Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Signal transduction induced by tumor necrosis factor (TNF) family members and their receptors has been an intensive area of research for several years. The major impact of these studies has been the delineation of apoptotic and cell survival signaling pathways. These discoveries, coupled with major advances in the study of mammalian apoptotic machinery, constitute a promising blueprint of the molecular network governing the fate of all living cells. In this review, we concentrate on the fate of cells in the immune system, where regulation of cell death and cell survival is a frequent and important exercise. A small imbalance in favor of either fate can result in disastrous pathological outcomes, such as cancer, autoimmunity or immune deficiency. It is an insurmountable task to discuss all molecules reported in the literature that are implicated in lymphocyte death or survival. We have therefore focused on discoveries made by mouse gene targeting, as these studies provide the most physiologically relevant information on each molecule. We begin with a description of signaling channels initiated by TNF receptor type 1 engagement, which can lead to either cell survival or to cell death. The point of bifurcation of this pathway and the decision-making molecules FADD, TRAF2 and RIP are discussed. We then follow apoptotic and survival pathways from upstream to downstream, describing many important players involved in signal transduction. Molecules important for NF-kappaB and JNK/stress-activated protein kinase activation such as IKKbeta, NEMO, MAP3K and TRAF6 are discussed, as is the impact of BAFF and its receptors on B-cell survival. Mouse mutants that have helped to define the mammalian apoptosis execution machinery, including animals lacking Apaf-1, caspase-3 and caspase-9, are also described. We conclude with a brief analysis of the potential therapeutic options arising from this body of work.
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PMID:Signaling for survival and apoptosis in the immune system. 1211 Jan 44

Alterations in gene expression represent key events in carcinogenesis. We have studied HPV-induced cervical carcinogenesis, using an HPV-33-positive cell line (UT-DEC-1) established from a low-grade vaginal dysplasia (VAIN-I). Early-passage cells contained HPV-33 in episomal form, but these were superseded at later passages by cells carrying only integrated virus. To gain insight into the biologic significance of HPV integration, we compared the level of gene expression in normal vaginal keratinocytes, early-passage and late-passage UT-DEC-1 cells, using cDNA microarrays. Total RNA was isolated from cells by CsCl-gradient centrifugation, reverse-transcribed with MMLV reverse transcriptase and labeled with alpha-(32)P ATP. A cDNA microarray expression profile analysis was performed with Clontech's Human Cancer 1.2 cDNA expression array kit. The 16 upregulated genes (cut-off 2-fold), identified by comparing both cell types to control keratinocytes, appeared to support cell-cycle progression or to be functional in mitosis. These included, e.g., MCM4 DNA replication licensing factor, cdc2p34 and chromatin assembly factor 1 p48 subunit. Downregulated genes (44 altogether) interfered with apoptosis and cell adhesion, including the apoptosis-inducing genes FRAP, Bik and caspase-9 precursor. The most significant differences between the late and early passages (29 and 46 constantly up- and downregulated genes without any fluctuation) were overexpression of the transcription factors E2F5 with its dimerization partner DP1, NF-kappa B and serine/threonine kinases and underexpression of enzymes of the MAPK pathway. Acquisition of a selective growth advantage after viral integration might be explained by a major shift from a MAPK pathway to cell-cycle dysregulation (G(2)/M).
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PMID:Transcriptional profiling of a human papillomavirus 33-positive squamous epithelial cell line which acquired a selective growth advantage after viral integration. 1211 47

Much of what we know about apoptosis in human cells stems from pioneering genetic studies in the nematode C. elegans. However, one important way in which the regulation of mammalian cell death appears to differ from that of its nematode counterpart is in the employment of TNF and TNF receptor superfamilies. No members of these families are present in C. elegans, yet TNF factors play prominent roles in mammalian development and disease. Here, we describe the cloning and characterization of Eiger, a unique TNF homolog in Drosophila. Like a subset of mammalian TNF proteins, Eiger is a potent inducer of apoptosis. Unlike its mammalian counterparts, however, the apoptotic effect of Eiger does not require the activity of the caspase-8 homolog DREDD, but it completely depends on its ability to activate the JNK pathway. Eiger-induced cell death requires the caspase-9 homolog DRONC and the Apaf-1 homolog DARK. Our results suggest that primordial members of the TNF superfamily can induce cell death indirectly by triggering JNK signaling, which, in turn, causes activation of the apoptosome. A direct mode of action via the apical FADD/caspase-8 pathway may have been coopted by some TNF signaling systems only at subsequent stages of evolution.
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PMID:Evolution of TNF signaling mechanisms: JNK-dependent apoptosis triggered by Eiger, the Drosophila homolog of the TNF superfamily. 1217 39

The p3 peptide [amyloid beta-peptide (Abeta) 17-40/42], derived by alpha- and gamma-secretase cleavage of the amyloid precursor protein (APP), is a major constituent of diffuse plaques in Alzheimer's disease and cerebellar pre-amyloid in Down's syndrome. However, the importance of p3 peptide accumulation in Alzheimer's disease and its toxic properties is not clear. Here, we demonstrate that treatment of cells with Abeta 17-42 leads to apoptosis in two human neuroblastoma cell lines, SH-SY5Y and IMR-32. Abeta 17-42 activated caspase-8 and caspase-3, induced poly(ADP-ribose) polymerase cleavage, but did not activate caspase-9. Selective caspase-8 and caspase-3 inhibitors completely blocked Abeta 17-42-induced neuronal death. Abeta 17-42 moderately activated c-Jun N-terminal kinase (JNK); however, overexpression of a dominant-negative mutant of SEK1, the upstream kinase of JNK, protected against Abeta 17-42 induced neuronal death. These results demonstrate that Abeta 17-42 induced neuronal apoptosis via a Fas-like/caspase-8 activation pathway. Our findings reveal the previously unrecognized toxic effect of Abeta 17-42. We propose that Abeta 17-42 constitutes an additional toxic peptide derived from APP proteolysis and may thus contribute to the neuronal cell loss characteristic of Alzheimer's disease.
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PMID:Abeta 17-42 in Alzheimer's disease activates JNK and caspase-8 leading to neuronal apoptosis. 1218 49

We investigated intracellular signalling pathways for apoptosis induced by epigallocatechin-3-gallate (EGCG) as compared with those induced by a toxic chemical substance (etoposide, VP16) or the death receptor ligand [tumour necrosis factor (TNF)]. EGCG as well as VP16 and TNF induced activation of two apoptosis-regulating mitogen-activated protein (MAP) kinases, namely c-Jun N-terminal kinase (JNK) and p38 MAP kinase, in both human leukaemic U937 and OCI-AML1a cells. In U937 cells, the apoptosis and activation of caspases-3 and -9 induced by EGCG but not VP16 and TNF were inhibited with SB203580, a specific inhibitor of p38, while those induced by EGCG and VP16 but not TNF were inhibited with SB202190, a rather broad inhibitor of JNK and p38. In contrast, the EGCG-induced apoptosis in OCI-AML1a cells was resistant to SB203580 but not to SB202190. Unlike TNF, EGCG did not induce the activation of nuclear factor-kappaB but rather induced the primary activation of caspase-9. N -Acetyl-L-cysteine (NAC) almost completely abolished apoptosis induced by EGCG under conditions in which the apoptosis induced by VP16 or TNF was not affected. The JNK/p38 activation by EGCG was also potently inhibited by NAC, whereas those by VP16 and TNF were either not or only minimally affected by NAC. In addition, dithiothreitol also suppressed both apoptosis and JNK/p38 activation by EGCG, and EGCG-induced activation of MAP kinase kinase (MKK) 3/6, MKK4 and apoptosis-regulating kinase 1 (ASK1) was suppressed by NAC. Dominant negative ASK1, MKK6, MKK4 and JNK1 potently inhibited EGCG-induced cell death. EGCG induced an intracellular increase in reactive oxygen species and GSSG, both of which were also inhibited by NAC, and the decreased synthesis of glutathione rendered the cell susceptible to EGCG-induced apoptosis. Taken together these results strongly suggest that EGCG executed apoptotic cell death via an ASK1, MKK and JNK/p38 cascade which is triggered by NAC-sensitive intracellular oxidative events in a manner distinct from chemically induced or receptor-mediated apoptosis.
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PMID:Oxidation-triggered c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein (MAP) kinase pathways for apoptosis in human leukaemic cells stimulated by epigallocatechin-3-gallate (EGCG): a distinct pathway from those of chemically induced and receptor-mediated apoptosis. 1220 15

Cellular redox is controlled by the thioredoxin (Trx) and glutathione (GSH) systems that scavenge harmful intracellular reactive oxygen species (ROS). Oxidative stress also evokes many intracellular events including apoptosis. There are two major pathways through which apoptosis is induced; one involves death receptors and is exemplified by Fas-mediated caspase-8 activation, and another is the stress- or mitochondria-mediated caspase-9 activation pathway. Both pathways converge on caspase-3 activation, resulting in nuclear degradation and cellular morphological change. Oxidative stress induces cytochrome c release from mitochondria and activation of caspases, p53, and kinases, including apoptosis signal-regulating kinase 1 (ASK1), c-Jun N-terminal kinase, and p38 mitogen-activated protein kinase. Trx inhibits apoptosis signaling not only by scavenging intracellular ROS in cooperation with the GSH system, but also by inhibiting the activity of ASK1 and p38. Mitochondria-specific thioredoxin (Trx-2) and Trx peroxidases (peroxiredoxins) are suggested to regulate cytochrome c release from mitochondria, which is a critical early step in the apoptotis-signaling pathway. dATP/ATP and reducing factors including Trx determine the manifestation of cell death, apoptosis or necrosis, by regulating the activation process and the activity of redox-sensitive caspases. As mitochondria are the most redox-active organelle and indispensable for cells to initiate or inhibit the apoptosis process, the regulation of mitochondrial function is the central focus in the research field of apoptosis and redox.
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PMID:Redox control of cell death. 1221 8

A number of highly virulent, intracellular bacteria are known to induce cell death by apoptosis in infected host cells. In this work we demonstrate that phagocytosis of bacteria from the Escherichia coli laboratory strain K12 DH5alpha is a potent cell death stimulus for mouse macrophages. RAW264.7 mouse macrophages took up bacteria and digested them within 2-4 h as investigated with green fluorescent protein-expressing bacteria. No evidence of apoptosis was seen at 8 h postexposure, but at 24 h approximately 70% of macrophages displayed an apoptotic phenotype by a series of parameters. Apoptosis was blocked by inhibition of caspases or by forced expression of the apoptosis-inhibiting protein Bcl-2. Processing of caspase-3 and caspase-9 but not caspase-8 was seen suggesting that the mitochondrial branch of the apoptotic pathway was activated. Active effector caspases could be detected in two different assays. Because the adapter molecule myeloid differentiation factor 88 (MyD88) has been implicated in apoptosis, involvement of the Toll-like receptor pathway was investigated. In RAW264.7 cells, heat-treated bacteria were taken up poorly and failed to induce significant apoptosis. However, cell activation was almost identical between live and heat-inactivated bacteria as measured by extracellular signal-regulated kinase activation, generation of free radicals, and TNF secretion. Furthermore, primary bone marrow-derived macrophages from wild-type as well as from MyD88-deficient mice underwent apoptosis upon phagocytosis of bacteria. These results show that uptake and digestion of bacteria leads to MyD88-independent apoptosis in mouse macrophages. This form of cell death might have implications for the generation of the immune response.
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PMID:Caspase-9/-3 activation and apoptosis are induced in mouse macrophages upon ingestion and digestion of Escherichia coli bacteria. 1221 35

MST1 is a member of the Sterile-20 family of cytoskeletal, stress, and apoptotic kinases. MST1 is activated by phosphorylation at previously unidentified sites. This study examines the role of phosphorylation at several sites and effects on kinase activation. We define Thr(183) in subdomain VIII as a primary site of phosphoactivation. Thr(187) is also critical for kinase activity. Phosphorylation of MST1 in subdomain VIII was catalyzed by active MST1 via intermolecular autophosphorylation, enhanced by homodimerization. Active MST1 (wild-type or T183E), but not inactive Thr(183)/Thr(187) mutants, was also highly autophosphorylated at the newly identified Thr(177) and Thr(387) residues. Cells expressing active MST1 were mostly detached, whereas with inactive MST1, adhesion was normal. Active MKK4, JNK, caspase-3, and caspase-9 were detected in the detached cells. These cells also contained all autophosphorylated and essentially all caspase-cleaved MST1. Similar phenotypes were elicited by a caspase-insensitive D326N mutant, suggesting that kinase activity, but not cleavage of MST1, is required. Interestingly, an S327E mutant mimicking Ser(327) autophosphorylation was also caspase-insensitive, but only when expressed in caspase-3-deficient cells. Together, these data suggest a model whereby MST1 activation is induced by existing, active MST kinase, which phosphorylates Thr(183) and possibly Thr(187). Dimerization promotes greater phosphorylation. This leads to induction of the JNK signaling pathway, caspase activation, and apoptosis. Further activation of MST1 by caspase cleavage is best promoted by caspase-3, although this appears to be unnecessary for signaling and morphological responses.
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PMID:Mapping of MST1 kinase sites of phosphorylation. Activation and autophosphorylation. 1222 93

Bile acid-induced apoptosis plays an important role in the pathogenesis of cholestatic liver disease, and its prevention is of therapeutic interest. The effects of betaine were studied on taurolithocholate 3-sulfate (TLCS) and glycochenodeoxycholate (GCDC)-induced apoptosis in rat hepatocytes in vitro and in vivo. Hepatocyte apoptosis, caspase activation, and poly (ADP-ribose) polymerase (PARP) cleavage, which are normally observed in response to both bile acids, were largely prevented after preincubation of hepatocytes with betaine. Betaine uptake was required for this protective effect, which was already observed at betaine concentrations of 1 mmol/L. Betaine did not affect the TLCS-induced membrane trafficking of CD95 and tumor necrosis factor-related apoptosis inducing ligand (TRAIL) receptor 2 to the plasma membrane or the TLCS-induced recruitment of Fas-associated death domain (FADD) and caspase 8 to the CD95 receptor. However, betaine largely prevented cytochrome c release and oxidative stress exerted otherwise by TLCS. Inhibition of caspase 9 strongly blunted TLCS-induced caspase-8 activation. Further betaine did not prevent the TLCS-induced c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (Erk), and p38 mitogen-activated protein kinase (p38(MAPK)) activation or TLCS-induced protein kinase B (PKB) dephosphorylation. The protective betaine effect was insensitive to inhibition of Erks by PD089059, of p38(MAPK) by SB203580, or of phosphatidylinositol 3-kinase (PI3-kinase) by LY294002. Betaine supplementation in the drinking water significantly ameliorated in vivo hepatocyte apoptosis following bile duct ligation. In conclusion, this study identifies betaine as a potent protectant against bile acid-induced apoptosis in vivo and in vitro, and its antiapoptotic action largely resides on an inhibition of the proapoptotic mitochondrial pathway.
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PMID:Prevention of bile acid-induced apoptosis by betaine in rat liver. 1229 30

The severe reduction in mRNA and protein levels of the mitochondrial protein frataxin, encoded by the X25 gene, causes Friedreich ataxia (FRDA), the most common form of recessive hereditary ataxia. Increasing evidence underlines the pathogenetic role of oxidative stress in this disease. We generated an in vitro cellular model of regulated human frataxin overexpression. We identified, by differential display technique, the mitogen activated protein kinase kinase 4 mRNA down regulation in frataxin overexpressing cells. We studied the stress kinases pathway in this cellular model and in fibroblasts from FRDA patients. Frataxin overexpression reduced c-Jun N-terminal kinase phosphorylation. Furthermore, exposure of FRDA fibroblasts to several forms of environmental stress caused an up regulation of phospho-JNK and phospho-c-Jun. To understand if this susceptibility results in cell death, we have investigated the involvement of caspases. A significantly higher activation of caspase-9 was observed in FRDA versus control fibroblasts after serum-withdrawal. Our findings suggest the presence, in FRDA patient cells, of a 'hyperactive' stress signaling pathway. The role of frataxin in FRDA pathogenesis could be explained, at least in part, by this hyperactivity.
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PMID:Up-regulation of c-Jun N-terminal kinase pathway in Friedreich's ataxia cells. 1239 10


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