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)

Tyrosine kinase growth factor receptors and Ras/Raf/MEK/MAPK signalling have been implicated in the suppression as well as augmentation of programmed cell death. In addition, a Ras-independent role for Raf as a suppressor of programmed cell death has been suggested by the recent finding that Craf1 interacts with members of the Bcl-2 family at mitochondrial membranes. However, genetic studies of C. elegans and Drosophila, as well as the targeted mutagenesis of the murine Araf gene, have failed to support such a role. Here we show that mice with a targeted disruption in the Braf gene die of vascular defects during mid-gestation. Braf -/- embryos, unlike Araf -/- or Craf1 -/- embryos (L.W. et al., unpublished), show an increased number of endothelial precursor cells, dramatically enlarged blood vessels and apoptotic death of differentiated endothelial cells. These results establish Braf as a critical signalling factor in the formation of the vascular system and provide the first genetic evidence for an essential role of Raf gene in the regulation of programmed cell death.
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PMID:Endothelial apoptosis in Braf-deficient mice. 920 79

Manganese is known to induce neurological disorders similar to parkinsonisms. A dopamine deficiency has been demonstrated in Parkinson's disease and in chronic manganese poisoning, suggesting that the mechanisms underlying the neurotoxic effects of the metal ion are related to a functional abnormality of the extrapyramidal system. However, the details have yet to be elucidated. Here we report that manganese causes characteristic internucleosomal DNA fragmentation, a biochemical hallmark of apoptosis, in PC12 cells. It was transcription dependent, relatively specific for manganese, and blocked in Bcl-2-overexpressed PC12 cells. The results indicate that apoptosis may play a role in the dopaminergic neurotoxicity associated with manganese, the first metal to be reported to induce this form of cell death. The early biochemical events show the impairment of energy metabolism, and the process may require new synthesis of proteins such as c-Fos and c-Jun. In addition, manganese induces phosphorylation of c-Jun at Ser63 and Ser73 and SEK1/MKK4 (c-Jun N-terminal kinase kinase) at Thr258 and tyrosine phosphorylation of several proteins. These results indicate that manganese activates specific signal cascades including the c-Jun N-terminal kinase pathway.
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PMID:Activation of JNK pathway and induction of apoptosis by manganese in PC12 cells. 975 Nov 94

Many growth factors and G protein-coupled receptors activate mitogen-activated protein (MAP) kinase pathways. The MAP kinase pathways are involved in the regulation of the ubiquitous process of apoptosis or programmed cell death. Two related MAP kinase kinase kinases, apoptosis-signal regulating kinase 1 (ASK1) and MAP kinase kinase kinase 1 (MEKK1), stimulate c-Jun kinase (JNK) activity and induce apoptosis. Transient transfection of dominant negative and constitutively active components of the JNK pathway in COS-7 cells showed that two G protein subunits, Galpha12 and Galpha13, stimulated the JNK pathway in a ASK1- and MEKK1-dependent manner. Moreover, the mutationally activated Galpha12 and Galpha13 stimulated the kinase activity of ASK1. Both Galpha12 and Galpha13 employ small GTPases, Cdc42 and Rac1, to transduce signal to MEKK1 and, subsequently, to JNK. However, activation of JNK by Cdc42 and Rac1 did not require ASK1. Additionally, ASK1 and MEKK1 are involved in the apoptosis induced by Galpha12 and Galpha13. We conclude that Galpha12 and Galpha13 can induce apoptosis using two separate MAP kinase pathways; one is initiated by ASK1, and the other is initiated by MEKK1. Furthermore, Bcl-2 can block apoptosis induced by Galpha12 and Galpha13. This death-sparing function was associated with increased Bcl-2 phosphorylation, suggesting that phosphorylation of Bcl-2 may be a critical mechanism protecting cells from Galpha12- and Galpha13-induced apoptosis.
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PMID:Regulation of apoptosis by alpha-subunits of G12 and G13 proteins via apoptosis signal-regulating kinase-1. 977 91

We have examined the effects of the macrocyclic lactone protein kinase C (PKC) activator bryostatin 1 on taxol-induced apoptosis and inhibition of clonogenicity in the human monocytic leukemia cell line U937. Exposure of cells to bryostatin 1 (10 nM; 15 hr) after (but not before) a 6-hr incubation with 0.5 microM taxol significantly increased apoptosis and resulted in an approximately 3 log reduction in clonogenicity. Cell cycle analysis revealed that the increase in apoptotic cells following bryostatin 1 treatment occurred primarily in the population undergoing taxol-mediated G2M arrest. The actions of bryostatin 1 were not attributable to potentiation of taxol-induced tubulin stabilization or to a reduction in the intracellular retention of taxol. Following exposure of cells to taxol, the Bcl-2 protein displayed an alteration in mobility that was not modified appreciably by bryostatin 1 treatment. The mobility shift in Bcl-2 protein from cells exposed to taxol followed by bryostatin 1 was eliminated by treatment of lysates with the protein phosphatase 2A (PP2A); the latter effect was blocked by okadaic acid. Treatment of cells with taxol followed by bryostatin 1 did not increase the amount of total Bax (compared with treatment with taxol alone), but did increase the amount of free Bax in the supernatant fraction. Finally, the ability of bryostatin 1 to potentiate taxol-induced apoptosis in U937 cells was mimicked closely by 2'-amino-3'-methoxyflavone (PD98059), a specific inhibitor of the mitogen-activated protein kinase (MAPK) kinase (MEK). Collectively, these findings indicate that bryostatin 1 increases the susceptibility of U937 cells to taxol-induced apoptosis and inhibition of clonogenicity. They also raise the possibility that this phenomenon may involve functional alterations in Bcl-2 and/or other proteins involved in regulation of the cell death pathway.
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PMID:Effect of bryostatin 1 on taxol-induced apoptosis and cytotoxicity in human leukemia cells (U937). 978 32

Prior investigations document that proliferative signaling cascades, under some circumstances, initiate apoptosis, although mechanisms that dictate the final outcome are largely unknown. In COS-7 cells, ceramide signals Raf-1 activation through Ras (Zhang, Y., Yao, B., Delikat, S., Bayoumy, S., Lin, X. H., Basu, S., McGinley, M., Chan-Hui, P. Y., Lichenstein, H., and Kolesnick, R. (1997) Cell 89, 63-72), but not apoptosis. However, expression of small amounts of the pro-apoptotic Bcl-2 family member, BAD, conferred ceramide-induced apoptosis onto COS-7 cells. Ceramide signaled apoptosis in BAD-expressing cells by a pathway involving sequentially kinase suppressor of Ras (KSR)/ceramide-activated protein kinase, Ras, c-Raf-1, and MEK1. Downstream, this pathway linked to BAD dephosphorylation at serine 136 by prolonged inactivation of Akt/PKB. Further, mutation of BAD at serine 136 abrogated ceramide signaling of apoptosis. The present study indicates that when ceramide signals through the Ras/Raf cascade, the availability of a single target, BAD, may dictate an apoptotic outcome.
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PMID:BAD enables ceramide to signal apoptosis via Ras and Raf-1. 980 8

The Tpl-2 kinase activates the nuclear factor of activated T cells (NFAT) and induces IL-2 expression in T-cell lines. Here we show that the activation of the IL-2 promoter by Tpl-2 is inhibited by mutant signaling molecules that inhibit the mitogen-activated protein kinase (MAPK) or the calcineurin/NFAT pathways and is promoted by combinations of signaling molecules that activate these pathways. We, therefore, conclude that signals generated by the convergence of the MAPK and the calcineurin/NFAT pathway are necessary and sufficient for the activation of the IL-2 promoter by Tpl-2. The activation of both the IL-2 promoter and an NFAT-driven minimal promoter were shown to depend on signals transduced by Raf1. However, it was only the IL-2 promoter whose activation by Tpl-2 was fully blocked by the dominant negative mutant MEK1S218/222A and the MEK1/MEK2 inhibitor PD098059. Since the activation of NFAT is MAPK-dependent these findings suggested that the activation of MAPK by Tpl-2 is either independent or only partially dependent on MEK1 and MEK2. In addition, they suggested that the activation of the IL-2 promoter is under the control of not only NFAT but also a second factor whose activation is MEK-dependent. Experiments in COS-1 and EL-4 cells confirmed both hypotheses and revealed that the second factor activated by Tpl-2 is NF-kappaB. While the activation of the IL-2 promoter and an NFAT-driven minimal promoter by Tpl-2 was fully blocked by the dominant negative mutant NFAT delta418, it was only partially blocked by the calcineurin inhibitor cyclosporin A suggesting that the Tpl-2-mediated NFAT activation is under the control of a combination of calcineurin-dependent and independent pathways. Both pathways were fully blocked by Bcl-2 or Bcl-X(L).
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PMID:Tpl-2 induces IL-2 expression in T-cell lines by triggering multiple signaling pathways that activate NFAT and NF-kappaB. 984 Sep 24

The Bcl-2 protein has an anti-apoptotic effect in neuronal and other cell types. We show for the first time that the Bcl-2 promoter is activated by the neuronal survival factor nerve growth factor (NGF) and that this effect is dependent on a region of the promoter from -1472 to -1414. This activation requires the Rap-1 G protein and the MEK-1 and p42/p44 MAPK enzymes but is independent of other NGF-activated signalling pathways involving protein kinase A or protein kinase C.
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PMID:Activation of the Bcl-2 promoter by nerve growth factor is mediated by the p42/p44 MAPK cascade. 1021 80

The ability of low-dose ionizing radiation (1 Gy) to modulate the activities of the mitogen-activated protein kinase (MAPK) and Jun NH2-terminal kinase (JNK1) cascades in human myeloid leukemia (HL60/pCEP4) cells and in cells overexpressing the anti-apoptosis protein BCL2 (HL60/Bcl-2) was investigated. Radiation exposure caused prolonged (3-4 h) activation of MAPK in HL60 cells. The ability of radiation to activate the MAPK pathway was attenuated by 30% in cells overexpressing BCL2. In contrast, low-dose irradiation of HL60/pCEP4 and HL60/Bcl-2 cells failed to modulate JNK1 activity. Inhibition of the MAPK pathway by use of the specific MEK1/2 inhibitor (10 microM PD98059) in both HL60/pCEP4 and HL60/Bcl-2 cells prior to irradiation permitted a similar prolonged radiation-induced activation of JNK1. Furthermore, combined treatment with PD98059 and radiation in both cell types caused a large decrease in growth of cells in suspension culture, a large increase in apoptosis, and a 90% decline in clonogenicity when compared to either treatment alone. Reduced proliferation after combined irradiation and PD98059 treatment in both cell types correlated with reduced Cdc2 activity and arrest in G2/M phase of the cell cycle. These data demonstrate that inhibition of MEK1/2 leading to blockade of the MAPK activation increases the radiation sensitivity of HL60 cells and decreases the ability of these cells to recover from the radiation-induced arrest at the G2/M-phase cell cycle checkpoint. In addition, our data demonstrate that elevated expression of BCL2 does not abrogate the ability of inhibition of MAPK to potentiate radiation-induced cell death in HL60 cells.
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PMID:Inhibition of the MAPK pathway abrogates BCL2-mediated survival of leukemia cells after exposure to low-dose ionizing radiation. 1031 29

The mechanism of Taxol-induced apoptosis was investigated in MCF-7 human breast carcinoma cells. Taxol-induced apoptosis was associated with phosphorylation of both c-Raf-1 and Bcl-2 and activation of ERK and JNK MAP kinases. The serine protease inhibitor N-tosyl-L-phenylalanine chloromethyl ketone (TPCK) effectively blocked apoptosis, but N-p-tosyl-L-lysine chloromethyl ketone (TLCK), another serine protease inhibitor, was without effect. TPCK treatment also prevented phosphorylation of c-Raf-1 and Bcl-2 in response to Taxol treatment. The serine protease inhibitor did not alter JNK activity, but it enhanced Taxol-induced activation of ERK1/2. Treatment of cells with the inhibitor of MEK activation, PD98059, prevented Taxol-induced ERK activation both in the presence and absence of TPCK, but did not influence survival of either Taxol- or Taxol plus TPCK-treated cells. In addition, PD98059 had no effect on c-Raf-1 or Bcl-2 phosphorylation. Thus, while the Taxol-induced phosphorylations of c-Raf-1 and Bcl-2 proteins appear to be coupled, these events can be disassociated from ERK1/2 activation. In summary, these findings suggest that phosphorylation of c-Raf-1 and Bcl-2, but not ERK1/2, are important signaling events in Taxol-induced apoptosis of MCF-7 breast cancer cells and that a TPCK inhibitable protease(s) is required for these processes.
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PMID:Serine protease inhibitor TPCK prevents Taxol-induced cell death and blocks c-Raf-1 and Bcl-2 phosphorylation in human breast carcinoma cells. 1037 21

p53-mediated apoptosis is antagonized by growth factor stimulation. Here, we show that p53-dependent cell death induced by DNA damage was effectively prevented by mitogen activation. The levels of Bcl-2, Bcl-xL, and Bax were not altered by cisplatin treatment and mitogen rescue. Instead, the protection against p53-regulated apoptosis was mediated by at least three distinct signaling pathways. Either phosphatidylinositol (PI) 3-kinase or mitogen-activated protein kinase kinase (MEK) antagonized p53-induced apoptosis, and an additive preventive effect was observed when both kinases were activated. However, the combination of PI 3-kinase and MEK was not sufficient to completely prevent apoptosis induced by DNA damage. Mitogen activation further suppressed cisplatin-induced p53 expression, and the inhibition was mainly dependent on the Ca2+ pathway. Our results demonstrate that effective antagonism of p53-dependent apoptosis by mitogenic activation requires the presence of multiple signal pathways, including PI 3-kinase, MEK, and Ca2+.
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PMID:Antagonism of p53-dependent apoptosis by mitogen signals. 1038 45


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