cells were low and unaffected by H. pylori, and ELISAs of H. pylori-conditioned AGS culture media showed no measurable IL-1beta secretion. These data indicate that an IL-1beta-dependent cis-response element lies downstream of -206 nt in the HKalpha promoter and that IL-1beta-mediated upregulation of HKalpha transcription is affected by an ERK1/2 kinase signal pathway. We conclude that an IL-1beta-responsive HKalpha cis element positively regulates HKalpha gene transcription in shortened deletion constructs and that H. pylori-induced inhibition of HKalpha transcription is not mediated by IL-1beta.
 ...
PMID:IL-1beta modulation of H,K-ATPase alpha-subunit gene transcription in Helicobacter pylori infection. 1720 45