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)

The classical mitogen-activated protein(MAP) kinase cascade is one of the central intracellular signaling pathways that play a crucial role in cell proliferation, cell differentiation, cell transformation, and many other cellular responses. Two novel MAP kinase cascades, the SAPK/JNK cascade and the p38/MPK2 cascade, were identified, and were shown to function in various stress responses and apoptotic processes. Intracellular distribution of classical MAP kinase kinase (MAPKK/MEK) is regulated by its nuclear export signal (NES) which may function to suppress malignant cell transformation. CRM1 protein has been identified as a receptor for leucine-rich NES. CRM1 binds to CAN/NUP214, one of nucleopore proteins, which has been suggested to be involved in myeloid leukemia. Thus, the nuclear export system may be by somehow related to cancer development.
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PMID:[Signal transductions by the MAP kinase cascades]. 970 53

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 effects of the protein kinase C (PKC) activator and down-regulator bryostatin 1 were examined with respect to paclitaxel-induced apoptosis and antiproliferative activity in human myeloid leukemia cells (U937) displaying enforced expression of the anti-apoptotic protein Bcl-xL. Overexpression of Bcl-xL blocked various aspects of paclitaxel-mediated apoptosis, including caspase-3 activation, degradation of poly(ADP-ribose) polymerase (PARP), loss of mitochondrial membrane potential (Delta Psim), and release of cytochrome c. However, subsequent (but not prior) exposure of paclitaxel-treated U937/Bcl-xL cells (500 nM; 6 h) to bryostatin 1 (10 nM; 15 h) restored the extent of apoptosis, caspase activation, and mitochondrial damage to levels approximating those in paclitaxel-treated empty-vector control cells (U937/Neo). Potentiation of paclitaxel-induced apoptosis by bryostatin 1 in U937/Bcl-xL cells occurred primarily in the G2M cell population, and was associated with alterations in Bcl-xL gel mobility and a reduction in paclitaxel-mediated stimulation of CDK1 activity. Enhancement of paclitaxel-induced apoptosis by bryostatin 1 in Bcl-xL overexpressors was accompanied by a corresponding reduction in clonogenic potential. In contrast to its effects on apoptosis, bryostatin 1 failed to restore paclitaxel-mediated increases in free Bax levels in U937/Bcl-xL cells. Lastly, the actions of bryostatin 1 were mimicked by a pharmacologic inhibitor of the MEK1/MAP kinase pathway (PD98059), but not by SB203580, an inhibitor of p 38 MAP kinase. Moreover, sequential exposure of both U937/Neo or/Bcl-xL cells to paclitaxel followed by bryostatin 1 or PD98059 was associated with a net reduction in MAP kinase activity. Collectively, these findings indicate that protection against paclitaxel-mediated mitochondrial dysfunction and apoptosis in human U937 leukemia cells conferred by Bcl-xL overexpression can be substantially overcome by bryostatin 1 and possibly other agents that interrupt the MAP kinase signal transduction pathway.
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PMID:Bryostatin 1 enhances paclitaxel-induced mitochondrial dysfunction and apoptosis in human leukemia cells (U937) ectopically expressing Bcl-xL. 1051 58

The role of the mitogen-activated protein kinase (MAPK) signal transduction pathway in the proliferation of mammalian cells has been well established. However, there are relatively few reports concerning cell differentiation being mediated by MAPK. The effect of phorbol 12-myristate 13-acetate (PMA) on cell differentiation and signal transduction in a human myeloid leukemia cell line, TF-1a, was investigated. When TF-1a cells were treated with 10(-6), 10(-7), 10(-8), and 10(-9) M PMA for 24 h, they underwent 98, 93, 91, and 51% macrophage-like differentiation, respectively. PMA treatment rapidly (10 min) induced phosphorylation of MAPK kinase (MEK and p44/42 MAPK), which persisted for at least 24 h. p44/42 MAPK immunoprecipitates from lysates of PMA-treated cells had increased ability to phosphorylate the transcription factor Elk-1. This is important because phosphorylated Elk-1 can be considered an "end-product" of the MAPK pathway. In contrast, treatment of TF-1a cells with granulocyte/macrophage-colony stimulating factor induced only transient activation of MEK and p44/42 MAPK (10-20 min) and an increase (approximately 50%) in cell proliferation, without any change in cellular differentiation. These results suggest that macrophage-like differentiation may be dependent on prolonged activation of the MAPK pathway. Additional support for this conclusion was obtained from experiments showing that treatment of TF-1a cells with antisense oligonucleotides for MEK1 coding sequences prior to adding PMA inhibited macrophage-like differentiation. Furthermore, transient transfection with an inactive, dominant-negative MEK mutant also inhibited PMA-induced differentiation, whereas transient transfection with a plasmid coding for constitutively activated MEK led to macrophage-like differentiation in the absence of PMA.
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PMID:Prolonged activation of the mitogen-activated protein kinase pathway is required for macrophage-like differentiation of a human myeloid leukemic cell line. 1077 36

Upstream signaling requirements of retinoic acid (RA)-induced blr1 expression and downstream signaling consequences of blr1 over-expression in a human myeloid leukemia cell line demonstrate that mitogen-activated protein kinase (MAPK) signaling complexes are involved in both avenues. RA-induced myeloid differentiation and G1/G0 growth arrest of HL-60 cells is known to require the activation of the RARalpha and RXR retinoid receptors, as well as activation of the MAPK, ERK2. Transcriptional activation of the Burkitt's lymphoma receptor 1 (blr1) gene occurs early during RA-induced differentiation of HL-60 cells and requires these same three activating processes. The use of retinoid ligands that activate either the RARalpha or the RXR retinoid receptors revealed that blr1 mRNA induction was detectable only when both RARalpha and RXR were activated. Neither the RARalpha nor RXR selective ligands alone induced expression of blr1, but the combination of the two ligands induced the expression of blr1 to the same extent as RA. The MAPKK (MEK) inhibitor, PD98059, was used to determine whether extracellular signal-regulated kinase (ERK2) activation was necessary for induction of blr1 mRNA. PD98059 inhibited induced blr1 mRNA expression, due to RA or activated RARalpha plus RXR ligands, indicating that ERK2 activation is necessary for blr1 mRNA expression. Previous studies showed that ectopic expression of blr1 also caused increased MAPK activation, in particular ERK2, and subsequently accelerated RA-induced differentiation and G1/G0 growth arrest. Inhibition of ERK2 activation inhibited differentiation of blr1 transfectants, suggesting that the accelerated differentiation reflected blr1-enhanced ERK2 activation. The present data also demonstrate that ectopic expression of blr1 increased JNK/SAPK activity, but JNK/ SAPK activation was not needed for accelerated RA-induced differentiation and growth arrest. The results show that the signals known to be required for HL-60 differentiation, activated RARalpha, RXR, and ERK2, are necessary for blr1 mRNA expression. Downstream consequences of blr1 overexpression include enhanced MAPK signaling.
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PMID:Retinoic acid-induced blr1 expression requires RARalpha, RXR, and MAPK activation and uses ERK2 but not JNK/SAPK to accelerate cell differentiation. 1121 36

Survivin, a member of the inhibitors-of-apoptosis gene family, is expressed in a cell-cycle-dependent manner in all the most common cancers but not in normal differentiated adult tissues. Survivin expression and regulation were examined in acute myeloid leukemia (AML). Survivin was detected by Western blot analysis in all myeloid leukemia cell lines and in 16 of 18 primary AML samples tested. In contrast, normal CD34(+) cells and normal peripheral blood mononuclear cells expressed no or very low levels of survivin. Cytokine stimulation increased survivin expression in leukemic cell lines and in primary AML samples. In cultured primary samples, single-cytokine stimulation substantially increased survivin expression in comparison with control cells, and the combination of G-CSF, GM-CSF, and SCF increased survivin levels even further. Conversely, all-trans retinoic acid significantly decreased survivin protein levels in HL-60, OCI-AML3, and NB-4 cells within 96 hours, parallel to the induction of myelomonocytic differentiation. Using selective pharmacologic inhibitors, the differential involvement of mitogen-activated protein kinase kinase (MEK) and phosphatidylinositol-3 kinase (PI3K) pathways were demonstrated in the regulation of survivin expression. The MEK inhibitor PD98059 down-regulated survivin expression in both resting and GM-CSF-stimulated OCI-AML3 cells, whereas the PI3K inhibitor LY294002 inhibited survivin expression only on GM-CSF stimulation. In conclusion, these results demonstrate that survivin is highly expressed and cytokine-regulated in myeloid leukemias and suggest that hematopoietic cytokines exert their antiapoptotic and mitogenic effects, at least in part, by increasing survivin levels.
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PMID:Cytokine-regulated expression of survivin in myeloid leukemia. 1131 72

Interactions between the kinase inhibitor STI571 and pharmacological antagonists of the mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK)/mitogen-activated protein kinase (MAPK) cascade have been examined in human myeloid leukemia cells (K562 and LAMA 84) that express the Bcr-Abl kinase. Exposure of K562 cells to concentrations of STI571 that minimally induced apoptosis (e.g., approximately 200 nM) resulted in early suppression (i.e., at 6 h) of p42/44 MAPK phosphorylation followed at later intervals (i.e., > or =24 h) by a marked increase in p42/44 MAPK phosphorylation/activation. Coadministration of a nontoxic concentration of the MEK1/2 inhibitor PD184352 (5 microM) prevented STI571-mediated activation of p42/44 MAPK. Cells exposed to STI571 in combination with PD184352 for 48 h demonstrated a very dramatic increase in mitochondrial dysfunction (e.g., loss of DeltaPsim and cytosolic cytochrome c release) associated with procaspase-3 activation, poly(ADP-ribose) polymerase cleavage, and the appearance of the characteristic morphological features of apoptosis. Similar results were obtained using other pharmacological MEK1/2 inhibitors (e.g., PD 98059 and U0126) as well as another leukemic cell line that expresses Bcr-Abl (e.g., LAMA 84). However, synergistic induction of apoptosis by STI571 and PD184352 was not observed in human myeloid leukemia cells that do not express the Bcr-Abl kinase (e.g., HL-60 and U937) nor in normal human peripheral blood mononuclear cells. Synergistic potentiation of STI571-mediated lethality by PD184352 was associated with multiple perturbations in signaling and apoptotic regulatory pathways, including caspase-dependent down-regulation of Bcr-Abl and Bcl-2; caspase-independent down-regulation of Bcl-x(L) and Mcl-1; activation of JNK, p38 MAPK, and p34(cdc2); and diminished phosphorylation of Stat5 and CREB. Significantly, coexposure to PD184352 strikingly increased the lethality of a pharmacologically achievable concentration of STI571 (i.e., 1-2 microM) in resistant K562 cells expressing marked increases in Bcr-Abl protein levels. Together, these findings raise the possibility that treatment of Bcr-Abl-expressing cells with STI571 elicits a cytoprotective MAPK activation response and that interruption of the latter pathway (e.g., by pharmacological MEK1/2 inhibitors) is associated with a highly synergistic induction of mitochondrial damage and apoptosis. They also indicate that in the case of Bcr-Abl-positive cells, simultaneous interruption of two signal transduction pathways may represent an effective antileukemic strategy.
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PMID:Pharmacologic mitogen-activated protein/extracellular signal-regulated kinase kinase/mitogen-activated protein kinase inhibitors interact synergistically with STI571 to induce apoptosis in Bcr/Abl-expressing human leukemia cells. 1178 77

Differentiation therapy for myeloid leukemia offers great potential as a supplement to the current treatment modalities. In the present report, we investigated if the pyranocoumarins, (+/-)-4'- O-acetyl-3'- O-angeloyl- cis-khellactone (or angular pyranocoumarin, APC) isolated from the medicinal plant Peucedanum praeruptorum Dunn, could induce human acute myeloid leukemic HL-60 cells to differentiate and elucidated the molecular mechanism(s) involved. The ability of HL-60 cells to reduce nitroblue tetrazolium (NBT) was significantly increased after APC treatment for 72 h. In these differentiating HL-60 cells, cell surface differentiation markers CD11b (for myeloid cells) and CD14 (for monocytic cells) were detected in 90.3 % and 70.1 % of the cells, respectively. The differentiation inducing effect of APC was time- and dose-dependent. Treatment with 20 microg/mL APC for 72 h inhibited cell growth by 90 % and cell cycle analysis revealed an increase in the proportion of G1 phase cells. In these growth-inhibited cells the expression of the cyclin-dependent kinase inhibitor p27 kip1, but not p21 WAF1, was up-regulated as shown by Western blotting. Differentiation inducing signal pathways were investigated and it was shown that phospho-MEK and phospho-ERK were elevated shortly after the addition of APC. Pre-incubation of the cells with MEK1 inhibitor PD98059 blocked this APC-induced differentiation. Our results suggest that APC are potent inducers of HL-60 cell differentiation along both the myelocytic and monocytic lineages and are potential agents for differentiation-treatment of leukemia.
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PMID:Pyranocoumarins isolated from Peucedanum praeruptorum as differentiation inducers in human leukemic HL-60 cells. 1267 25

Use of all-trans-retinoic acid (ATRA) in combinatorial differentiation therapy of acute promyelocytic leukemia (APL) results in exceptional cure rates. However, potent cell differentiation effects of ATRA are so far largely restricted to this disease and long-term survival rates in non-APL acute myelogeneous leukemia (AML) remain unacceptably poor, requiring development of novel therapeutic strategies. We demonstrate here that myelomonocytic growth factors (granulocyte colony-stimulating factor [G-CSF] and/or granulocyte macrophage colony-stimulating factor [GM-CSF]) potentiate differentiation effects of ATRA in different AML cell lines and primary cells from patients with myeloid leukemia. The ligand-dependent activities of endogenous and transiently expressed retinoic acid receptor alpha (RARalpha) isoforms can be potentiated by G/GM-CSF in U-937 cells and correlate with increased expression of ATRA-inducible RARalpha2 isoform. Specific inhibitors of mitogen mitogen-activated protein kinase (MAPK) (MEK)-1/-2 or p38 extracellular signal-related kinase (ERK) kinase diminish the ATRA as well as ATRA and G/GM-CSF-induced activation of the RARalpha proteins and decreased the differentiation-induced decline in cell numbers. Our data demonstrate that acting, at least in part, via the MAP kinase pathways, myelomonocytic growth factors enhance ATRA-dependent activation of the RARalpha isoforms and maturation of myeloid leukemia cells. These results suggest that combinatorial use of these agents may be effective in differentiation therapy of AML.
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PMID:Retinoids and myelomonocytic growth factors cooperatively activate RARA and induce human myeloid leukemia cell differentiation via MAP kinase pathways. 1533 53

M1 mouse myeloid leukemia cells exhibit growth arrest and differentiation to monocytes/macrophages in response to leukemia inhibitory factor (LIF) stimulation. Although recent studies have demonstrated that STAT3 plays a central role in this process, it is unknown whether STAT3 activation alone is sufficient. To address this issue, we have established M1/STAT3ER cells, where STAT3 is selectively activated by 4-hydroxytamoxifen (4HT). 4HT stimulation did not have any effect on growth and morphology of M1/ STAT3ER cells, and did not induce the down-regulation of mRNA of c-myc and c-myb, which is necessary for M1 cell differentiation. On the other hand, mRNA of jun-B, IRF1 and p19 was increased by 4HT. DNA precipitation assay indicated that both stimulation of LIF and 4HT similarly activated STAT3ER. Introduction of a constitutive active MAP kinase kinase (MEK1) into M1/STAT3ER cells did not induce differentiation either. Together, our present data suggest that signaling other than the activation of STAT3 and MEK1 may be necessary for M1 cell-growth arrest and differentiation, while a set of early genes of LIF are induced by only STAT3 activation.
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PMID:Functional analysis of the effect of forced activation of STAT3 on M1 mouse leukemia cells. 1564 43


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