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:2.7.12.2 (MEK)
18,161 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The regulation of mitogen-activated protein (MAP) kinase by endothelin-1 (ET-1) in cultured rat puerperal uterine myometrial cells was investigated. ET-1 caused the rapid stimulation of MAP kinase activity. ET-1-induced MAP kinase activation is neither extracellular Ca2+- nor intracellular Ca2+-dependent. ET-1 stimulation also led to an increase in phosphorylation of son-of-sevenless (SOS), and transfection of dominant negative SOS attenuated the ET-1-induced MAP kinase activity. Phorbol-12-myristate 13-acetate (PMA) also induced the MAP kinase activity, but pretreatment of the cultured cells with PMA, to down-regulate protein kinase C (PKC), did not abolish the activation of MAP kinase by ET-1. In addition, down-regulation of PKC had no effect on ET-1-induced SOS phosphorylation. Pertussis toxin, which inactivates Gi/Go proteins, blocked the ET-1-induced MAP kinase activation but not the PMA-induced MAP kinase activation. The results suggested that MAP kinase is acutely activated by ET-1 through a pertussis toxin-sensitive G protein and SOS, not through the PMA-sensitive PKC. In addition, although reverse-transcriptase PCR assays detected messenger RNA for both ET- 1 receptor subtypes in cultured rat puerperal uterine myometrial cells, ET-1-induced MAP kinase activity and uterine contraction were blocked by treatment with BQ485, an antagonist selective for an ET type A receptor (but not by BQ788, an ET type B receptor antagonist). Ritodrine, which is known to relax uterine muscle contraction, attenuated ET-1-induced MAP kinase activity. We further examined the role of MAP kinase pathway in uterine contraction using an inhibitor of MEK activity, PD098059. This inhibitor completely inhibited the ET-1-induced MAP kinase activation and partially, but significantly, inhibited the ET-1-induced uterine contraction. These results indicate that ET-1-induced MAP kinase signaling cascade may play an important role in the ET-1-induced uterine contraction.
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PMID:Mitogen-activated protein kinase cascade is involved in endothelin-1-induced rat puerperal uterine contraction. 992 99

ICAM-1 is an Ig-like cell adhesion molecule expressed by several cell types, including the endothelium. Cross-linking of ICAM-1 on the surface of different cell types has previously been shown to cause an increase in cellular activation within the cytoplasm. In this study, we have compared signaling events following ligation of ICAM-1 by cross-linking with mAbs with events after activation of HUVEC by TNF. ICAM-1 cross-linking caused activation of Erk-1 and the AP-1 transcription factor complex, without any increase in NF-kappaB activity, in contrast to TNF stimulation. Transcription of VCAM-1 mRNA was observed by reverse-transcriptase PCR after ICAM-1 cross-linking, with no associated transcription of E-selectin. This was reflected by the presence of VCAM-1 protein after immunoprecipitation, without E-selectin expression, in ICAM-1 cross-linked cells. In contrast, mRNA and protein for both VCAM-1 and E-selectin were observed in TNF-treated HUVEC, as expected. Addition of the MEK (MAP/Erk kinase) inhibitor PD98059 reduced expression of VCAM-1 after ICAM-1 cross-linking, suggesting that the Erk pathway is involved in ICAM-1-mediated VCAM-1 expression. In conclusion, ICAM-1-induced expression of VCAM-1 represents a pathway for adhesion molecule up-regulation that is distinct from the TNF-induced pathway. It may be similar to the IL-4 pathway or it may represent a novel pathway.
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PMID:Ligation of ICAM-1 on endothelial cells leads to expression of VCAM-1 via a nuclear factor-kappaB-independent mechanism. 1007 50

The traditional view on the role of serine proteases in tumor biology has changed with the recent discovery of a family of protease-activated receptors (PARs). In this study we explored the expression and functional role of the thrombin receptor PAR-1 in human colon cancer cells. Reverse transcriptase-polymerase chain reaction analysis showed that PAR-1 mRNAs are present in 11 of 14 human colon cancer cell lines tested but not in normal human colonic epithelial cells. This is in line with the immunolocalization of PAR-1 in human colon tumors and its absence in normal human colonic mucosa. The functional significance of the aberrant expression of PAR-1 in colon cancer cells was then investigated. We found that 1) a prompt increase in intracellular calcium concentration was observed on thrombin (10 nmol/L) or PAR-1 agonist AP1 (100 micro mol/L) challenge of HT29 cells; 2) HT29 quiescent cells treated with thrombin (0.01 to 20 nmol/L) or AP1 (1 to 300 micro mol/L) exhibited dramatic mitogenic responses (3.5-fold increase in cell number). Proliferative effects of thrombin or AP1 were also observed in other colon cancer cell lines expressing PAR-1. This effect was reversed by the MEK inhibitor PD98059 in consonance with the ability of thrombin or AP1 to induce phosphorylation of p42/p44 extracellular-regulated protein kinases. 3) PAR-1 activation by thrombin or AP1 led to a two-fold increase in cell motility of wounded HT29-D4. Our results demonstrate for the first time the aberrant expression of the functional thrombin receptor PAR-1 in colon cancers and its important involvement in cell proliferation and motility. Thrombin should now be considered as a growth factor for human colon cancer.
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PMID:Aberrant expression and activation of the thrombin receptor protease-activated receptor-1 induces cell proliferation and motility in human colon cancer cells. 1270 33

Nicotinic acetylcholine receptors are found in microvascular endothelial cells. To reveal the functional role in cerebral angiogenic processes, we studied the nicotinic modulation of proliferation activity in cultured bovine and porcine cerebral microvascular endothelial cells. The proliferation activity was determined by an increase in the number of cells present in culture dishes. When the bovine cerebral endothelial cells at different passages were cultured in the presence of nicotine (10 nM), the proliferation activities were significantly increased in the cells at passage 1 and passage 3, but not at passage 4. Reverse transcriptase-polymerase chain reaction studies demonstrated that the expression of mRNAs coding for alpha3 nicotinic receptor subunit was significantly reduced in the bovine cerebral endothelial cells at passage 4, compared with that at passage 1. The proliferation of porcine cerebral endothelial cells (passage 1) was enhanced by acetylcholine (10 nM-100 microM) in the presence of atropine, a muscarinic antagonist, and this enhancing effect was inhibited by hexamethonium (100 microM, a nicotinic antagonist). The stimulation by acetylcholine (1 microM, with atropine) or nicotine (10 nM) induced the phosphorylation of a mitogen-activated protein (MAP) kinase (extracellular-signal regulated kinase: ERK) in the serum-starved endothelial cells. In the presence of PD98059 (2 microM, a MAP kinase kinase inhibitor) and atropine, acetylcholine (1 microM) failed to enhance the proliferation of porcine cerebral endothelial cells. These results demonstrate that nicotinic stimulation promotes the proliferation of bovine and porcine cerebral microvascular endothelial cells, at least in part, through the MAP kinase activation.
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PMID:Nicotinic enhancement of proliferation in bovine and porcine cerebral microvascular endothelial cells. 1557 11

In order to find a suppressor(s) of tumor progression in vivo for oral carcinoma (OC), we searched for molecules down-regulated in OC cells when the cells were treated with epidermal growth factor (EGF), whose receptor is frequently over-activated in OC. The expression of BRAK, which is also known as CXC chemokine ligand14 (CXCL14), was down-regulated significantly by the treatment of OC cells with EGF as observed by cDNA microarray analysis followed by reverse-transcriptase polymerase chain reaction analysis. The EGF effect was attenuated by the co-presence of a MEK inhibitor. The rate of tumor formation in vivo of BRAK-expressing vector-transfected tumor cells in athymic nude mice was significantly lower than that of mock vector-transfected ones. In addition tumors formed in vivo by the BRAK-expressing cells were significantly smaller than those of the mock-transfected ones. These results indicate that BRAK/CXCL14 is a chemokine, having suppressive activity toward tumor progression of OC in vivo.
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PMID:BRAK/CXCL14 expression suppresses tumor growth in vivo in human oral carcinoma cells. 1688 87

Chemokines participate in cellular processes associated with tumor proliferation, migration, and angiogenesis. We previously demonstrated that stromal cell-derived factor 1 (SDF1) exerts a mitogenic activity in glioblastomas through the activation of its receptor CXCR4. Here we studied the expression of this chemokine in human meningiomas and its possible role in cell proliferation. Reverse transcriptase-PCR analysis for CXCR4 and SDF1 was performed on 55 human meningiomas (47 WHO grade I, 5 WHO II, and 3 WHO III). Immunolabeling for CXCR4 and SDF1 was performed on paraffin-embedded sections of these tumors. [(3)H]Thymidine uptake and Western blot analyses were performed on primary meningeal cell cultures of tumors to evaluate the proliferative activity of human SDF1alpha (hSDF1alpha) in vitro and the involvement of extracellular signal-regulated kinase 1/2 (ERK1/2) activation in this process. CXCR4 mRNA was expressed by 78% of the tumor specimens and SDF1 mRNA by 53%. CXCR4 and SDF1 were often detected in the same tumor tissues and colocalized with epithelial membrane antigen immunostaining. In 9 of 12 primary cultures from meningiomas, hSDF1alpha induced significant cell proliferation that was strongly reduced by the mitogen-activated protein kinase kinase inhibitor PD98059, involving ERK1/2 activation in the proliferative signal of hSDF1alpha. In fact, CXCR4 stimulation led to ERK1/2 phosphorylation/activation. In addition, the hSDF1alpha-induced cell proliferation was significantly correlated with the MIB1 staining index in the corresponding surgical specimen. In conclusion, we found that human meningiomas express CXCR4 and SDF1 and that hSDF1alpha induces proliferation in primary meningioma cell cultures through the activation of ERK1/2.
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PMID:CXCR4 and SDF1 expression in human meningiomas: a proliferative role in tumoral meningothelial cells in vitro. 1710 64

Lung caner cells have a striking tendency to metastasize to bone. The chemokine stromal cell-derived factor-1 (SDF-1) is constitutively secreted by osteoblasts and bone marrow stromal cells and plays a key role for homing of hematopoietic cells to the bone marrow. Reverse transcriptase-polymerase chain reaction and flow cytometry studies demonstrated SDF-1 receptor (CXCR4) messenger RNA (mRNA) and surface expression of CXCR4 in lung cancer cell lines, especially higher in those with high invasiveness (A549) as compared with lower level in H928 cells and H1299 cells. SDF-1, osteoblast-conditioned medium (OBCM) and stromal cell-conditioned medium all induced the invasiveness of lung cancer cells. Matrix metalloproteinase (MMP)-9 small interfering RNA inhibited the SDF-1alpha- or OBCM-induced MMP-9 expression and thereby significantly inhibited the SDF-1alpha- or OBCM-induced cell invasion. Furthermore, mitogen-activated protein kinase kinase inhibitor PD98059 suppressed SDF-1alpha-induced MMP-9 mRNA expression. Transient transfection with dominant-negative extracellular signal-regulated kinase (ERK) mutant also showed that the ERK-signaling pathway was involved in SDF-1alpha-induced MMP-9 expression. Moreover, nuclear factor-kappaB (NF-kappaB) decoy oligodeoxynucleotide suppressed the MMP-9 promoter activity enhanced by SDF-1alpha. Both mitogen-activated protein kinase kinase inhibitor and ERK mutant also antagonized SDF-1alpha-induced NF-kappaB-driven luciferase promoter activity. Taken together, our results indicated that bone marrow-derived-SDF-1alpha enhances the invasiveness of lung cancer cells by increasing MMP-9 expression through the CXCR4/ERK/NF-kappaB signal transduction pathway.
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PMID:Involvement of matrix metalloproteinase-9 in stromal cell-derived factor-1/CXCR4 pathway of lung cancer metastasis. 1791 7

A member of a new subfamily of G protein-coupled receptors, protease-activated receptor 2 (PAR2), is highly expressed on endothelial cells and plays an important role in inflammation. The purpose of this study was to determine the molecular mechanism used by PAR2 to induce IL-8 production and thereby mediate cell adhesion. We observed that PAR2-activating peptide (PAR2-AP) significantly increase peripheral blood mononuclear cells adhere to endothelial cells. Both PAR2-AP and the endogenous PAR2 activator trypsin caused concentration- and time-dependent increase in endothelial IL-8 production, and this effect was concentration dependently and selectively attenuated by the p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580. Western blotting analysis showed that PAR2-AP induced phosphorylation of p38 MAPK and its upstream protein kinase MAPK kinase 3/6 (MKK3/6) in a time-dependent manner. Using reverse-transcriptase-polymerase chain reaction and enzyme-linked immunosorbent assay, PAR2-AP was found to cause an increase in IL-8 mRNA expression and its transcription factor activating transcription factor 2, respectively,. As expected, these signals were suppressed by SB203580 in a concentration-dependent manner. Furthermore, introduction of dominant-negative vectors targeting p38 MAPK, MKK3, and MKK6 abolished PAR2-AP-mediated IL-8 production and cell adhesion function. In conclusion, PAR2 via p38 MAPK signaling regulates IL-8 production and thereby mediates cell adhesion.
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PMID:The p38 mitogen-activated protein kinase pathway plays a critical role in PAR2-induced endothelial IL-8 production and leukocyte adhesion. 1827 46

Aurora-A is a mitotic kinase implicated in oncogenesis and is known to be overexpressed in B-cell lymphomas and plasma cell myeloma. The expression of Aurora-A kinase (henceforth referred to as Aurora-A) in T-cell lymphomas is not well characterized. In this study, we assessed Aurora-A expression by immunohistochemical analysis in 100 lymphomas encompassing a variety of T-cell lymphomas as categorized in the World Health Organization classification. Aurora-A expression was highest in anaplastic large-cell lymphomas and variably expressed in other types of T-cell lymphomas. In addition, the pattern of Aurora-A expression was predominantly cytoplasmic in ALK-positive anaplastic large-cell lymphoma and was nuclear in ALK-negative anaplastic large-cell lymphoma and other T-cell lymphomas, suggesting altered biochemical mechanisms of Aurora-A nuclear transport in ALK-positive anaplastic large-cell lymphoma. Reverse transcriptase-PCR analysis showed that Aurora-A is more highly expressed in ALK-positive anaplastic large-cell lymphoma than in ALK-negative anaplastic large-cell lymphoma, and is relatively lower in peripheral T-cell lymphomas. Using western blot analysis and the DEL cell line (derived from ALK-positive anaplastic large-cell lymphoma), we showed that Aurora-A expression is decreased after treatment with either MYC or MEK inhibitors, consistent with the MYC and MAP kinase signaling pathways being involved in driving Aurora-A expression; the greatest decrease was observed after MYC inhibition. These findings provide insights into the possible importance of Aurora-A overexpression in anaplastic large-cell lymphoma pathogenesis, and also suggest that Aurora-A inhibition could be a potential therapeutic approach for patients with anaplastic large-cell lymphoma.
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PMID:Differential expression of aurora-A kinase in T-cell lymphomas. 2341 87

In order to find a suppressor(s) of tumor progression in vivo for head and neck squamous cell carcinoma (HNSCC), we searched for molecules downregulated in HNSCC cells when the cells were treated with epidermal growth factor (EGF), whose receptor is frequently overactivated in HNSCC. The expression of BRAK, which is also known as CXC chemokine ligand 14 (CXCL14), was downregulated significantly by the treatment of HNSCC cells with EGF as observed by cDNA microarray analysis followed by reverse-transcriptase polymerase chain reaction analysis and western blotting. The EGF effect on the expression of CXCL14/BRAK was attenuated by the copresence of inhibitors of the EGF receptor, MEK, and ERK. The rate of tumor formation in vivo of BRAK-expressing vector-transfected tumor cells in athymic nude mice or SCID mice was significantly lower than that of mock vector-transfected ones. In addition tumors formed in vivo by the BRAK-expressing cells were significantly smaller than those of the mock-transfected ones. These results indicate that CXCL14/BRAK is a chemokine having suppressive activity toward tumor progression of HNSCC in vivo. Our approach will be useful to find new target molecules to suppress progression of tumors of various origins in addition to HNSCC.
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PMID:A New Strategy to Find Targets for Anticancer Therapy: Chemokine CXCL14/BRAK Is a Multifunctional Tumor Suppressor for Head and Neck Squamous Cell Carcinoma. 2376 19


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