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)

1alpha,25-Dihydroxyvitamin D3 added to human keratinocytes increases differentiation through an activation of the transcription factor activator protein 1. We have previously reported that the 1alpha,25-dihydroxyvitamin D3-induced increase of activator protein 1 DNA binding activity is mediated by a protein kinase C-independent mechanism. The purpose of this study was to investigate further the mechanisms by which 1alpha,25-dihydroxyvitamin D3 modulates activator protein 1 DNA binding activity in cultured normal human keratinocytes. Western blotting experiments revealed that 1alpha,25-dihydroxyvitamin D3 caused a rapid and transient activation of the mitogen-activated protein kinases, extracellular signal regulated kinase 1/2 and c-Jun N-terminal kinase 1. 1alpha,25-Dihydroxyvitamin D3 also enhanced the expression of the activator protein 1 subunits, c-Fos, Fra1, and c-Jun as determined by northern and western blotting. The 1alpha,25-dihydroxyvitamin D3-induced activator protein 1 DNA binding activity was completely blocked by the MEK inhibitor PD 98059 indicating that the MEK/extracellular signal regulated kinase pathway is involved in the activation of activator protein 1. Transfection experiments showed that 1alpha,25-dihydroxyvitamin D3 also increased the activator protein 1-dependent transactivation, which was completely blocked by expression of a dominant negative Ras, suggesting that the 1alpha,25-dihydroxyvitamin D3-induced activator protein 1 activity involves Ras-dependent signaling. Furthermore, preincubation of the keratinocytes with the specific phosphatidylinositol 3-kinase inhibitors, Wortmannin and LY294002, demonstrated that the 1alpha,25-dihydroxyvitamin D3-induced activation of extracellular signal regulated kinase 1/2 and c-Jun N-terminal kinase 1 required phosphatidylinositol 3-kinase activity. Finally, preincubation of keratinocytes with a polyclonal antibody against the membrane receptor annexin II, blocked the 1alpha,25-dihydroxyvitamin D3-induced activation of extracellular signal regulated kinase 1/2 and c-Jun N-terminal kinase 1. Taken together, our results indicate that 1alpha,25-dihydroxyvitamin D3, via binding to the membrane receptor annexin II, induces activation of the phos-phatidylinositol 3-kinase/Ras/MEK/extracellular signal regulated kinase 1/2 and c-Jun N-terminal kinase 1 signal transduction pathway resulting in increased expression of c-Fos, Fra1, and c-Jun, and subsequently increased activator protein 1 DNA binding activity and gene transcription.
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PMID:1alpha,25-dihydroxyvitamin D3 stimulates activator protein 1 DNA-binding activity by a phosphatidylinositol 3-kinase/Ras/MEK/extracellular signal regulated kinase 1/2 and c-Jun N-terminal kinase 1-dependent increase in c-Fos, Fra1, and c-Jun expression in human keratinocytes. 1264 18

Stimulation of the APC by Porphyromonas gingivalis LPS has been shown to result in the production of certain pro- and anti-inflammatory cytokines. However, the signaling pathways that regulate these processes are currently unknown. In the present study, the role of the phosphatidylinositol 3 kinase (PI3K)-Akt pathway in regulating P. gingivalis LPS-induced production of IL-10, IL-12 p40, and IL-12 p70 by human monocytes was investigated. P. gingivalis LPS selectively activates the PI3K-Akt pathway via Toll-like receptor 2, and inhibition of this pathway results in an abrogation of extracellular signal-regulated kinase 1/2 phosphorylation, whereas the activation of p38 and c-Jun N-terminal kinase 1/2 kinases were unaffected. Analysis of cytokine production following stimulation of monocytes with P. gingivalis LPS revealed that inhibition of the PI3K pathway differentially regulated IL-10 and IL-12 synthesis. IL-10 production was suppressed, whereas IL-12 levels were enhanced. Inhibition of P. gingivalis LPS-mediated activation of the PI3K-Akt pathway resulted in a pronounced augmentation of NF-kappaB p65 that was independent of IkappaB-alpha degradation. Furthermore, the ability of the PI3K-Akt pathway to modulate IL-10 and IL-12 production appears to be mediated by the selective suppression of extracellular signal-regulated kinase 1/2 activity, as the MEK1 inhibitor PD98059 closely mimicked the effects of wortmannin and LY294002 to differentially regulate IL-10 and IL-12 production by P. gingivalis LPS-stimulated monocytes. These studies provide new insight into how engagement of the PI3K-Akt pathway by P. gingivalis LPS affects the induction of key immunoregulatory cytokines that control both qualitative and quantitative aspects of innate and adaptive immunity.
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PMID:Role of the phosphatidylinositol 3 kinase-Akt pathway in the regulation of IL-10 and IL-12 by Porphyromonas gingivalis lipopolysaccharide. 1284 38

Overexpression of catalase, but not manganese superoxide dismutase (MnSOD), inhibited glucose deprivation-induced cytotoxicity and c-Jun N-terminal kinase 1 (JNK1) activation in human prostate adenocarcinoma DU-145 cells. Suppression of JNK1 activation by catalase overexpression resulted from inhibition of apoptosis signal-regulating kinase 1 (ASK1) activation by preventing dissociation of thioredoxin (TRX) from ASK1. Overexpression of catalase also inhibited relocalization of Daxx from the nucleus to the cytoplasm as well as association of Daxx with ASK1 during glucose deprivation. Taken together, hydrogen peroxide (H(2)O(2)) rather than superoxide anion (O(2) (*-)) acts as a second messenger of metabolic oxidative stress to activate the ASK1-MAPK/extracellular signal-regulated kinase (ERK) kinase (MEK)-mitogen-activated protein kinase (MAPK) signal transduction pathway.
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PMID:Catalase, but not MnSOD, inhibits glucose deprivation-activated ASK1-MEK-MAPK signal transduction pathway and prevents relocalization of Daxx: hydrogen peroxide as a major second messenger of metabolic oxidative stress. 1450 47

Activating transcription factor 2 (ATF2) has been shown to regulate gene expression in the cellular response to environmental stresses such as ultraviolet (UV) irradiation. However, the signal transduction mechanism of ATF2 activation by UV is not as yet completely understood. In the present study, we provide evidence showing that UVC-stimulated phosphorylation of ATF2 (Thr71) was to varying degrees prevented by a dominant negative mutant of p38beta kinase, c-Jun N-terminal kinase 1 (JNK1) or extracellular signal-regulated kinase 2 (ERK2). The phosphorylation was also suppressed by PD98059, an MEK inhibitor, or H89, a potent inhibitor of mitogen- and stress-activated protein kinase 1 (MSK1), and a C- or N-terminal 'kinase-dead' mutant of MSK1 (MSK1-Cd or MSK1-Nd). Furthermore, co- immunoprecipitation experiments revealed a potential intracellular signaling complex consisting of ATF2 and ERKs and/or MSK1. In vitro kinase assays revealed that ERK1, ERK2 and MSK1, like p38 kinase and JNK2, directly phosphorylate ATF2 at Thr71, but addition of RSK2 or Akt1 had almost no effect. Active kinase immunoprecipitated by an MSK1, ERKs or p38 antibody from an extract of JB6 cells irradiated by UVC can directly phosphorylate ATF2 at Thr71, suggesting UVC induces a direct phosphorylation of ATF2 by ERKs or MSK1. Overall, our results reveal that MSK1 and ERKs, like p38 kinase and JNKs, are required for ATF2 phosphorylation (Thr71) in the UVC response.
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PMID:Involvement of ERKs and mitogen- and stress-activated protein kinase in UVC-induced phosphorylation of ATF2 in JB6 cells. 1519 15

Mechanical forces related to pressure and flow are important for cell hypertrophy and proliferation. There are still a few studies that examine responses of human vascular smooth muscle cells to pure pressure stress (transmural pressure). It is unclear as to which mechanisms are involved in cellular responses to pressure elevation. On the other hand, although the involvement of the local renin-angiotensin system (RAS) in pressure-induced responses was reported, the results were contradictory. It still remains to be determined whether RAS in human vascular smooth muscle cells is activated by pure pressure stress. We studied the upstream signal transduction events of extracellular signal kinase (ERK) in response to atmospheric pressure stress and involvement of angiotensin II in pressure-induced cell proliferation in human aortic smooth muscle cells (HASMC). A pressure-loading apparatus was set up to examine the effects of atmospheric pressure on human aortic smooth muscle cells. Pressure application of 160 mmHg for 3 h produced cell proliferation and activated ERK and c-JUN N-terminal kinase (JNK). ACE inhibitor suppressed all of them. ERK kinase (MEK) inhibitor also suppressed cell proliferation stimulated by pure pressure. The phosphorylated c-Src was increased by pure pressure stress. The treatment with c-Src kinase inhibitor suppressed pressure-induced proliferative response. In summary, our study found that ERK activation mediated pure pressure-induced proliferative response of HASMC. This activation was partly mediated by c-Src.
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PMID:N-terminal kinase, and c-Src are activated in human aortic smooth muscle cells by pressure stress. 1553 11

Bovine type I collagen (BIC), which is widely used as a fibrous extracellular matrix component in cell culture models, inhibits the progression of melanoma cell cycle via p27 up-regulation. BIC also induces nitric oxide synthase in macrophages through JunB/AP-1 and NF-kappaB activation. Given the previous observations, this study investigates the effect of BIC on the cell cycle progression and regulatory function of Raw264.7 macrophage cells and the responsible signaling pathways. Cell cycle analysis revealed that BIC completely suppressed proliferation of Raw264.7 cells with inhibition of the percentage of cells in the S phase and the reciprocal decrease in the G0/G1 phase. DNA synthesis was also inhibited by BIC, as evidenced by a decrease in the cellular incorporation of [3H]thymidine. The G1/S arrest induced by BIC was reversed by chemical inhibition of phosphatidylinositol 3-kinase (PI3-kinase) or overexpression of the p85 subunit of PI3-kinase. Either PD98059 or stable transfection with mitogen-activated protein kinase kinase-1 [MKK1(-)] or c-Jun N-terminal kinase 1 [JNK1(-)] also released the cell cycle arrest. Immunoblot analyses revealed that the levels of cyclins D1, A and B1 were partly or completely down-regulated by BIC, but cyclin E, p21 and p27 were minimally changed. Chemical inhibition and dominant negative mutant overexpression experiments revealed that either PI3-kinase inhibition or JNK1(-) transfection prevented the decreases in cyclin D1, A and B1 by BIC, indicating that the PI3-kinase and JNK1 pathways were associated with disruption of the cyclins. The pathway involving MKK1-extracellular signal-regulated kinase-1/2 (ERK1/2) was responsible for the suppression of cyclin A and B1, but not that of cyclin D1. The present study showed that BIC inhibited proliferation of Raw264.7 cells and that the pathways involving PI3-kinase and mitogen-activated protein kinases regulate the cell cycle arrest.
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PMID:Bovine type I collagen inhibits Raw264.7 cell proliferation through phosphoinositide 3-kinase- and mitogen-activated protein kinase-dependent down-regulation of cyclins D1, A and B1. 1587 97

Interferon alpha (IFN-alpha) inhibits growth, at least in part, through induction of apoptosis. However, the molecular mechanisms underlying IFN-alpha-induced apoptosis are not completely understood. In the present study, we found that IFN-alpha induced a sustained activation of c-Jun N-terminal kinase 1 (JNK1), but not extracellular kinases (ERKs), in Daudi B lymphoma cells, as assessed by Western blotting using phospho-specific antibodies. Several lines of evidence support the notion that the IFN-alpha-induced activation of JNK is responsible for IFN-alpha-induced apoptosis, at least in part, through upregulation of TNF-related apoptosis-inducing ligand (TRAIL). First, pretreatment of Daudi cells with a JNK inhibitor reduced IFN-alpha-induced upregulation of TRAIL and loss of mitochondrial membrane potential (DeltaPsim) and annexin-positive cells, which was assessed by flow cytometry. Second, a dominant-negative form of JNK1 (dnJNK1) also reduced these apoptotic events, while a constitutively active form of JNK1, MKK7-JNK1beta, enhanced them. Finally, treatment with IFN-alpha enhanced the promoter activity of the TRAIL gene, which was partially abrogated by either JNK inhibitor or dnJNK1, while it was moderately enhanced by MKK7-JNK1beta. These findings are useful for understanding molecular mechanisms of IFN-alpha-induced apoptosis and also for development of treatment modalities of some tumors with IFN-alpha.
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PMID:Requirement of c-Jun NH2-terminal kinase activation in interferon-alpha-induced apoptosis through upregulation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in Daudi B lymphoma cells. 1609 54

Numerous studies have demonstrated the neuroprotective effects of estrogen in experimental cerebral ischemia. To investigate molecular mechanisms of estrogen neuroprotection in global ischemia, immunoblotting, immunohistochemistry and Nissel-staining analysis were used. Our results showed that chronic pretreatment with beta-estradiol 3-benzoate (E2) enhanced Akt1 activation and reduced the activation of mixed-lineage kinase 3 (MLK3), mitogen-activated protein kinase kinase 4/7 (MKK4/7), and c-Jun N-terminal kinase 1/2 (JNK1/2) in the hippocampal CA1 subfield during reperfusion after 15 min of global ischemia. In addition, E2 reduced downstream JNK nuclear and non-nuclear components, c-Jun and Bcl-2 phosphorylation and Fas ligand protein expression induced by ischemia/reperfusion. Administration of phosphoinositide 3-kinase (PI3K) inhibitor LY 294,002 prevented both activation of Akt1 and inhibition of MLK3, MKK4/7 and JNK1/2. The interaction between ERalpha and the p85 subunit of PI3K was also examined. E2 and antiestrogen ICI 182,780 promoted and prevented this interaction, respectively. Furthermore, ICI 182,780 blocked both the activation of Akt1 and the inhibition of MLK3, MKK4/7 and JNK1/2. Photomicrographs of cresyl violet-stained brain sections showed that E2 reduced CA1 neuron loss after 5 days of reperfusion, which was abolished by ICI 182,780 and LY 294,002. Our data indicate that in response to estrogen, ERalpha interacts with PI3K to activate Akt1, which may inhibit the MLK3-MKK4/7-JNK1/2 pathway to protect hippocampal CA1 neurons against global cerebral ischemia in male rats.
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PMID:Inhibition of MLK3-MKK4/7-JNK1/2 pathway by Akt1 in exogenous estrogen-induced neuroprotection against transient global cerebral ischemia by a non-genomic mechanism in male rats. 1706 55

Matrix metalloproteinases (MMPs) contribute to the matrix-degrading phenotype of mycobacterial diseases. Considering that MMPs could contribute to the mutual exacerbation of both Mycobacterium avium and HIV in coinfections, it is of importance to understand the mechanisms of M. avium-induced MMP induction. Focusing on MMP-9, our work demonstrates that a cyclooxygenase-2 (COX-2)-dependent signalling loop is critical for activation of MMP-9 transcription in RAW264.7 cells and murine bone marrow-derived macrophages. M. avium-stimulated MMP-9 induction involves the p65 and p50 subunits of NF-kappaB and the c-Fos and c-jun subunits of AP-1. The c-Fos gene is upregulated in a MEK1-dependent manner in M. avium-challenged macrophages. M. avium-induced MMP-9 gene induction requires the histone acetyltransferase p300 and chromatin modifications involving phosphorylation of p65 at serine 276 and its acetylation at lysines 221 and 310. At the same time, histone H3 modified by mitogen and stress-activated protein kinase 1 (MSK1)-dependent phosphorylation on serine 10 and by acetylation on lysine 14, typical signatures linked to transcriptional activation, also associates with the MMP-9 promoter following M. avium challenge. Taken together, our results show that co-ordinated post-translational modifications of p65 and histone H3 involving phosphorylation and acetylation drive COX-2-dependent transcriptional activation of the MMP-9 gene in response to challenge of macrophages with M. avium.
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PMID:Mycobacterium avium-induced matrix metalloproteinase-9 expression occurs in a cyclooxygenase-2-dependent manner and involves phosphorylation- and acetylation-dependent chromatin modification. 1759 Jan 63

Protein kinase C (PKC) has been shown to be a signal transducer during tumorigenesis, tumor cell invasion, and metastasis. Recent studies have reported that the PKC inhibitor, 7-hydroxystaurosporine, inhibits tumor cell invasion. However, the molecular mechanisms of this inhibition of invasion and metastasis are not well understood. In the present study, we attempt to clarify the mechanism by which H7, a PKC inhibitor, inhibits tumor cell invasion and metastasis in the melanoma cell line B16BL6. It was found that H7 inhibits B16BL6 cell invasion and metastasis. We also observed that H7 inhibits the mRNA expression and protein activities of matrix metalloproteinase (MMP)-1, -2, -9 and MT1-MMP. Furthermore, H7 suppresses phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2). However, other signal transduction factors, such as p38 mitogen-activated protein kinase (p38MAPK) and c-Jun N-terminal kinase 1/2 (JNK1/2), were unaffected. Moreover, U0126, a MEK1/2 inhibitor, also inhibited B16BL6 cell invasion and metastasis, as well as the mRNA expression and protein activities of MMP-1, -2, -9 and MT1-MMP. This indicates that H7 inhibits signal transduction through the PKC/MEK/ERK pathway, thereby inhibiting B16BL6 cell invasion and metastasis. These results suggest that PKC inhibitors have potential clinical applications in the treatment of tumor cell metastasis.
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PMID:The protein kinase C inhibitor, H7, inhibits tumor cell invasion and metastasis in mouse melanoma via suppression of ERK1/2. 1763 10


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