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)

ERK5 activity is increased by agents known to activate receptor tyrosine kinases, G-protein coupled receptors, and stress response pathways. We now find a role for cAMP in the regulation of ERK5. ERK5 is activated by forskolin, isoproterenol, and epinephrine in NIH3T3 cells and C2C12 myoblasts. ERK1/2 are also activated by cAMP in NIH3T3 cells, but not in C2C12 myoblasts, demonstrating differential regulation of ERK5 and ERK1/2 by cAMP. We examined the effect of cell context on activation of ERK5 and discovered ERK5 activity is inhibited, rather than activated, by cAMP in confluent, serum-deprived NIH3T3 cells and C2C12 myoblasts. Our results suggest that regulation of MAP kinase pathways by cAMP is not only dictated by cell type, but also by cell context.
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PMID:Cell condition-dependent regulation of ERK5 by cAMP. 1229 10

1,8-Diaza-anthracene-tetraones are novel intermediates in the synthesis of the antifolate antibiotic diazaquinomycin A that was found before to have potent antitumor activity. Three of them (CV65, CV66, and CV70) were found to inhibit growth of a panel of several human tumor cell lines. The IC50s ranged from 0.05 to 1.5 microM and are comparable with that of doxorubicin. Among the three drugs, CV70 showed the highest cytotoxic activity. The growth-inhibitory action of these compounds was unrelated to the p53 status of the cells. At micromolar concentrations, all three compounds induced apoptosis, CV70 being the most proapoptotic. The incubation of HeLa cells with CV65, CV66, and CV70, at concentrations between 10 and 20 microM, inhibited the activation of c-Jun NH2-terminal kinase by various stimuli and prevented growth factor-induced extracellular signal-regulated kinase (ERK) 5 activation. At least one drug, CV65, also inhibited p38. This was surprising because proapoptotic antitumor drugs activate stress signaling pathways. Activation of ERK1/ 2 by growth factors or phorbol esters was unaffected by preincubation of cells with CV compounds. In vitro, CV compounds inhibit the enzyme quinone reductase but not c-Jun NH2-terminal kinase or ERK5. Because doxorubicin also inhibits quinone reductase, we conclude that the inhibitory effect of CV compounds on stress signaling kinases is not a direct effect on the kinases and is likely attributable to upstream elements of the activation cascades.
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PMID:Mitogen-activated protein kinase routes as targets in the action of diaza-anthracene compounds with a potent growth-inhibitory effect on cancer cells. 1249 14

The activation of natural killer (NK) cells and induction of cytotoxicity are complex processes whose molecular mechanisms have not been clearly elucidated. Stimulation of the NKL human NK cell line with interleukin-2 (IL-2) or protein-bound polysaccharide K (PSK) leads to sustained growth and cytolytic activity in comparison to unstimulated NKL cells. Our previous results shown that IL-2 and PSK regulate different nuclear transcription factors in NKL cells, and that the signal transduction pathway used by these inducers is different. To determine the molecular basis for the different action of IL-2 and PSK, we investigated the upstream effects generated in human NKL cells by IL-2 and PSK on protein kinase C (PKC) isoenzymes and mitogen-activated protein kinases (MAPK). Here we report the profile of unstimulated NKL cells as: PKCbeta>PKCalpha>PKCdelta =PKCepsilon. The PKCeta form was not expressed. The effects of PSK and IL-2 on these isoenzymes were different. IL-2 increased the expression of PKCalpha, PKCdelta and PKCepsilon, whereas PSK decreased the expression of PKCalpha, and also increased PKCdelta and PKCepsilon to higher levels than did IL-2. In MAPK expression we found that unstimulated NKL cells have the following profile: ERK2>ERK6>p38gamma>p38beta>ERK1. ERK3, ERK3 rel, ERK5/ERK4 and p38delta were not expressed. IL-2 decreased the expression of ERK2, whereas PSK did not, and both agents increased the expression of ERK3. These results shown that PSK and IL-2 produce different variations in PKC isoenzymes and MAPK in NKL cells.
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PMID:Different regulation of PKC isoenzymes and MAPK by PSK and IL-2 in the proliferative and cytotoxic activities of the NKL human natural killer cell line. 1253 41

Lead, a possible human carcinogen, affects signal transduction pathways in many aspects, yet exhibits low mutagenicity in human cells. In this study, we explore whether signaling pathways including the four MAPKs and AKT affect DNA repair and mutagenicity in the exposure of mammalian cells to lead acetate [Pb(II)]. Pb(II) increased the phosphorylated ERK1/2 and phosphorylated AKT but not the phosphorylated ERK5, phosphorylated p38 and JNK activity in human non-small cell lung adenocarcinoma CL3 cells. The duration of ERK1/2 activation was much longer than AKT activation and these two signals were independently activated by Pb(II) in CL3 cells. Intriguingly, a MKK1/2 inhibitor PD98059 (25-50 micro M) markedly suppressed ERK1/2 activation and greatly promoted the hprt mutation frequency and cytotoxicity in Pb(II)-treated CL3 cells. Conversely, inhibition of the AKT signal by wortmannin did not exhibit such effects. Inhibition of the persistently activated ERK1/2 in Pb(II)-treated diploid human fibroblasts by PD98059 also markedly increased the mutagenicity and cytotoxicity. The Pb(II)-induced mutagenicity and cytotoxicity were significantly higher in nucleotide excision repair (NER)-deficient UVL-10 rodent cells than their counterpart AT3-2 cells; also, ERK1/2 activation by Pb(II) was observed in AT3-2 but not UVL-10 cells. Furthermore, cellular NER synthesis was enhanced by Pb(II) exposure, which was markedly suppressed by PD98059. Activation of ERK1/2 by expressing a constitutively active form of MKK1 in CL3 cells also elevated cellular NER synthesis. Together, these results indicate that persistent activation of ERK1/2 signaling by Pb(II) enhances cellular NER synthesis, thereby conferring anti-cytotoxicity and anti-mutagenicity.
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PMID:Persistent activation of ERK1/2 by lead acetate increases nucleotide excision repair synthesis and confers anti-cytotoxicity and anti-mutagenicity. 1253 49

The novel mitogen/extracellular-signal-regulated kinase kinase 5/extracellular signal-regulated kinase-5 (MEK5/ERK5) pathway has been implicated in the regulation of cellular proliferation. MEK5 expression has been detected in prostate cancer cells, although the significance of the MEK5/ERK5 pathway in human prostate cancer has not been tested. We examined MEK5 expression in 127 cases of prostate cancer and 20 cases of benign prostatic hypertrophy (BPH) by immunohistochemistry and compared the results to clinical parameters. We demonstrated that MEK5 expression is increased in prostate cancer as compared to benign prostatic tissue. Strong MEK5 expression correlates with the presence of bony metastases and less favourable disease-specific survival. Furthermore, among the patients with high Gleason score of 8-10, MEK5 overexpression has an additional prognostic value in survival. MEK5 transfection experiments confirm its ability to induce proliferation (P < 0.0001), motility (P = 0.0001) and invasion in prostate cancer cells (P = 0.0001). MEK5 expression drastically increased MMP-9, but not MMP-2 mRNA expression. Luciferase report assays suggest that the -670/MMP-9 promoter is upregulated by MEK5 and electromobility shift assay further suggests the involvement of activator protein-I (AP-1), but not the NF-kappa B, binding site in the MMP-9 promoter. Using an AP-1 luciferase construct, activation of MEK5 was confirmed to enhance AP-1 activities up to twofold. Taken together, our results establish MEK5 as a key signalling molecule associated with prostate carcinogenesis. As the MEK5/ERK5 interaction is highly specific, it represents a potential target of therapy.
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PMID:MEK5 overexpression is associated with metastatic prostate cancer, and stimulates proliferation, MMP-9 expression and invasion. 1261 64

The gap junction protein, Cx43, plays a pivotal role in coupling cells electrically and metabolically, and the putative phosphorylation sites that modulate its function are reflected as changes in gap junction communication. Growth factor stimulation has been correlated with a decrease in gap junction communication and a parallel activation of ERK1/2; the inhibition of epidermal growth factor (EGF)-induced Cx43 gap junction uncoupling was observed by using the MEK1/2 inhibitor, PD98059. Because 1) BMK1/ERK5, another MAPK family member also activated by growth factors, possesses a phosphorylation motif similar to ERK1/2, and 2) it has been reported that PD98059 can inhibit not only MEK1/2-ERK1/2 but also MEK5-BMK1 activation, we investigated whether BMK1 can regulate EGF-induced Cx43 gap junction uncoupling and phosphorylation, comparing this to the role of ERK1/2 on Cx43 function and phosphorylation induced by EGF. Selective activation or inactivation of ERK1/2 by using a constitutively active form or a dominant negative form of MEK1 did not regulate Cx43 gap junction coupling. In contrast, we found that BMK1, selectively activated by constitutively active MEK5alpha, induced gap junction uncoupling, and the inhibition of BMK1 activation by transfection of dominant negative BMK1 prevented EGF-induced gap junction uncoupling. Activated BMK1 selectively phosphorylates Cx43 on Ser-255 in vitro and in vivo, but not on S279/S282, which are reported as the consensus phosphorylation sites for MAPK. Furthermore, by co-immunoprecipitation, we found that BMK1 directly associates with Cx43 in vivo. These data indicate that BMK1 is more important than ERK1/2 in EGF-mediated Cx43 gap junction uncoupling by association and Cx43 Ser- 255 phosphorylation.
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PMID:Regulation of epidermal growth factor-induced connexin 43 gap junction communication by big mitogen-activated protein kinase1/ERK5 but not ERK1/2 kinase activation. 1263 2

The present study was undertaken to elucidate the G-protein and mitogen-activated kinase (MAP kinase) coupled signaling profile in a genetic model of hypertension and congestive heart failure (CHF) that mimics similar disease in humans. At the receptor level, Ang II type 1 receptor (AT1R) increased in left ventricular hypertrophy (LVH) and reverted to normal in CHF, whereas there was a downregulation of the Ang II type 2 receptor (AT2R) in CHF. At the transducer level, Galphaq and Galpha12 protein levels were unchanged during LVH but decreased significantly in CHF. In contrast, Gbeta and Galpha13 protein content were markedly upregulated in CHF. Furthermore, using phospho-specific antibodies in Western blots and in vitro kinase assays, we found at the effector level an upregulation of the small G-protein Rac1 activity during LVH but a decrease during CHF. In parallel, small G-protein Rho activity was significantly increased during LVH but was unchanged in failure. We found at the downstream level that MAP kinase isoforms extracellular signal regulated-kinase (ERK1/2), big mitogen-activated kinase (BMK1/ERK5), C-jun N-terminal-activated kinase (JNKs/SAPKs), and stress-activated kinase (p38) bioactivities were increased during LVH. During CHF, ERK1/2 and JNK1/2 kinase activities were decreased, whereas BMK1/ERK5 kinase activity reverted to normal values. In conclusion, this study demonstrates, for the first time, multistep alterations of G-protein and MAP kinase signaling pathways in LVH and progression to failure in a genetic model of hypertension and failure.
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PMID:Alterations in G protein and MAP kinase signaling pathways during cardiac remodeling in hypertension and heart failure. 1264 4

MAPK/ERK kinase kinase 2 (MEKK2) is a member of the mitogen-activated protein kinase kinase kinase (MAP3K) family of protein kinases. MAP3Ks are components of a three-tiered protein kinase pathway in which a MAP3K phosphorylates and activates a mitogen-activated protein kinase kinase (MAP2K), which in turn activates a mitogen-activated protein kinase (MAPK). We have previously identified residues within protein kinase subdomain X in the MAP3K, MEKK1, that are critical for its interaction with the MAP2K, MKK4, and MEKK1-induced MKK4 activation. We report here that kinase subdomain X also plays a critical role in MEKK2 activity. Select point mutations in subdomain X impair MEKK2 phosphorylation of the MAP2Ks, MKK7 and MEK5, abolish MEKK2-induced activation of the MAPKs, JNK1 and ERK5, and diminish MEKK2-dependent activation of an AP-1 reporter gene. Interestingly, the spectrum of mutations in subdomain X of MEKK2 that affects its activity is overlapping with but not identical to those that have effects on MEKK1. Thus, mutations in subdomain X differentially affect MEKK2 and MEKK1.
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PMID:Mutations in protein kinase subdomain X differentially affect MEKK2 and MEKK1 activity. 1265 51

Reactive oxygen species (ROS) are generated during cellular metabolism or by external factors. Recently, it was learned that ROS can stimulate cellular proliferation and act as a second messenger in cellular signaling. We previously reported that hydroxyl radicals might be the signaling molecules. In the present experiment, phenazine methosulfate (PMS) was used to generate superoxide anion intracellularly. Treatment with 3 microM PMS in V79 cells increased cellular proliferation by 50%. PMS also activated the c-Jun N-terminal kinase (JNK) and p38 MAPK, but not extracellular signal-regulated kinase (ERK) 1/2 and ERK5. In particular, increased proliferation was blocked by pretreatment with SB203580 (an inhibitor of p38 MAPK). At the transcriptional level, the phosphorylation of c-Jun and ATF-2, which are mediated by JNK and p38 MAPK, were also increased by treatment with PMS.
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PMID:Cell proliferation induced by reactive oxygen species is mediated via mitogen-activated protein kinase in Chinese hamster lung fibroblast (V79) cells. 1266 67

Atherosclerosis preferentially occurs in areas of turbulent flow and low fluid shear stress, while laminar flow and high shear stress are atheroprotective. Well characterized atheroprotective mechanisms include inhibition of thrombosis (increased tissue-type plasminogen activator and decreased plasminogen activator inhibitor-1), inhibition of endothelial cell apoptosis, limitation of permeability (uptake of low-density lipoprotein), prevention of white blood cell binding and transmigration (no expression of adhesion molecules such as intercellular adhesion molecule-1 [ICAM-1] and vascular cell adhesion molecule-1 [VCAM-1] and no release of monocyte chemotactic protein-1) and increased bioavailability of nitric oxide (because of increased expression of endothelial nitric oxide synthase and manganese superoxide dismutase). Our lab has investigated flow-mediated inhibition of inflammatory cytokine action. In particular, we have shown that flow prevents tumor necrosis factor-alpha (TNF-alpha) mediated signal transduction. TNF regulates inflammatory gene expression (e.g., ICAM-1 and VCAM-1) in endothelial cells, in part, by stimulating mitogen activated protein (MAP) kinases that phosphorylate transcription factors. We hypothesized that fluid shear stress inhibits TNF inflammatory effects on endothelial cells by inhibiting TNF mediated activation of the c-Jun N-terminal kinase. To test this hypothesis, we determined the effects of steady laminar flow on TNF-stimulated activity of c-Jun N-terminal kinase. The results show that flow inhibits c-Jun N-terminal kinase activation through multiple mechanisms, including stimulation of counter-regulatory MAP kinases (extracellular signal regulated kinases [ERK]1/2 and ERK5) and inhibition of apoptosis signal-regulated kinase. In summary, the atheroprotective effects of steady laminar flow on the endothelium involve multiple synergistic mechanisms. These multiple mechanisms offer attractive targets for new drug therapies aimed at limiting atherosclerosis development and progression. (c) 2002 Prous Science. All rights reserved.
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PMID:Atheroprotective Mechanisms Activated by Fluid Shear Stress in Endothelial Cells. 1267 55


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