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)

Stress-activated protein kinase/c-Jun NH2-terminal kinase (SAPK/JNK), which belongs to the family of mitogen-activated protein kinase (MAPK), is activated by many types of cellular stress or extracellular signals. Recent studies, including the analysis with knockout cells and mice, have led towards understanding the molecular mechanism of stress-induced SAPK/JNK activation and the physiological roles of SAPK/JNK in embryonic development and immune responses. Two SAPK/JNK activators, SEK1 and MKK7, are required for full activation of SAPK/JNK, which responds to various stimuli in an all-or-none manner in mouse embryonic stem (ES) cells. SAPK/JNK activation plays essential roles in organogenesis during mouse development by regulating cell proliferation, survival or apoptosis and in immune responses by regulating cytokine gene expression. Furthermore, SAPK/JNK is involved in regulation of mRNA stabilization, cell migration, and cytoskeletal integrity. Thus, SAPK/JNK has a wide range of functions in mammalian cells.
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PMID:Activation mechanism and physiological roles of stress-activated protein kinase/c-Jun NH2-terminal kinase in mammalian cells. 1506 57

Programmed cell death (PCD) in the ascidian species Ciona intestinalis (Tunicata; Chordata) is investigated from early larvae to juvenile stages, by means of digoxigenin-based terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling (TUNEL) technique. At first, PCD in the swimming larva affects trunk mesenchyme and central nervous system (CNS), then it participates extensively to metamorphosis, until it is restricted to developing organs of juveniles. Analysis of patterns of cell death and division in the larval CNS question old models on the genesis of the adult C. intestinalis brain. Upon performing immunochemical and functional assays for mitogen-activated protein kinase (MAPK) kinase kinase-1 (MEKK1), MAPK kinase 1/2 (MEK1/2), c-Jun NH2-terminal kinase (JNK), and dual phosphorylated extracellular regulated kinase 1/2 (dpERK1/2), the neurogenic competence of the larval brain appears to rely on a combinatorial regulation of PCD by the mitogen-activated protein kinase signaling cascade. These results show that, in tunicates, PCD consists of a multistep program implicated in growth and patterning with various roles.
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PMID:Time course of programmed cell death in Ciona intestinalis in relation to mitotic activity and MAPK signaling. 1516 4

Flavonoids from medicinal plants have been therapeutically administered for cancer therapy. We recently reported that nobiletin (5,6,7,8,3',4'-hexamethoxy flavone) exhibits novel antitumor invasive activities by suppressing the production of pro-matrix metalloproteinases (proMMPs) and augmenting the expression of tissue inhibitor of metalloproteinases-1 (TIMP-1) in vivo and in vitro. In the present study, intracellular target molecules associated with the actions of nobiletin against tumor invasion were identified. Nobiletin inhibited the phosphorylation of mitogen-activated protein/extracellular signal-regulated kinase (MEK) 1/2, but not the activity of Ras or the phosphorylation of Raf. Moreover, a MEK1/2 inhibitor, U0126, mimicked nobiletin's ability to decrease the production of proMMPs-1 and 9 in human fibrosarcoma HT-1080 cells stimulated by 12-O-tetradecanoyl phorbol-13-acetate (TPA). In addition, neither the activity of phosphatidylinositol 3-kinase (PI3K) nor the phosphorylation of Akt was influenced by nobiletin. However, nobiletin was found to augment the phosphorylation of c-Jun NH2-terminal kinase (JNK), a downstream signal factor of the PI3K-Akt pathway, in TPA-treated HT-1080 cells. A similar augmentation of JNK phosphorylation was observed on treatment with a PI3K inhibitor, LY-294002. Furthermore, nobiletin enhancement of TIMP-1 production in TPA-stimulated HT-1080 cells was found to be diminished by adding a JNK inhibitor, SP600125. Moreover, protein kinase C (PKC) inhibitor experiments showed that PKCbetaII/epsilon were associated with the nobiletin-mediated augmentation of JNK phosphorylation. Therefore, these results introduce novel evidence that the antitumor effects of nobiletin are finely regulated by the following intracellular mechanisms: (1) the inhibition of MEK1/2 activity is involved in the suppression of MMP expression and (2) the activation of the novel PKCbetaII/epsilon-JNK pathway is associated with the augmentation of TIMP-1 expression.
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PMID:Activation of protein kinase C betaII/epsilon-c-Jun NH2-terminal kinase pathway and inhibition of mitogen-activated protein/extracellular signal-regulated kinase 1/2 phosphorylation in antitumor invasive activity induced by the polymethoxy flavonoid, nobiletin. 1525 45

Increased iron store in the body may increase the risk of many diseases such as cancer and inflammation. However, the precise pathogenic mechanism of iron has not yet been elucidated. In the present study, the early biological responses of cells to iron treatment were investigated in AP-1 luciferase reporter stably transfected mouse epidermal JB6 cells and primary rat hepatocytes. It was shown that water-soluble iron compounds, such as FeSO4 and Fe2(SO4)3, were more active in inducing AP-1 in JB6 cells than water-insoluble iron compounds, such as Fe2O3 and FeS. Iron stimulated mitogen-activated protein kinase (MAPK) family members of extracellular signal-regulated kinases (ERKs) and p38 MAPK but not c-jun NH2 terminal kinases (JNKs), both in JB6 cells and in primary rat hepatocytes, as determined by the phosphorylation assay. Interestingly, the increase in AP-1 luciferase activity by iron was inhibited by the pretreatment of the cells with PD98059, a specific MEK1 inhibitor, and SB202190, a p38 kinase inhibitor. Levels of interleukin-6 (IL-6), a pro-inflammatory cytokine, were increased in JB6 cells by iron in a dose-dependent manner. The increase in IL-6 and its mRNA by iron was also eliminated by the pretreatment of the cells with PD98059 and SB202190. Since the IL-6 promoter contains an AP-1 binding site, our studies indicate that the iron-induced IL-6 gene expression may be mediated through ERKs and p38 MAPK pathways, possibly one of the important mechanisms for the pathogenesis of iron overload.
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PMID:Iron-induced interleukin-6 gene expression: possible mediation through the extracellular signal-regulated kinase and p38 mitogen-activated protein kinase pathways. 1536 95

The statin family of drugs are well-established inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase and are used clinically in the control of hypercholesterolemia. Recent evidence, from ourselves and others, shows that statins can also trigger tumor-specific apoptosis by blocking protein geranylgeranylation. We and others have proposed that statins disrupt localization and function of geranylgeranylated proteins responsible for activating signal transduction pathways essential for the growth and/or survival of transformed cells. To explore this further, we have investigated whether the mitogen-activated protein kinase (MAPK) signaling cascades play a role in regulating statin-induced apoptosis. Cells derived from acute myelogenous leukemia (AML) are used as our model system. We show that p38 and c-Jun NH2-terminal kinase/stress-activated kinase MAPK pathways are not altered during lovastatin-induced apoptosis. By contrast, exposure of primary and established AML cells to statins results in significant disruption of basal extracellular signal-regulated kinase (ERK) 1/2 phosphorylation. Addition of geranylgeranyl PPi reverses statin-induced loss of ERK1/2 phosphorylation and apoptosis. By establishing and evaluating the inducible Raf-1:ER system in AML cells, we show that constitutive activation of the Raf/MAPK kinase (MEK)/ERK pathway significantly represses but does not completely block lovastatin-induced apoptosis. Our results strongly suggest statins trigger apoptosis by regulating several signaling pathways, including the Raf/MEK/ERK pathway. Indeed, down-regulation of the Raf/MEK/ERK pathway potentiates statin-induced apoptosis because exposure to the MEK1 inhibitor PD98059 sensitizes AML cells to low, physiologically achievable concentrations of lovastatin. Our study suggests that lovastatin, alone or in combination with a MEK1 inhibitor, may represent a new and immediately available therapeutic approach to combat tumors with activated ERK1/2, such as AML.
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PMID:Blocking the Raf/MEK/ERK pathway sensitizes acute myelogenous leukemia cells to lovastatin-induced apoptosis. 1537 55

Tumor cells frequently synthesize an N-terminally extended the FGF-2 isoform of 24 kDa devoid of signal peptide but that contains a functional nuclear localization sequence (NLS). Although the signaling pathways elicited by secreted FGF-2 are well described, the molecular mechanisms involved in the growth promoting action of nuclearized 24 kDa FGF-2 remain unknown. The cancer cell line AR4-2J was engineered to stably express only the 24 kDa FGF-2 isoform and cDNA microarrays were used to identify targets implicated in the intracrine-induced cell proliferation. Levels of 27 transcripts were found either upregulated or downregulated compared to control cells. Among the 18 upregulated genes was c-jun, which is often involved in cell proliferation. Real-time PCR and Western blot analyses confirmed c-jun induction at both mRNA and protein levels. The c-jun antisense oligonucleotide strategy pointed out the involvement of c-Jun in the 24 kDa FGF-2-induced cell proliferation. The mitogenic effect was found to depend on ERK pathway and not on phosphoinositide 3-kinase, p38 MAPK, c-Jun NH2-terminal kinase signal transducers. In addition, the MEK inhibitor PD98059 reduced the 24 kDa FGF-2-dependent c-Jun level. These data show that intracrine FGF-2-mediated regulation of cell growth involves ERK activation and consequent c-Jun expression. Thus, despite its incapacity to be secreted, the intracellular-localized 24 kDa FGF-2 can activate a growth-related signaling pathway normally elicited by cell surface receptors.
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PMID:Identification of c-Jun as a critical mediator for the intracrine 24 kDa FGF-2 isoform-induced cell proliferation. 1560 98

MKK4 (MAP2K4/SEK1) is a member of the mitogen-activated protein kinase family, originally identified as a kinase involved in the stress-activated protein kinase pathway by directly phosphorylating c-Jun NH2-terminal kinase. MKK4 genetic inactivation has been observed in a subset of pancreatic carcinomas, implicating deregulation of the stress-activated protein kinase pathway in pancreatic carcinogenesis. We evaluated Mkk4 protein expression patterns by immunohistochemical labeling in a series of 60 resected primary infiltrating pancreatic adenocarcinomas (24 cases with known MKK4 genetic status), and 14 different tissue arrays representing the primary carcinoma and all of the gross metastases from 26 patients that died of metastatic pancreatic cancer. Among the surgically resected carcinomas, focal or diffuse-positive immunolabeling for Mkk4 protein was found in 52 of 60 cases (86.7%). Among the eight carcinomas with negative Mkk4 immunolabeling, three harbored a homozygous deletion or intragenic mutation of the MKK4 gene, in contrast to none of the 52 cases with positive Mkk4 immunolabeling (P < 0.01). Loss of Mkk4 immunolabeling showed a trend toward shorter survival, with Mkk4-positive carcinomas having half the risk of death than Mkk4-negative carcinomas (P = 0.09). Mkk4 immunolabeling patterns were also evaluated among unresectable primary and metastatic cancer tissues from autopsy specimens, indicating intact Mkk4 immunolabeling in 88.8% of the unresectable primary carcinomas as compared with 63.3% of distant metastases (P < 0.001). Our data indicate that the loss of Mkk4 protein expression in pancreatic carcinomas may be more frequent than suggested by the rates of genetic inactivation alone and that MKK4 loss may contribute to disease progression. The correlation of MKK4 genetic status with immunolabeling patterns validate this approach for the evaluation of MKK4 status in routine histologic sections and may provide useful information regarding patient prognosis.
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PMID:MAP2K4/MKK4 expression in pancreatic cancer: genetic validation of immunohistochemistry and relationship to disease course. 1562 33

This study first investigates the anticancer effect of asiatic acid in two human breast cancer cell lines, MCF-7 and MDA-MB-231. Asiatic acid exhibited effective cell growth inhibition by inducing cancer cells to undergo S-G2/M phase arrest and apoptosis. Blockade of cell cycle was associated with increased p21/WAF1 levels and reduced amounts of cyclinB1, cyclinA, Cdc2, and Cdc25C in a p53-independent manner. Asiatic acid also reduced Cdc2 function by increasing the association of p21/WAF1/Cdc2 complex and the level of inactivated phospho-Cdc2 and phospho-Cdc25C. Asiatic acid treatment triggered the mitochondrial apoptotic pathway indicated by changing Bax/Bcl-2 ratios, cytochrome c release, and caspase-9 activation, but it did not act on Fas/Fas ligand pathways and the activation of caspase-8. We also found that mitogen-activated protein kinases (MAPKs), extracellular signal-regulated kinase (ERK1/2), and p38, but not c-Jun NH2-terminal kinase (JNK), are critical mediators in asiatic acid-induced cell growth inhibition. U0126 [1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio)butadiene] or SB203580 [4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-1H-imidazole], specific inhibitors of mitogen-activated protein kinase kinase and p38 kinase activities, significantly decreased or delayed apoptosis. Asiatic acid was likely to confine the breast cancer cells in the S-G2/M phase mainly through the p38 pathway, because both SB203580 and p38 small interfering RNA (siRNA) inhibition significantly attenuated the accumulation of inactive phospho-Cdc2 and phospho-Cdc25C proteins and the cell numbers of S-G2/M phase. Moreover, U0126 and ERK siRNA inhibition completely suppressed asiatic acid-induced Bcl-2 phosphorylation and Bax up-regulation, and caspase-9 activation. Together, these results imply a critical role for ERK1/2 and p38 but not JNK, p53, and Fas/Fas ligand in asiatic acid-induced S-G2/M arrest and apoptosis of human breast cancer cells.
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PMID:Asiatic acid, a triterpene, induces apoptosis and cell cycle arrest through activation of extracellular signal-regulated kinase and p38 mitogen-activated protein kinase pathways in human breast cancer cells. 1562 23

Dracorhodin perchlorate, an anthocyanin red pigment, induces human melanoma A375-S2 cell death through the apoptotic pathway. Caspase-3, -8, -9, and -10 inhibitors partially reversed the cell death induced by dracorhodin perchlorate. Caspase-3 and -8 were activated, followed by the degradation of caspase-3 substrates, the inhibitor of caspase-activated DNase, and poly-(ADP-ribose) polymerase. Dracorhodin perchlorate upregulated the expression ratio of Bax/Bcl-2 and significantly increased the expression of p53 and p21(WAF1) proteins. The cell death was partially reduced by the mitogen-activated protein kinase c-JUN NH2-terminal protein kinase (JNK MAPK) inhibitor (SP600125) and p38 MAPK inhibitor (SB 203580), while the MEK inhibitor (PD98059) augmented cell death; the drug induced sustained phosphorylation of JNK and p38 MAPK. Moreover, the Fas agonistic antibody CH-11 has a synergistic effect with dracorhodin perchlorate. The phoshatidylinositol 3-kinase (PI3-K) family inhibitor wortmanin and tyrosine kinase inhibitor genistein rescued the viability loss induced by dracohodin perchlorate. Taken together, dracorhodin perchlorate induces apoptosis in A375-S2 cells via accumulation of p53, alters the Bax/Bcl-2 ratio, and activates caspases and p38/JNK MAPKs.
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PMID:Dracorhodin perchlorate induces A375-S2 cell apoptosis via accumulation of p53 and activation of caspases. 1568 74

The antitumor effect of curcumin (diferuloylmethane) is well established. However, there have been no unbiased studies to identify novel molecular targets of this compound. We therefore undertook a gene expression profiling study to identify novel targets of curcumin. A cDNA array comprised of 12,625 probes was used to compare total RNA extracted from curcumin-treated and untreated MDA-1986 cells for differential gene expression. We identified 202 up-regulated mRNAs and 505 transcripts decreased > or =2-fold. The proapoptotic activating transcription factor 3 (ATF3) was induced >4-fold. Two negative regulators of growth control [antagonizer of myc transcriptional activity (Mad) and p27kip1] were induced 68- and 3-fold, respectively. Additionally, two dual-activity phosphatases (CL 100 and MKP-5), which inactivate the c-jun-NH2-kinases, showed augmented expression, coinciding with reduced expression of the upstream activators of c-jun-NH2-kinase (MEKK and MKK4). Of the repressed genes, the expression of Frizzled-1 (Wnt receptor) was most strongly attenuated (8-fold). Additionally, two genes implicated in growth control (K-sam, encoding the keratinocyte growth factor receptor, and HER3) as well as the E2F-5 transcription factor, which regulates genes controlling cell proliferation, also showed down-regulated expression. Considering its role in apoptosis, we determined the contribution of ATF3 to the antitumor effect of curcumin. Curcumin-treated MDA-1986 cells showed a rapid, dose-dependent increase in ATF3/mRNA protein. Moreover, expression of an exogenous ATF3 cDNA synergized with curcumin in inducing apoptosis. Thus, we have identified several putative, novel molecular targets of curcumin and showed that one, (ATF3) contributes to the proapoptotic effects of this compound.
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PMID:Gene expression profiling identifies activating transcription factor 3 as a novel contributor to the proapoptotic effect of curcumin. 1571 95


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