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)

The effects of the solvents n-hexane, butanone (methyl-ethyl-ketone, MEK) and a mixture of both in the intrapulmonary nerve system of rats were studied by light and electron microscopy. The alteration in the fine structures of the tissue consisted in a disseminated swelling of axons due to a striking multiplication of neurofilaments. Nonspecific axonal alterations could be demonstrated as well. The latter consisted in clusters of phospholipid material within the axoplasm of nerve fibers and the cytoplasm of Schwann cells plus an accumulation of glycogen granules in the axoplasm. Additionally, single degenerative changes of Schwann cells were observed. An enzyme-associated metabolic damage with a concomitant impairment of axonal flow is discussed as a possible underlying pathomechanism.
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PMID:Ultrastructural alteration of intrapulmonary nerves after exposure to organic solvents. A contribution to 'sniffers disease'. 652 43

It is well known that n-hexane produces peripheral neuropathy, and 2,5-hexanedione, one of the metabolites of n-hexane, is thought to be the main causative agent. Recently, the metabolites of n-hexane in urine have been measured by gas chromatography, and 2,5-hexanedione was proved to be useful for the biological monitoring of n-hexane exposure. In the present experiment, we intended to clarify the change of n-hexane metabolites in the urine of rats exposed to various concentrations of n-hexane and to its mixture with toluene of MEK. In the first experiment, five separate groups of five rats each were exposed to 100, 500, 1000, or 3000 ppm of n-hexane, or fresh air respectively in an exposure chamber for 8 h a day. Urinary samples were gathered during exposure, 16, 24, and 40 h after exposure. Half of each sample was analyzed by gas chromatography after hydrolysis with acid and enzymes, and the other half was analyzed without hydrolysis. 2,5-Dimethylfuran, MBK, 2-hexanol, 2,5-hexanedione, and gamma-valerolactone could be identified as n-hexane metabolites in the urine. The main metabolites were 2-hexanol and 2,5-hexanedione. 2-Hexanol was mostly excreted during exposure, while most of the 2,5-hexanedione was excreted after the end of exposure. The amount of metabolites in the urine correlatively increased with the concentration of n-hexane from 100 to 1000 ppm, but the amount of metabolites scarcely increased when the concentration of n-hexane increased from 1000 to 3000 ppm.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Changes of n-hexane metabolites in urine of rats exposed to various concentrations of n-hexane and to its mixture with toluene or MEK. 665 98

Three patients developed facial dermatitis after contact with preparations containing estradiol benzoate. Patch tests were positive to estradiol benzoate 0.1% in MEK but negative to other related estrogens including estradiol. All three patients also had positive tests to resorcinol monobenzoate and two out of three to balsam of Peru. Most likely estradiol benzoate was the primary sensitizer.
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PMID:Contact dermatitis to estradiol benzoate. 727 28

An historical prospective study was undertaken of 262 men who had worked on an isopropyl alcohol plant and 446 men who had worked on two MEK dewaxing plants. All of the former have been traced, and only one man from the latter group was lost to follow-up. These studies linked occupational records with cause of death data for those who had died; the average follow-up was 15.5 years for the IPA plant workers and 13.9 years for those on the MEK dewaxing plants. For the IPA workers the observed deaths (26) were slightly above the expected (23.6), and there was a non-significant excess of deaths from neoplasms (0 = 9, E = 6.19). One person died from nasal cancer (E = 0.02, p = 0.017); though based on small numbers this finding is unlikely to be due to chance and agrees with the original hazard. For those who had worked on the MEK dewaxing plants the observed deaths (46) were below the expected (55.51) and there was also a slight deficiency of deaths from neoplasms (0 = 13, E = 14.26). When the seven sites of malignancy, which had been examined in a recent American study, were compared there were significantly more deaths from buccal cavity and pharynx cancers (0 = 2; E = 0.13; p = 0.008) and significantly fewer from lung cancer (0 = 1; E = 6.02; p less than 0.045). After reviewing the American and present results, it was concluded that there is no clear evidence of a cancer hazard in these workers, though further follow-up of larger numbers is necessary for a more precise estimate of the confidence limits of these findings.
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PMID:Mortality of workers on an isopropyl alcohol plant and two MEK dewaxing plants. 737 Jan 97

We investigated the effects of epidermal growth factor (EGF) and arginine vasopressin (AVP) on Raf-1-MAP kinase cascade, including Raf-1-kinase (Raf-1-K), MAP kinase kinase (MAPKK), MAP kinase (MAPK) and S6 kinase (S6K) in Madin-Darby canine kidney (MDCK) cells. In a dose-dependent manner (10(-10) M to 10(-6) M), EGF increased autophosphorylation of Raf-1-K and activated MAPKK, MAPK and S6K. Sequential activation of these kinases was indicated by their peak times of activation (Raf-1-K 5 min; MAPKK 10 min; MAPK 15 min; and S6K 30 min). AVP (10(-9) M to 10(-6) M) inhibited EGF-stimulated MAP kinase cascade. 8-Bromo-cyclic AMP (cAMP) could mimic the inhibitory effect of AVP on EGF-stimulated MAP kinase cascade. These results were confirmed using H-89, an inhibitor of protein kinase A (PKA) that blocked the effect of AVP on EGF-stimulated MAPK activity. We conclude that AVP inhibits EGF-stimulated Raf-1-K, MAPKK, MAPK, and S6K activity via cAMP in MDCK cells. Our results indicate that MAP kinase cascade may play an important role in integrating the effects of AVP and EGF on distal tubule function.
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PMID:AVP inhibits EGF-stimulated MAP kinase cascade in Madin-Darby canine kidney cells. 747 60

Eukaryotic cells respond to different extracellular stimuli by recruiting homologous signalling pathways that use members of the MEKK, MEK and ERK families of protein kinases. The MEKK-->MEK-->ERK core pathways of Saccharomyces cerevisiae may themselves be regulated by members of the STE20 family of protein kinases. Here we report specific activation of the mammalian stress-activated protein kinase (SAPK) pathway by germinal centre kinase (GCK), a human STE20 homologue. SAPKs, members of the ERK family, are activated in situ by inflammatory stimuli, including tumour-necrosis factor (TNF) and interleukin-1, and phosphorylate and probably stimulate the transactivation function of c-Jun. Although GCK is found in many tissues, its expression in lymphoid follicles is restricted to the cells of the germinal centre, where it may participate in B-cell differentiation. Activation of the SAPK pathway by GCK illustrates further the striking conservation of eukaryotic signalling mechanisms and defines the first physiological function of a mammalian Ste20.
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PMID:Activation of the SAPK pathway by the human STE20 homologue germinal centre kinase. 747 68

The sphingomyelin pathway, initiated by hydrolysis of sphingomyelin to ceramide and stimulation of a Ser/Thr ceramide-activated protein (CAP) kinase, mediates tumour necrosis factor-alpha (TNF-alpha) and interleukin-1 beta action. CAP kinase is membrane-bound and proline-directed, recognizing the minimal substrate motif Thr-Leu-Pro. TNF may use the sphingomyelin pathway to signal Raf1 to activate the MAP kinase cascade. Evidence shows that cytoplasmic Raf1 binds to GTP-ras upon cellular stimulation, is recruited to the plasma membrane, and activated. How membrane-bound Raf1 is activated is uncertain, but regulation of its kinase activity may involve its phosphorylation. Specific Raf kinases, however, have not hitherto been identified. Here we report that CAP kinase phosphorylates Raf1 on Thr 269, increasing its activity towards MEK (MAP kinase or ERK kinase). Moreover, in intact HL-60 cells, CAP kinase complexes with Raf1 and, in response to TNF and ceramide analogues, phosphorylates and activates Raf1, implicating CAP kinase as a link between the TNF receptor and Raf1.
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PMID:Phosphorylation of Raf by ceramide-activated protein kinase. 747 54

The sequential activation of the mitogen-activated protein kinase kinase and its substrate, the mitogen-activated protein kinase is involved in a cascade of protein kinases which link a number of cell surface signals to intracellular changes in enzyme activity and gene expression. In vitro, mitogen-activated protein kinase is able to phosphorylate the microtubule-associated protein tau at Ser-Pro and Thr-Pro sites, thereby generating abnormally hyperphosphorylated tau species that are similar to paired helical filament-tau found in Alzheimer's disease. In the present study, we analysed the levels of immunoreactive mitogen-activated protein kinase kinase and mitogen-activated protein kinase in the temporal cortex (area 22) of patients with Alzheimer's disease by means of enzyme-linked immuno-sorbent assays and compared these changes with the content of abnormally phosphorylated paired helical filament-tau. The levels of immunochemically detected mitogen-activated protein kinase kinase and mitogen-activated protein kinase were both increased in Alzheimer's disease by between 35 and 40% compared with age-matched controls. Elevation of mitogen-activated protein kinase kinase was most pronounced during early stages of Alzheimer's disease and was inversely related to the tissue content of abnormally phosphorylated paired helical filament-tau. Pronounced immunoreactivity of mitogen-activated protein kinase kinase and mitogen-activated protein kinase was present in both tangle bearing neurons and unaffected neurons of the temporal cortex. Immunoreactive neurons were most often localized in the direct vicinity of neuritic plaques. In Alzheimer's disease, the subcellular distribution of mitogen-activated protein kinase kinase and mitogen-activated protein kinase showed a striking translocation from the cytoplasmic to the nuclear compartment. It is suggested that the activation of the mitogen-activated protein kinase cascade which appears to be an early feature of Alzheimer's disease might be critically involved in self-stimulating processes of neurodegeneration and aberrant repair under these conditions.
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PMID:Increased expression and subcellular translocation of the mitogen activated protein kinase kinase and mitogen-activated protein kinase in Alzheimer's disease. 747 34

Figure 2 summarizes our current interpretation of data concerning signals from the activated PDGF receptor involved in directed migration and proliferation of human arterial SMC. Binding of PDGF (PDGF-BB or PDGF-AA) causes PDGF-receptor dimerization, tyrosine autophosphorylation, and subsequent binding of several molecules containing SH2 domains to the activated receptor. Binding and activation of PLC gamma by the PDGF receptor leads to PIP2 hydrolysis, resulting in generation of diacylglycerol (DAG) and IP3. Subsequently, intracellular levels of calcium are elevated as a result of IP3-mediated calcium release from intracellular compartments. The decreased levels of PIP2 and increased levels of calcium both favor actin-filament disassembly by inducing capping of actin-filament barbed ends and actin-monomer sequestration. A localized, and transient, actin-filament disassembly enables the cell to extend filopodia towards PDGF, thereby enabling chemotaxis to take place. At a later time and/or in a different compartment, actin-filament assembly is promoted by PDGF by a mechanism that is not completely understood, but that may involve small GTP-binding proteins, such as Rho, and formation of DAG. Migration on collagen requires functional alpha 2 beta 1 integrins, which may either constitute a permissive state required for a cell to migrate, or which may be actively involved in intracellular signals leading to migration. PDGF-induced DNA synthesis and proliferation involves activation of Ras, MAP kinase kinase, and MAP kinase. Cross-talk between PKA signaling and tyrosine-kinase receptor signaling results in PKA inhibition of the MAP kinase cascade, probably at the level of Raf. Activation of PI 3-kinase, or a PI 3-kinase-like enzyme, is also likely to contribute to the mitogenic effects of PDGF in these cells (Bornfeldt, unpublished observation). What determines if a SMC will migrate and/or proliferate in response to PDGF? Results are starting to emerge that show regulation of expression of molecules involved in intracellular signaling with different phenotypic states of SMC. For example, expression of PLC gamma is very low in intact vascular wall (where SMC show a "contractile phenotype"), and induced when SMC are converted to a "synthetic phenotype" in culture. Proliferation and expression of MAP kinase, but not calcium signaling, appear to be regulated by the extracellular matrix, and the profile of integrin expression is different in SMC in culture compared to SMC in the vascular wall. Thus, the relation between expression of signaling molecules involved in migration and signaling molecules involved in proliferation, as well as cross-talk between different signal-transduction pathways, may determine the net effect of PDGF.
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PMID:Platelet-derived growth factor. Distinct signal transduction pathways associated with migration versus proliferation. 748 87

Neurons require a mechanism to transmit stable signals over the large distance from the nerve growth cone or terminal to the cell body, in order that information from the target tissue can be relayed to the cell body where it is required. Nerve growth factor (NGF), a target-derived neurotrophic factor, is thought to signal over this distance by receptor mediated internalization of NGF, followed by retrograde axonal transport of the NGF-receptor complex. In this paper we show, by immunohistochemistry of rat sciatic nerve, accumulation of phosphotyrosine immunoreactivity only on the distal side of a nerve crush, suggesting axonal transport of tyrosine kinases and/or tyrosine phosphorylated proteins primarily in a retrograde direction. Furthermore, we also show retrograde axonal transport of phosphoinositide 3-kinase, ERK, MEK and MEK kinase, of which all but MEK kinase are known to be activated downstream of tyrosine receptor kinase activation. The retrograde transport of these proteins suggests that they may be involved in transmission of signals along the axon, relaying neurotrophic factor receptor activation at the nerve terminal to the nerve cell body.
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PMID:Retrograde axonal transport of signal transduction proteins in rat sciatic nerve. 749 7


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