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)

Cell death and cell survival are central components of normal development and pathologic states. Transforming growth factor beta1 (TGF-beta1) is a pleiotropic cytokine that regulates both cell growth and cell death. To better understand the molecular mechanisms that control cell death or survival, we investigated the role of TGF-beta1 in the apoptotic process by dominant-negative inhibition of both TGF-beta1 and mitogen-activated protein kinase (MAPK) signaling pathways. Murine macrophages (RAW 264.7) undergo apoptosis following serum deprivation, as determined by DNA laddering assay. However, apoptosis is prevented in serum-deprived macrophages by the presence of exogenous TGF-beta1. Using stably transfected RAW 264.7 cells with the kinase-deleted dominant-negative mutant of TbetaR-II (TbetaR-IIM) cDNA, we demonstrate that this protective effect by TGF-beta1 is completely abrogated. To determine the downstream signaling pathways, we examined TGF-beta1 effects on the MAPK pathway. We show that TGF-beta1 induces the extracellular signal-regulated kinase (ERK) activity in a time-dependent manner up to 4 h after stimulation. Furthermore, TGF-beta1 does not rescue serum deprivation-induced apoptosis in RAW 264.7 cells transfected with a dominant-negative mutant MAPK (ERK2) cDNA or in wild type RAW 264.7 cells in the presence of the MAPK kinase (MEK1) inhibitor. Taken together, our data demonstrate for the first time that TGF-beta1 is an inhibitor of apoptosis in cultured macrophages and may serve as a cell survival factor via TbetaR-II-mediated signaling and downstream intracellular MAPK signaling pathway.
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PMID:Transforming growth factor beta1 rescues serum deprivation-induced apoptosis via the mitogen-activated protein kinase (MAPK) pathway in macrophages. 1019 28

Interactions between the checkpoint abrogator UCN-01 and several pharmacological inhibitors of the mitogen-activated protein kinase (MAPK) kinase (MEK)/MAPK pathway have been examined in a variety of human leukemia cell lines. Exposure of U937 monocytic leukemia cells to a marginally toxic concentration of UCN-01 (e.g., 150 nM) for 18 h resulted in phosphorylation/activation of p42/44 MAPK. Coadministration of the MEK inhibitor PD184352 (10 microM) blocked UCN-01-induced MAPK activation and was accompanied by marked mitochondrial damage (e.g., cytochrome c release and loss of DeltaPsi(m)), caspase activation, DNA fragmentation, and apoptosis. Similar interactions were noted in the case of other MEK inhibitors (e.g., PD98059; U0126) as well as in multiple other leukemia cell types (e.g., HL-60, Jurkat, CCRF-CEM, and Raji). Coadministration of PD184352 and UCN-01 resulted in reduced binding of the cdc25C phosphatase to 14-3-3 proteins, enhanced dephosphorylation/activation of p34(cdc2), and diminished phosphorylation of cyclic AMP-responsive element binding protein. The ability of UCN-01, when combined with PD184352, to antagonize cdc25C/14-3-3 protein binding, promote dephosphorylation of p34(cdc2), and potentiate apoptosis was mimicked by the ataxia telangectasia mutation inhibitor caffeine. In contrast, cotreatment of cells with UCN-01 and PD184352 did not substantially increase c-Jun-NH(2)-terminal kinase activation nor did it alter expression of Bcl-2, Bcl-x(L), Bax, or X-inhibitor of apoptosis. However, coexposure of U937 cells to UCN-01 and PD184352 induced a marked increase in p38 MAPK activation. Moreover, SB203580, which inhibits multiple kinases including p38 MAPK, partially antagonized cell death. Lastly, although UCN-01 +/- PD184352 did not induce p21(CIP1), stable expression of a p21(CIP1) antisense construct significantly increased susceptibility to this drug combination. Together, these findings indicate that exposure of leukemic cells to UCN-01 leads to activation of the MAPK cascade and that interruption of this process by MEK inhibition triggers perturbations in several signaling and cell cycle regulatory pathways that culminate in mitochondrial injury, caspase activation, and apoptosis. They also raise the possibility that disrupting multiple signaling pathways, e.g., by combining UCN-01 with MEK inhibitors, may represent a novel antileukemic strategy.
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PMID:Pharmacological inhibitors of the mitogen-activated protein kinase (MAPK) kinase/MAPK cascade interact synergistically with UCN-01 to induce mitochondrial dysfunction and apoptosis in human leukemia cells. 1143 48

The mitogen-activated protein kinase (MAPK) pathway regulates growth and survival of many cell types, and its constitutive activation has been implicated in the pathogenesis of a variety of malignancies. In this study we demonstrate that small-molecule MEK inhibitors (PD98059 and PD184352) profoundly impair cell growth and survival of acute myeloid leukemia (AML) cell lines and primary samples with constitutive MAPK activation. These agents abrogate the clonogenicity of leukemic cells but have minimal effects on normal hematopoietic progenitors. MEK blockade also results in sensitization to spontaneous and drug-induced apoptosis. At a molecular level, these effects correlate with modulation of the expression of cyclin-dependent kinase inhibitors (p27(Kip1) and p21(Waf1/CIP1)) and antiapoptotic proteins of the inhibitor of apoptosis proteins (IAP) and Bcl-2 families. Interruption of constitutive MEK/MAPK signaling therefore represents a promising therapeutic strategy in AML.
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PMID:Therapeutic targeting of the MEK/MAPK signal transduction module in acute myeloid leukemia. 1156 Sep 54

Interleukin 15 (IL-15) is a potent stimulator of proliferation and an inhibitor of apoptosis in lymphocytes. We attempted to elucidate the mechanism of IL-15 function in HaCaT keratinocytes. We found that 5-bromo-2(')-deoxyuridine incorporation increased in a dose-dependent manner with IL-15. This was blocked by MEK inhibitor U0126 or PI 3-K inhibitor LY294002. ERK1/2 and Akt phosphorylation by IL-15 were detected in a dose- and time-dependent manner. U0126 and LY294002 abolished ERK1/2 and Akt phosphorylation, respectively. DNA fragmentation and Annexin V binding accompanied by UVB-induced apoptosis were reduced by 30-50% with IL-15. Taken together, IL-15 induced cellular proliferation and had an anti-apoptotic effect on keratinocytes, in which ERK1/2 and Akt phosphorylation played crucial roles. The signal transduction pathways of IL-15 in keratinocytes were partially elucidated; they share a substantial part with growth signals induced by EGF. These results suggest a therapeutic approach to inflammatory skin diseases by controlling these signals.
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PMID:Interleukin 15 induces the signals of epidermal proliferation through ERK and PI 3-kinase in a human epidermal keratinocyte cell line, HaCaT. 1258 89

Neutrophils and monocytes/macrophages are derived from common progenitors, but exhibit markedly different lifespans. Differentiated neutrophils are short-lived and die rapidly by apoptosis, while monocytic cells are longer-lived. In this report we used the HL-60 cell line as a model system to identify differences in apoptotic pathways which might account for the differing lifespans of granulocytic vs monocytic cells. We observed that induction of granulocytic differentiation by retinoic acid led to robust activation of the executioner protease caspase-3, and early onset of apoptosis. By contrast, caspase-3 was not appreciably activated during phorbol 12-myristate 13-acetate (PMA)-induced monocytic differentiation, and apoptosis was delayed in these cells. Since the activation of caspase-3 is inhibited by members of the inhibitor of apoptosis (IAP) and Bcl-2 protein families, we investigated the expression of anti-apoptotic members of these families. Induction of monocytic differentiation led to marked upregulation of the IAP protein XIAP, as well as the Bcl-2 family member Bcl-X(L). During granulocytic differentiation the levels of XIAP progressively declined, while Bcl-X(L) levels remained unchanged. A different IAP protein, survivin, was downregulated during differentiation along either lineage, as was expression of Bcl-2. The upregulation of Bcl-X(L) during monocytic differentiation coincided with phosphorylation/activation of STAT3, a known activator of bcl-X gene transcription. Moreover, Bcl-X(L) upregulation was dependent on MEK/ERK signaling. Upregulation of XIAP proceeded in a MEK/ERK-independent fashion. Treatment with antisense Bcl-X(L) or XIAP oligonucleotides resulted in significant loss of viability in cells differentiating along the monocytic lineage. Together, these findings indicate that the levels of XIAP and Bcl-X(L) are regulated by distinct pathways during monocytic differentiation, and that upregulation of these proteins contributes to the increased longevity of cells in the monocytic lineage.
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PMID:Differential activation of apoptosis regulatory pathways during monocytic vs granulocytic differentiation: a requirement for Bcl-X(L)and XIAP in the prolonged survival of monocytic cells. 1259 39

The impact of disruption of the PI3K (phosphatidylinositol 3-kinase) pathway on the response of human leukemia cells to pharmacological cyclin-dependent kinase (CDK) inhibitors has been examined. Exposure of U937 monocytic leukemia cells to minimally toxic concentrations of flavopiridol (FP), roscovitine, or CGP74514A for 3 h in conjunction with the PI3K inhibitor LY294002 (abbreviated LY in the article) resulted in a marked decrease in Akt phosphorylation. Coexposure of cells to LY and CDK inhibitors also resulted in an early (i.e., within 3 h) and striking increase in mitochondrial damage [e.g., cytochrome c, second mitochondria-derived activator of caspases/direct inhibitor of apoptosis (IAP)-binding protein with low isoelectric point (Smac/DIABLO), and apoptosis-initiating factor (AIF) release], caspase activation, and apoptosis. Similar interactions were observed in a variety of other leukemia cell types (e.g., HL-60, Jurkat, Raji, and NB4). Apoptosis, induced by FP/LY, was substantially blocked by ectopic expression of Bcl-2, but to a considerably lesser extent by dominant-negative caspase-8. FP-induced apoptosis was not enhanced by agents that inhibited protein kinase (PK) A (H89), PKC (GFX), mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK) kinase (MEK1/2; U0126), p38 MAP kinase (MAPK; SB202190), m-target of rapamycin (TOR; rapamycin), or ataxia-telangiectasia mutation (ATM; caffeine), whereas the PI3K inhibitor wortmannin exerted effects similar to those of LY. The dramatic potentiation of CDK inhibitor-induced apoptosis by LY was accompanied by diminished Bad phosphorylation, induction of Bcl-2 cleavage, and down-regulation of X-linked IAP (XIAP) and Mcl-1. Cells exposed to CDK inhibitors + LY also exhibited reduced phosphorylation of glycogen synthase kinase (GSK)-3, forkhead transcription factor (FKHR), p70(S6K), and ERK, but increased activation of p34(cdc2) and p38 MAPK. LY/CDK inhibitor-treated cells also displayed diminished pRb dephosphorylation on CDK2- and CDK4-specific sites, retinoblastoma protein cleavage, and down-regulation of cyclin D(1). Inducible expression of constitutively active (myristolated) Akt significantly, albeit partially, attenuated apoptosis in Jurkat leukemia cells treated with either FP alone or the combination of FP and LY. Finally, cotreatment with LY and FP resulted in a dramatic increase in apoptosis in primary leukemic blasts obtained from a patient with acute myeloblastic leukemia. Together, these findings suggest that the PI3K/Akt pathway plays a major role in regulating the apoptotic response of human leukemia cells to pharmacological CDK inhibitors and raise the possibility that combined interruption of CDK- and PI3K-related pathways may represent a novel therapeutic strategy in hematological malignancies.
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PMID:The lethal effects of pharmacological cyclin-dependent kinase inhibitors in human leukemia cells proceed through a phosphatidylinositol 3-kinase/Akt-dependent process. 1270 69

The mitochondrial release of cytochrome c and Smac/DIABLO has been implicated in the activation of apoptosis in response to cell stress. Smac promotes cytochrome c-induced activation of caspases by sequestering the inhibitor of apoptosis protein (IAP) family of potent caspase suppressors. Differential release from mitochondria of cytochrome c and Smac can occur, but the underlying mechanism and physiological significance of this are unclear. Here we show that the mechanism by which fibroblast growth factor 2 (FGF-2) protects small cell lung cancer (SCLC) cells from etoposide-induced cell death involves inhibition of Smac release but not of cytochrome c release. This process is MEK dependent and correlates with an increased expression of XIAP and cellular IAP-1, mediated principally through translational regulation. Exogenous expression of XIAP is sufficient to inhibit caspase 9 activation, Smac release, and cell death induced by etoposide. Prevention of the FGF-2-promoted increase in levels of functional IAPs by RNA interference or the cell-permeant Smac amino-terminal peptide blocked FGF-2-induced protection. FGF-2 can thus protect SCLC cells from chemotherapeutic drugs by modulating IAP levels via posttranscriptional regulation, providing a mechanism for postmitochondrial survival signaling by the MEK/mitogen-activated protein kinase pathway.
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PMID:Fibroblast growth factor 2-mediated translational control of IAPs blocks mitochondrial release of Smac/DIABLO and apoptosis in small cell lung cancer cells. 1456 6

Among other cellular responses, tumor necrosis factor (TNF) induces different forms of cell death and the activation of the p38 mitogen-activated protein kinase (MAPK). The influence of p38 MAPK activation on TNF-induced apoptosis or necrosis is controversially discussed. Here, we demonstrate that pharmacological inhibition of p38 MAPK enhances TNF-induced cell death in murine fibroblast cell lines L929 and NIH3T3. Furthermore, overexpression of dominant-negative versions of p38 MAPK or its upstream kinase MKK6 led to increased cell death in L929 cells. While overexpression of the p38 isoforms alpha and beta did not protect L929 cells from TNF-induced toxicity, overexpression of constitutively active MKK6 decreased TNF-induced cell death. Although the used inhibitors of p38 MAPK decreased the phosphorylation of the survival kinase PKB/Akt, this effect could be ruled out as cause of the observed sensitization to TNF-induced cytotoxicity. Finally, we demonstrate that the nuclear factor kappaB (NF-kappaB)-dependent gene expression, shown as an example for the anti-apoptotic gene cellular inhibitor of apoptosis (c-IAP2), was reduced by p38 MAPK inhibition. In consequence, we found that inhibition of p38 MAPK led to the activation of the executioner caspase-3.
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PMID:Inhibition of p38 mitogen-activated protein kinase reduces TNF-induced activation of NF-kappaB, elicits caspase activity, and enhances cytotoxicity. 1472 57

We recently reported that cAMP suppresses apoptosis in colon cancer cells and induces cellular inhibitor of apoptosis protein-2 (c-IAP2) via a cAMP-responsive element (CRE), suggesting a mechanism for chemoprevention of colon cancer by non-steroidal anti-inflammatory drugs. In this study, we used T84 human colon cancer cells to define the pathway by which increases in cAMP induce c-IAP2 expression. Treatment with several different cAMP agonists stimulated phosphorylation of CRE-binding protein (CREB) and activated expression of c-IAP2 in a CREB-dependent manner. Studies with pharmacological inhibitors revealed that cAMP-dependent phosphorylation of CREB required activation of ERK1/2 and p38 MAPK but was largely independent of protein kinase A. Immunoblots and transcriptional reporter assays using specific inhibitors, as well as expression of constitutively active forms of MEK1 and MKK3, showed that c-IAP2 induction by cAMP is regulated predominantly through ERK1/2 and p38 MAPK and suggested involvement of p90 ribosomal protein S6 kinase and mitogen and stress response kinase-1 as well. Consistent with those results, we found that cAMP-dependent suppression of apoptosis was blocked by treatment with inhibitors of ERK1/2 and p38 MAPK. We conclude that cAMP can induce c-IAP2 expression in colon cancer cells through CREB phosphorylation and CRE-dependent transcription in a manner that involves activation of ERK1/2 and p38 MAPK. These results emphasize that activation of kinases other than protein kinase A can mediate the actions of agents that increase cAMP, particularly in the regulation of CREB-dependent events.
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PMID:Cyclic AMP promotes cAMP-responsive element-binding protein-dependent induction of cellular inhibitor of apoptosis protein-2 and suppresses apoptosis of colon cancer cells through ERK1/2 and p38 MAPK. 1507 90

Insulin significantly reduced tumor necrosis factor (TNF)-alpha-induced cleavage of procaspase-8, -9, and -3 and poly(ADP-ribose) polymerase when observed for up to 24 hours in a dose-dependent manner. Signaling pathways responsible for the inhibitory effects of insulin were investigated by using protein kinase inhibitors. Both phosphatidylinositol 3'-kinase (PI3K) and mitogen-activated protein kinase kinase pathways mediate the ability of insulin to decrease the TNF-alpha-induced cleavage of procaspase-8. In contrast, only the PI3K inhibitor reversed the effect of insulin on the TNF-alpha-induced cleavage of procaspase-9. Moreover, insulin decreased the apoptotic level induced by TNF-alpha, whereas the PI3K inhibitor enhanced it. The protein level of Apaf-1, an activator of procaspase-9, remained constant with the application of agents affecting the cleavage of procaspase-9. In examining another regulator of cleaved caspase-9, X chromosome-linked inhibitor of apoptosis protein (XIAP), we observed that TNF-alpha treatment induced fragmentation of XIAP, which was also enhanced by the PI3K inhibitor. In addition, XIAP was coimmunoprecipitated with procaspase-9. The treatment with TNF-alpha reduced the level of XIAP precipitated with procaspase-9, whereas insulin reversed this effect. Moreover, PI3K and Akt inhibitors, but not mammalian target of rapamycin inhibitor, inhibited the effect of insulin on the coprecipitation of procaspase-9 and XIAP. Our data suggest that insulin decreases the TNF-alpha-induced cleavage of procaspase-9 and subsequent apoptosis by regulating XIAP via the PI3K/Akt pathway.
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PMID:Insulin regulates cleavage of procaspase-9 via binding of X chromosome-linked inhibitor of apoptosis protein in HT-29 cells. 1560 74


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