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)

We recently demonstrated through theoretical modeling that the exhaled ethanol (EtOH) profile from humans is consistent with a molecular diffusion coefficient (cm2/s) in the bronchial mucosa (Dti) that is only 8% of the diffusion coefficient in water (Dw; J. Appl. Physiol. 75: 2439-2449, 1993). Because of the small oil-water partition coefficient (lambda o:w) of EtOH (lambda o:w = 0.074), the reduced diffusion coefficient may be due, in part, to the epithelial tight junction in the paracellular pathway. We hypothesized that opening the tight junction would open an aqueous pathway and increase the diffusion coefficient of small (mol wt < 100) hydrophilic compounds. We mounted the mucosa from the membranous canine trachea in an Ussing-type diffusion cell and measured the diffusion coefficient of 2-ethoxyethanol (2-Ethx; lambda o:w = 0.042), EtOH, and methyl ethyl ketone (MEK; lambda o:w = 1.04) in the presence and absence of the epithelial tight junction. The tight junction was opened using a phosphate-buffered saline free of Ca2+ and Mg2+ with 0.5 mM ethylene glycol-bis (beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid, and its integrity was assessed by measuring the transepithelial electrical resistance. Dti/Dw in the presence of Ca2+ and Mg2+ was 0.39, 0.34, and 0.39 for 2-Ethx, EtOH, and MEK, respectively, and increased 24.6, 11.7, and 1.11% in the absence of Ca2+ and Mg2+. We conclude that the effect of the tight junction on Dti increases with increasing water solubility but can account for only a small portion of the reduced Dti of EtOH as predicted by exhaled profiles.
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PMID:Diffusion of nonelectrolytes in the canine trachea: effect of tight junction. 872 56

The cellular mechanisms that underlie nerve growth factor (NGF) induced increase in Ca(2+)-channel current in adult bullfrog sympathetic B-neurons were examined by whole cell recording techniques. Cells were maintained at low density in neuron-enriched, defined-medium, serum-free tissue culture for 6 days in the presence or absence of NGF (200 ng/ml). The increase in Ba2+ current (IBa) density induced by NGF was attenuated by the RNA synthesis inhibitor cordycepin (20 microM), by the DNA transcription inhibitor actinomycin D (0.01 microgram/ml), by inhibitors of Ras isoprenylation (perillic acid 0.1-1.0 mM or alpha-hydroxyfarnesylphosphonic acid 10-100 microM), by tyrosine kinase inhibitors genistein (20 microM) or lavendustin A (1 microM), and by PD98059 (10-100 microM), an inhibitor of mitogen-activated protein kinase kinase. Inhibitors of the phosphatidylinositol 3-kinase (PI3K) pathway (wortmannin, 100 nM, or LY29400, 100 microM) were ineffective as were inhibitors of phospholipase C gamma (U73122 or neomycin, both 100 microM). The effect of NGF persisted in Ca(2+)-free medium that contained 1.8 mM Mg2+ and 2 mM ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid. It was mimicked by a Trk antibody that was capable of inducing neurite outgrowth in explant cultures of bullfrog sympathetic ganglion. Antibodies raised against the low-affinity p75 neurotrophin receptor were ineffective in blocking the effect of NGF on IBa. These results suggest that NGF-induced increase in Ca2+ channel current in adult sympathetic neurons results, at least in part, from new channel synthesis after Trk activation of Ras and mitogen activated protein kinase by a mechanism that is independent of extracellular Ca2+.
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PMID:Involvement of Ras/MAP kinase in the regulation of Ca2+ channels in adult bullfrog sympathetic neurons by nerve growth factor. 974 44

Monocyte chemotactic protein-1 (MCP-1), a potent chemoattractant for monocytes, is thought to play a major role in atherosclerosis, but whether its atherogenic effects involve the direct modulation of vascular smooth muscle cell (SMC) functions remains unclear. This study examined the effects of MCP-1 on the migration of cultured A7r5 SMCs and the signaling pathways involved. Addition of recombinant MCP-1 stimulated SMC migration in modified Boyden chambers coated with type I collagen in a concentration-dependent manner, with 10(-9) M being maximally effective. Using untreated A7r5 cells, two MCP-1 receptors, CCR2 and CCR4, were detected and MCP-1 secretion was significantly increased by stimulation with platelet-derived growth factor. MCP-1-stimulated A7r5 migration was completely blocked by the NAD(P)H oxidase inhibitor, diphenylene iodonium (DPI), and dose-dependently inhibited by polyethylene glycol-conjugated superoxide dismutase (PEG-SOD), suggesting a role for reactive oxygen species (ROS) in this process. During MCP-1 stimulation, ROS production increased rapidly, then gradually decayed over 60 min, and this effect was markedly decreased by pretreatment with DPI or PEG-SOD. Interestingly, U0126 and PD98059, which inhibit activation of extracellular signal-regulated kinases 1/2 (ERK 1/2), significantly inhibited MCP-1-activated ROS generation. Furthermore, transfection of an active mutant of MEK1 (ERK 1/2 kinase) markedly increased superoxide production in rat aortic smooth muscle cells, as detected by dihydroethydium staining, suggesting that ERK 1/2 activation stimulates ROS generation. ERK 1/2 activation was increased for at least 30 min in cells incubated with MCP-1, and this effect was abolished by U0126 or DPI pretreatment. These results demonstrate that MCP-1 is a chemoattractant for SMCs and that MCP-1-stimulated migration requires both ROS production and ERK 1/2 activation in a positive activation loop, which may contribute to the atherogenic effects of MCP-1.
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PMID:Reactive oxygen species and ERK 1/2 mediate monocyte chemotactic protein-1-stimulated smooth muscle cell migration. 1591 91

In Caenorhabditis elegans, several distinct apoptosis pathways have been characterized in the germline. The physiological pathway is though to eliminate excess germ cells during oogenesis to maintain gonad homeostasis and it is activated by unknown mechanisms. The DNA damage-induced germ cell apoptosis occurs in response to genotoxic agents and involves the proteins EGL-1 and CED-13, and the DNA damage response protein p53. Germ cell apoptosis can also be induced in response to pathogen infection through an EGL-1 dependent pathway. To gain insight into the mechanism and functions of germ cell apoptosis, we investigated whether and how other forms of stress induce this cell death. We found that oxidative, osmotic, heat shock and starvation stresses induce germ cell apoptosis through a p53 and EGL-1 independent pathway. We also learned that the MAPK kinases MEK-1 and SEK-1, and the p53 antagonist protein ABL-1, are essential for stress-induced germ cell apoptosis. We conclude that in C. elegans responses to various stresses that do not involve genotoxicity include an increase in germ cell apoptosis through the physiological pathway.
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PMID:Stress-induced germ cell apoptosis by a p53 independent pathway in Caenorhabditis elegans. 1672 24

We previously reported that PEGylated conjugated linoleic acid (PCLA) as a pro-drug treatment of cultures of 3T3-L1 cells containing differentiated adipocytes caused de-differentiation by downregulation of PPARgamma2-induced adipogenesis, and cell apoptosis induced by PCLA was lower than that induced by conjugated linoleic acid (CLA) owing to the biocompatible and hydrophilic properties of poly(ethylene glycol) (PEG). To further investigate our previous observations, the present study is designed to evaluate the lipolytic action of PCLA and its role in biochemical signaling pathways of 3T3-L1 cells when compared to the CLA itself. Although both CLA and PCLA stimulated lipolysis, our results indicated a sensitivity difference between CLA and PCLA treatment: a time-dependent effect on lipolysis and p-extracellular signal-related kinases (ERK) expression was observed for PCLA-treated, but not for CLA-treated cultures. Also, the induction by PCLA of mitogen-activated protein kinase kinase (MEK)/ERK mitogen-activated protein kinase (MAPK) activation was linked to secretion of adipo-cytokines, interleukin-6 (IL-6), and interleukin-8 (IL-8), in time-dependent manners. Interestingly, adenylyl cyclase inhibitor, 2', 5'-dideoxyadenosine (DDA), pre-treatment did not prevent PCLA-stimulated lipolysis. In fact, isoproterenol, but not PCLA, caused a significant increase in cyclic adenosine monophosphate (cAMP) levels, suggesting that the PCLA-induced lipolysis was not mediated in the conventional cAMP-dependent pathway and the cAMP was the intracellular mediator for isoproterenol-induced lipolysis. Overall, our findings provide support for a role for PCLA as a pro-drug in the regulation of metabolism in adipose tissue.
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PMID:Lipolysis is stimulated by PEGylated conjugated linoleic acid through the cyclic adenosine monophosphate-independent signaling pathway in 3T3-L1 cells: activation of MEK/ERK MAPK signaling pathway and hyper-secretion of adipo-cytokines. 1765 85

The ipomoelin gene (IPO) was identified to be a wound-inducible gene from Ipomoea batatas, and its expression was stimulated by methyl jasmonate (MeJA) and hydrogen peroxide. IPO protein was also characterized as a defence-related protein, and it is also a carbohydrate-binding protein. In this study, the expression of IPO was used as a molecular probe to study the effects of Ca2+ on the signal transduction of ethylene. A confocal microscope monitored the Ca2+ within cells, and Northern blotting examined IPO expression. The presence of Ca2+ channel blocker, including diltiazem, neomycin or ruthenium red, abolished the increase of cytosolic Ca2+, and reduced the IPO expression in the cells induced by ethylene. Furthermore, both Ca2+ influxes and IPO expression stimulated by ethylene were prohibited in the presence of 10 mm ethylene glycol-bis(2-aminoethyl ether)-N, N, N', N'-tetraacetic acid (EGTA). These results indicated that Ca2+ influxes into the cytosol induced by ethylene are from both apoplast and organelles, and are required for activating IPO expression. However, in the presence of 1 mm EGTA, ethylene can still stimulate IPO expression, but mechanical wounding failed to do it. Therefore, Ca2+ channels in the plasma membrane induced by ethylene have higher affinity to Ca2+ than that stimulated by wounding. Moreover, the addition of A23187, an ionophore, raised cytosolic Ca2+, but was unable to stimulate IPO expression. These findings showed that IPO induction did not solely depend on Ca2+, and Ca2+ elevation in cytosol is necessary but not sufficient for IPO expression. The application of PD98059, a mitogen-activated protein kinase kinase (MAPKK) inhibitor, did not prevent Ca2+ from increasing in the cytosol induced by ethylene, but inhibited the IPO expression stimulated by staurosporine (STA), a protein kinase inhibitor. Conclusively, elevation of cytosolic Ca2+ by ethylene may stimulate protein phosphatase and MAPKK, which finally activates IPO expression.
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PMID:Calcium influxes and mitogen-activated protein kinase kinase activation mediate ethylene inducing ipomoelin gene expression in sweet potato. 1797 Oct 62

Receptor Tyrosine Kinase (RTK)/Ras GTPase/MAP kinase (MAPK) signaling pathways are used repeatedly during metazoan development to control many different biological processes. In the nematode Caenorhabditis elegans, two different RTKs (LET-23/EGFR and EGL-15/FGFR) are known to stimulate LET-60/Ras and a MAPK cascade consisting of the kinases LIN-45/Raf, MEK-2/MEK and MPK-1/ERK. This Ras/MAPK cascade is required for multiple developmental events, including induction of vulval, uterine, spicule, P12 and excretory duct cell fates, control of sex myoblast migration and axon guidance, and promotion of germline meiosis. Studies in C. elegans have provided much insight into the basic framework of this RTK/Ras/MAPK signaling pathway, its regulation, how it elicits cell-type specific responses, and how it interacts with other signaling pathways such as the Wnt and Notch pathways.
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PMID:RTK/Ras/MAPK signaling. 1805 Apr 74

20-HETE increases the expression of VEGF in human dermal microvascular endothelial cells (ECs). Since VEGF is regulated by hypoxia inducible factor (HIF)-1, we studied whether 20-HETE also upregulates HIF-1alpha using the stable 20-HETE analog 20-hydroxyeicosa-5(Z),14(Z)dienoic acid (WIT003; 1-10 microM) and found that it induced a marked increase in HIF-1alpha protein levels. The increases in VEGF after the addition of WIT003 preceded the changes in HIF-1alpha, and the increases in HIF-1alpha were prevented by a VEGF neutralizing antibody. This suggests that 20-HETE first causes increases in VEGF, which then, in turn, cause the upregulation of HIF-1alpha. Stimulation with exogenously added VEGF also led to an upregulation of HIF-1alpha. Incubation with the MEK1/ERK1/2 inhibitor U-0126 (10 microM) completely abolished the increases in VEGF and thus HIF-1alpha, suggesting the involvement of ERK1/2 activation. The addition of WIT003 resulted in a rapid and sustained increase in superoxide formation. When WIT003 was added in the presence of the nitric oxide (NO) synthase (NOS) inhibitor N-nitro-L-arginine, no changes in superoxide, VEGF, or HIF-1alpha were observed. This suggests that NOS is responsible for the early changes in superoxide induced by WIT003. Furthermore, WIT003 induced the expression of the NADPH oxidase subunit p47(phox) in ECs before the increases in HIF-1alpha. Incubation with polyethylene glycol-superoxide dismutase (400 U/ml), apocynin (100 microM), diphenylene iodonium (10 microM), or p47(phox) downregulation with small interfering (si)RNA all inhibited the increases in HIF-1alpha expression. This indicates that the early changes in superoxide lead to VEGF increases and thereby NADPH oxidase-dependent superoxide production, which is required for HIF-1alpha upregulation. We also found that the higher HIF-1alpha expression induced by WIT003 was accompanied by higher expression of erythropoietin receptor and angiopoietin-2 proteins. These increases were caused by HIF-1alpha because their levels were markedly decreased by siRNA downregulation of HIF-1alpha. 20-HETE may be a novel nonhypoxic regulator of HIF-1alpha and HIF-1alpha-regulated genes in ECs.
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PMID:20-HETE can act as a nonhypoxic regulator of HIF-1alpha in human microvascular endothelial cells. 1950 54

Glucocorticoid-induced apoptosis is exploited clinically for the treatment of hematologic malignancies. Determining the required molecular events for glucocorticoid-induced apoptosis will identify resistance mechanisms and suggest strategies for overcoming resistance. In this study, we found that glucocorticoid treatment of WEHI7.2 murine thymic lymphoma cells increased the steady-state [H(2)O(2)] and oxidized the intracellular redox environment before cytochrome c release. Removal of glucocorticoids after the H(2)O(2) increase resulted in a 30% clonogenicity; treatment with PEG-CAT increased clonogenicity to 65%. Human leukemia cell lines also showed increased H(2)O(2) in response to glucocorticoids and attenuated apoptosis after PEG-CAT treatment. WEHI7.2 cells that overexpress catalase (CAT2, CAT38) or were selected for resistance to H(2)O(2) (200R) removed enough of the H(2)O(2) generated by glucocorticoids to prevent oxidation of the intracellular redox environment. CAT2, CAT38, and 200R cells showed a 90-100% clonogenicity. The resistant cells maintained pERK survival signaling in response to glucocorticoids, whereas the sensitive cells did not. Treating the resistant cells with a MEK inhibitor sensitized them to glucocorticoids. These data indicate that: (1) an increase in H(2)O(2) is necessary for glucocorticoid-induced apoptosis in lymphoid cells, (2) increased H(2)O(2) removal causes glucocorticoid resistance, and (3) MEK inhibition can sensitize oxidative stress-resistant cells to glucocorticoids.
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PMID:Hydrogen peroxide signaling is required for glucocorticoid-induced apoptosis in lymphoma cells. 2196 7

One of the major advance concerning skin carcinoma is the development of targeted therapy: anti-patch/sonic/hedgehog for basal cell carcinoma (BCC) and anti-EGFR for squamous cell carcinoma (SCC). These therapies are indicated for advanced non surgically removable tumors. Their anti-tumoral efficacy has been shown, their effect seems to be suspensive which raises the question of their tolerability for long term use. Laboratory work have shown that BCC and SCC stem cells locate in different cell compartments and follow distinct molecular events which explains their distinct behaviour. The role of HPV in EBDR skin cancers has been ruled out. Photodynamic therapy induced-immunosuppression can be prevented by lowering the light fluence. The gene responsible for the Ferguson Smith syndrome has been identified: it is the gene encoding TGFBR1. Its implication in SCC needs to be determined. A new compound, PEP005, (ingenol mebutate) should soon enlarge therapeutical options for actinic keratosis. Concerning melanoma, results of the two phase III studies using two innovative therapies (anti-Braf and ipilimumab) have been published. Comparative study between anti-Braf and DTIC has shown a response rate of 48.4 % with vemurafenib and 5.5 % with DTIC. The risk of death was diminished by 67 %. These results have allowed to switch to vemurafenib patients with progression under DTIC. However, the initial response is followed by relapse in a majority of cases. Mechanisms of this resistance have been studied and the inhibition of several molecules involved in different or identical pathway should help to resolve that problem. The combination ipilimumab+ DTIC gives better results than DTIC alone. The adverse events of this association are slightly different than those seen with ipilimumab alone. They must be known by prescribers. Some discussions are on their way between the two companies developping anti-Braf and ipilimumab to develop therapeutic strategies combining both treatments. 20 to 30 % of patients taking anti-Braf drugs will develop SCC (due to paradoxal activation of MAPK in non Braf mutated cells). PEG-interferon seems to be indicated in ulcerated melanoma with lymph node micrometastasis. Some other targeted molecules such as C-KIT and anti-MEK are under evaluation. The effect of sunscreens on melanoma risk prevention has been reported in an Australian study. A low vitamine D status is reported to have a bad prognosis in melanoma and is observed in fair skin patients at risk. Recommendations for the care and follow up of patients with Merkel carcinoma have been published. The elevated risk of positive sentinel lymph nodes in these patients does not allow to define a subgroup of Merkel patients that could be spared from the technique. Sarcoma also benefit from targeted therapy especially DFSP with imatinib. Other molecules among which mTOR inhibitors are being evaluated in sarcomas. A collaborative work has allowed to classify and evaluate in a more standardized way cutaneous T lymphomas and should help future trials. Some microRNA can be used as diagnostic tools or therapies in T cell cutaneous lymphomas. Finally a review of modern therapeutical strategies in cutaneous lymphomas has been published.
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PMID:[What's new in dermato-oncology?]. 2220 47


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