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)

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 Raf-1 kinase has a well established role in activating the MEK-ERK/MAPK pathway. However, accumulating evidence including the phenotype of Raf-1(-/-) mice suggested that Raf-1 may have other functions independent of its role as MEK activator, in particular pertaining to protection against apoptosis. We have recently demonstrated a new role of Raf-1 by showing that Raf-1 controls the proapoptotic kinase MST2/Hippo. In mammalian cells MST2 is activated by stress signals and causes apoptosis when overexpressed. Its Drosophila homologue Hippo regulates apoptosis and cell cycle arrest during differentiation. Raf-1 inhibits MST2 by preventing its dimerisation and recruiting a phosphatase that removes activating phosphorylations on MST2. Both functions require Raf-1 binding to MST2, but are independent of Raf-1's kinase activity and the ERK pathway. Downregulation of MST2 by siRNA reverts the apoptosis hypersensitivity of Raf-1(-/-) mouse fibroblasts. In contrast, the downregulation of Raf-1 in Raf-1(+/+) cells and human cancer cell lines enhances susceptibility to Fas induced apoptosis, which is rescued by concomitant downregulation of both Raf-1 and MST2. The MST2:Raf-1 complex is dissociated by stress signals as well as mitogens. Stress signals robustly activate MST2 and trigger apoptosis. Mitogens only make MST2 permissive for activation by releasing it from Raf-1, and in addition activate survival pathways allowing proliferation. Thus, by linking mitogenic and apoptotic signalling the MST:Raf-1 complex may serve as a safeguard against unlicensed proliferation.
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PMID:Taming the Hippo: Raf-1 controls apoptosis by suppressing MST2/Hippo. 1570 72

Bystander B cells may be initially stimulated through CD40, which enhances susceptibility to Fas-mediated apoptosis, before encountering Ag, which produces Fas resistance. A key issue in this process is to what extent CD40 cross-talk might affect subsequent BCR signaling. It has previously been shown that CD40 engagement bypasses or mitigates the need for Bruton's tyrosine kinase in subsequent BCR signaling for NF-kappaB activation. However, the full extent of the effects of CD40 on BCR signaling has not been delineated. In the present study we evaluated the possibility that CD40-mediated cross-talk also affects another principal outcome of BCR signaling: MAPK activation. We found that prior stimulation of primary murine B cells with CD40L markedly enhanced the level of ERK and JNK (but not p38 MAPK) phosphorylation produced by subsequently added anti-Ig Ab, and much, but not all, of this enhancement was independent of PI3K and phospholipase C. CD40L treatment similarly enhanced BCR-induced MAPK kinase (MEK) phosphorylation, and MEK was required for enhancement of ERK. Although BCR-induced c-Raf phosphorylation was also enhanced by prior CD40L treatment, c-Raf was not required for MEK/ERK phosphorylation. These results identify a novel system of receptor cross-talk between CD40 and BCR and indicate that the effects of CD40 engagement on subsequent BCR stimulation spread beyond NF-kappaB to involve the MAPK pathway.
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PMID:B cell receptor (BCR) cross-talk: CD40 engagement enhances BCR-induced ERK activation. 1574 69

Hibiscus sabdariffa Linne (Malvaceae), an attractive plant believed to be native to Africa, is cultivated in the Sudan and Eastern Taiwan. Anthocyanins exist widely in many vegetables and fruits. Some reports demonstrated that anthocyanins extracted from H. sabdariffa L., Hibiscus anthocyanins (HAs) (which are a group of natural pigments existing in the dried calyx of H. sabdariffa L.) exhibited antioxidant activity and liver protection. Therefore, in this study, we explored the effect of HAs on human cancer cells. The result showed that HAs could cause cancer cell apoptosis, especially in HL-60 cells. Using flow cytometry, we found that HAs treatment (0-4 mg/ml) markedly induced apoptosis in HL-60 cells in a dose- and time-dependent manner. The result also revealed increased phosphorylation in p38 and c-Jun, cytochrome c release, and expression of tBid, Fas, and FasL in the HAs-treated HL-60 cells. We further used SB203580 (p38 inhibitor), PD98059 (MEK inhibitor), SP600125 (JNK inhibitor), and wortmannin (phosphatidylinositol 3-kinase; PI-3K inhibitor) to evaluate their effect on the HAs-induced HL-60 death. The data showed that only SB203580 had strong potential in inhibiting HL-60 cell apoptosis and related protein expression and phosphorylation. Therefore, we suggested that HAs mediated HL-60 apoptosis via the p38-FasL and Bid pathway. According to these results, HAs could be developed as chemopreventive agents. However, further investigations into the specificity and mechanism(s) of HAs are needed.
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PMID:Hibiscus anthocyanins rich extract-induced apoptotic cell death in human promyelocytic leukemia cells. 1592 6

RAS is a small GTP binding protein mutated in approximately 30% human cancer. Despite its important role in the initiation and progression of human cancer, the underlying mechanism of RAS-induced human epithelial transformation remains elusive. In this study, we probe the cellular and molecular mechanisms of RAS-mediated transformation, by profiling two human ovarian epithelial cell lines. One cell line was immortalized with SV40 T/t antigens and the human catalytic subunit of telomerase (T29), while the second cell line was transformed with an additional oncogenic ras(V12) allele (T29H). In total, 32 proteins associated with RAS-mediated transformation have been identified using peptide mass fingerprinting. These protein targets are involved in several cellular pathways, including metabolism, redox balance, calcium signaling, apoptosis, and cellular methylation. One such target, the 40 kDa procaspase 4 is significantly upregulated at the protein level in RAS-transformed T29H cells, related directly to signaling through MEK, but not PI3 kinase. Cellular caspase 4 activity is, however, suppressed in the T29H cells, suggesting that the maturation process of caspase 4 is abrogated in RAS-transformed T29H cells. Consistent with this notion, transformed T29H cells were less susceptible to the toxic effects of anti-Fas antibody than were immortalized, nontransformed T29 cells, associated with less activation of caspase 4. This study demonstrates that functional proteomic analysis of a genetically defined cancer model provides a powerful approach toward systematically identifying cellular targets associated with oncogenic transformation.
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PMID:Proteomics analysis of H-RAS-mediated oncogenic transformation in a genetically defined human ovarian cancer model. 1594 Feb 60

Dendritic cells (DCs) and chemokines are important in linking innate and adaptive immunity. We previously reported that Fas ligation induced interleukin 1beta (IL-1beta)-dependent maturation and IL-1beta-independent survival of DCs, with extracellular signal-regulated kinase (ERK) and nuclear factor-kappaB (NF-kappaB) signaling pathways involved, respectively. We describe here that Fas ligation induced DCs to rapidly produce both CXC and CC chemokines, including macrophage inflammatory protein 2 (MIP-2), MIP-1alpha, MIP-1beta, monocyte chemoattractant protein 1 (MCP-1), RANTES (regulated on activation normal T cell expressed and secreted), and TARC (thymus and activation-regulated chemokine), resulting in enhanced chemoattraction of neutrophils and T cells by Fas-ligated DCs in vivo or by its supernatant in vitro. These chemokines work synergistically in chemoattraction of neutrophils and T cells with MIP-2 more important for neutrophils, MIP-1alpha and TARC more important for T cells. Moreover, Fas-ligated DCs increased endocytosis by neutrophils and activation and proliferation of antigen-specific naive T cells. Fas ligation-induced DC secretion of chemokines involves Ras/Raf/mitogen-activated protein kinase kinase (MEK)/ERK activation and is ERK, but not NF-kappaB, dependent. Activation of caspases, including caspase 1, but not IL-1 autocrine action, is involved in this process. These data indicate that Fas signaling provides a key link between innate response and adaptive immunity by promoting DC chemokine production.
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PMID:Fas signal links innate and adaptive immunity by promoting dendritic-cell secretion of CC and CXC chemokines. 1594 11

Growth factors are known to favor both proliferation and survival of hepatocytes. In the present study, we investigated if c-FLIP(L) (cellular FLICE-inhibitory protein, long isoform) could be involved in epidermal growth factor (EGF)-stimulated proliferation of rat hepatocytes since c-FLIP(L) regulates both cell proliferation and procaspase-8 maturation. Treatment with MEK inhibitors prevented induction of c-FLIP(L) by EGF along with total inhibition of DNA replication. However, EGF failed to inhibit processing of procaspase-8 in the presence of EGF suggesting that c-FLIP(L) does not play its canonical anti-apoptotic role in this model. Downregulation of c-FLIP expression using siRNA oligonucleotides strongly reduced DNA replication but did not result in enhanced apoptosis. Moreover, intermediate cleavage products of c-FLIP(L) and caspase-8 were found in EGF-treated hepatocytes in the absence of caspase-3 maturation and cell death. To determine whether the Fas/FADD/caspase-8/c-FLIP(L) complex was required for this activity, Fas, procaspase-8 and Fas-associated death domain protein (FADD) expression or function was inhibited using siRNA or constructs encoding dominant negative mutant proteins. Inhibition of any of these components of the Fas/FADD/caspase-8 pathway decreased DNA replication suggesting a function of these proteins in cell-cycle arrest. Similar results were obtained when the IETD-like caspase activity detectable in EGF-treated hepatocytes was inhibited by the pan-caspase inhibitor, z-ASP. Finally, we demonstrated co-immunoprecipitation between EGFR and Fas within 15 min following EGF stimulation. In conclusion, our results indicate that the Fas/FADD/c-FLIP(L)/caspase-8 pathway positively controls the G(1)/S transition in EGF-stimulated hepatocytes. Our data provide new insights into the mechanisms by which apoptotic proteins participate to mitogenic signals during the G(1) phase.
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PMID:A role for caspase-8 and c-FLIPL in proliferation and cell-cycle progression of primary hepatocytes. 1603 71

Phosphorylated p38 mitogen-activated protein kinase (p38MAPK), but not activated c-jun-N-terminal kinase (JNK), increases in the motor neurons of transgenic mice overexpressing ALS-linked SOD1 mutants at different stages of the disease. This effect is associated with a selective increase of phosphorylated MKK3-6, MKK4 and ASK1 and a concomitant upregulation of the TNFalpha receptors (TNFR1 and TNFR2), but not IL1beta and Fas receptors. Activation of both p38 MAPK and JNK occurs in the activated microglial cells of SOD1 mutant mice at the advanced stage of the disease; however, this effect is not accompanied by the concomitant activation of the upstream kinases ASK1 and MKK3,4,6, while both the TNFRs are overexpressed in these cells. No changes of the upstream p38MAPK cascade kinases or TNFRs occur in reactive astrocytes. These findings highlight the activation of a selective intracellular signaling pathway in the motor neurons of SOD1 mutant mice, which is likely implicated in their death.
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PMID:Activation of the p38MAPK cascade is associated with upregulation of TNF alpha receptors in the spinal motor neurons of mouse models of familial ALS. 1621 74

Herein we report that the prosurvival sphingolipid sphingosine 1-phosphate regulates the activities of both Bad and Bax during apoptosis of Jurkat cells. First, sphingosine 1-phosphate treatment results in Bad inactivation via the ERK/Rsk-1 pathway. Second, sphingosine 1-phosphate blocks the translocation of Bax to the mitochondria induced by Fas ligation. MEK inhibition by PD98059 or U0126 not only abrogates sphingosine 1-phosphate-induced Bad phosphorylation, but also its cytoprotective effect. Furthermore, inhibition of both mitochondrial cytochrome c efflux and Bax translocation to the mitochondria by sphingosine 1-phosphate could be overcome by PD98059 or U0126. Hence, the MEK/ERK pathway seems to be crucial for the survival effects initiated by sphingosine 1-phosphate.
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PMID:Regulation by sphingosine 1-phosphate of Bax and Bad activities during apoptosis in a MEK-dependent manner. 1641 56


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