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:2.7.11.24 (mitogen-activated protein kinase)
95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Apoptosis occurs in influenza virus (IV)-infected cells. There are a number of mechanisms for the regulation of apoptosis. However, the molecular mechanism of IV infection-induced apoptosis is still controversial. Apoptosis signal-regulating kinase1 (ASK1) is a ubiquitously expressed mitogen-activated protein kinase kinase kinase (MAPKKK) that activates the SEK1-c-Jun N-terminal kinase (JNK) and MKK3/MKK6-p38 MAPK signaling cascades. ASK1 has been implicated in cytokine- and stress-induced apoptosis. Here, we show the following: (1) IV infection activated ASK1 and concomitantly phosphorylated JNK and p38 MAPK in human bronchial epithelial cells; (2) the activation of JNK and p38 MAPK but not extracellular-regulated kinase (ERK) in embryonic fibroblasts (MEFs) derived from ASK1 knockout mice (ASK1(-/-) MEFs) was depressed compared to MEFs derived from wild type mice (ASK1(+/+) MEFs); and (3) ASK1(-/-) MEFs were defective in IV infection-induced caspase-3 activation and cell death. These results indicate that apoptosis in IV-infected BEC is mediated through ASK1-dependent cascades.
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PMID:ASK1 regulates influenza virus infection-induced apoptotic cell death. 1287 92

The temporal and spatial distribution of active c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) in the brain was investigated in an experimental virus-mouse system in which neurovirulent influenza A virus caused lethal acute encephalitis. Following stereotaxic microinjection into the olfactory bulb, virus-infected neurons appeared in several midbrain structures, including the ventral tegmental area, amygdala and the pyramidal layer of the hippocampus. Infected neurons exhibited apoptosis on day 5, as demonstrated by in situ detection of DNA fragmentation and active caspase-3. The stress-responsive JNK signal transduction pathway was activated in virus-infected neurons. Activation of p38 MAPK was widespread and occurred in astrocytes on day 7 after infection. Active p38 MAPK in astrocytes showed no association with apoptosis but appeared to be involved in regulation of TNF-alpha production. These results indicate that these two stress-activated protein kinases may play distinct roles during the course of lethal acute influenza virus encephalitis.
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PMID:Differential activation of the c-Jun N-terminal kinase/stress-activated protein kinase and p38 mitogen-activated protein kinase signal transduction pathways in the mouse brain upon infection with neurovirulent influenza A virus. 1291 61

The current study sought to define the molecular mechanisms involved in the cross talk between 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] and activators of PKC in the regulation of 25(OH)D(3) 24-hydroxlyase [24(OH)ase]. Transfection of the h24(OH)ase promoter construct [-5,500/-22 luciferase; vitamin D response elements at -294/-274 and -174/-151; AP-1 site at -1,167/-1,160] in vitamin D receptor (VDR)-transfected COS-7 cells resulted in strong activation by 1,25(OH)(2)D(3). In these cells, cotreatment with the PKC activator TPA and 1,25(OH)(2)D(3) yielded a 27-fold increase in luciferase activity, which was 2- to 3-fold greater than activation obtained with 1,25(OH)(2)D(3) alone (P < 0.05). Similar results were observed using LLCPK-1 kidney cells, suggesting that the previously observed enhancement of 1,25(OH)(2)D(3)-induced renal 24(OH)ase mRNA and activity by PKC activation occurs at the level of transcription. The functional cooperation between PKC activation and VDR was not found to be mediated by the AP-1 site in the h24(OH)ase promoter or by enhanced binding of GRIP or DRIP205 to VDR and was also not due to PKC-mediated phosphorylation of VDR on Ser(51). Our study demonstrates that, in LLCPK-1 kidney cells, the PKC enhancement of 1,25(OH)(2)D(3)-stimulated transcription may be due, in part, to an increase in VDR concentration. In addition, inhibitors of the MAPK pathway were found to decrease the TPA enhancement (P < 0.05). Because activation of MAPK has been reported to result in the phosphorylation of SRC-1 and in functional cooperation between SRC-1 and CREB binding protein, we propose that the potentiation of VDR-mediated transcription may also be mediated through changes in the phosphorylation of specific VDR coregulators.
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PMID:Integration of hormone signaling in the regulation of human 25(OH)D3 24-hydroxylase transcription. 1466 42

Coinfections of bacteria and influenza are a major cause of excessive mortality during influenza epidemics. However, the mechanism of the synergy between influenza virus and bacteria are poorly understood. In this study, mice were inoculated with influenza virus, followed 2 days later by inoculation with Streptococcus pneumoniae. The kinetics of viral titres, bacterial numbers and the immune response (cytokine and chemokine production) were also analysed. Short-term survival correlated with pathological changes in the lungs of infected mice. Influenza virus or S. pneumoniae infection alone induced moderate pneumonia; however, severe bronchopneumonia with massive haemorrhage in coinfected mice, which caused death of these mice approximately 2 days after inoculation with S. pneumoniae, was noted. Intrapulmonary levels of inflammatory cytokines/chemokines, type-1 T-helper cell cytokines and Toll-like receptors, and the related mitogen-activated protein kinase signalling molecules (phosphorylated extracellular signal-regulated kinase -1 and - 2, p38 and c-Jun N-terminal kinase), were increased in coinfected mice. These results suggest that immune mediators, including cytokines and chemokines, through Toll-like receptors/mitogen-activated protein kinase pathways, play important roles in the pathology of coinfection caused by influenza virus and Streptococcus pneumoniae.
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PMID:Immunokinetics in severe pneumonia due to influenza virus and bacteria coinfection in mice. 1529 17

Wound healing in its complexity depends on the concerted activity of many signaling pathways. Here, we analyzed how the simultaneous presence of glucocorticoids (GC), retinoic acid (RA) and epidermal growth factor (EGF) affect wound healing at the molecular, cellular and tissue levels. We found that GC inhibit wound healing by inhibiting keratinocyte migration, whereas RA does not. Furthermore, GC block EGF-mediated migration, whereas RA does not. On the molecular level, these compounds target expression of one of the earliest markers of wound healing, cytoskeletal components, keratins K6 and K16. Both GC and RA repress their transcription, whereas EGF induces it. Interestingly, the GC inhibition is mediated by a repressosome complex consisting of four monomers of the GC receptor, beta-catenin and coactivator-associated-arginine-methyltransferase-1. GC are dominant, EGF cannot rescue GC-mediated inhibition. Pre-treatment of keratinocytes with GC shifts the balance towards the repressosome, allowing for dominant inhibition of K6 even in the presence of EGF or c-fos/c-jun. Although RA receptor gamma and glucocorticoid receptor bind to the same response element repressing transcription of keratins K6/K16, RA receptor interacts with the components of the EGF-enhanceosome (co-activators: glucocorticoid-receptor-interactive protein-1(GRIP-1)/steroid-receptors coactivator-1 (SRC-1)) without breaking it. Consequently, RA has a co-dominant effect with EGF: when present simultaneously, their effects balance each other. When keratinocytes are pre-treated with mitogen-activated protein kinase (MAPK) inhibitor, thus blocking EGF, the balance is shifted towards the RA repression. Similar to clinical findings, pre-treatment of keratinocytes with RA blocks GC-mediated inhibition. In summary, our results identify complex molecular mechanisms through which RA alleviates GC-mediated inhibition of wound healing.
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PMID:From an enhanceosome to a repressosome: molecular antagonism between glucocorticoids and EGF leads to inhibition of wound healing. 1564 6

Toll-like receptors (TLRs) initiate an innate immune response. TLR3 on dendritic cells recognize double-stranded (ds) RNA and then signal increases in cytokines and recognition molecules important for immune cell interactions. In this report, we demonstrate TLR3 mRNA and protein are expressed on Fisher rat thyroid cell line-5 (FRTL-5) thyroid cells and are functional because incubating cells with polyinosine-polycytidylic acid causes 1) transcriptional activation of both the nuclear factor kappaB (NF-kappaB)/Elk1 and interferon (IFN) regulatory factor-3/IFN-beta signal paths, 2) posttranscriptional activation of NF-kappaB and ERK1/2, and 3) increased IFN-beta mRNA. TLR3 can be overexpressed, along with dsRNA-dependent protein kinase, major histocompatibility complex-I or II, and IFN regulatory factor-1, by transfecting dsRNA into the cells, infection with Influenza A virus, or incubation with IFN-beta, but not by incubation with dsRNA or IFNgamma, or by dsDNA transfection. A methimazole (MMI) derivative, phenylmethimazole, to a significantly greater degree than MMI, prevents overexpression by inhibiting increased transcriptional activation of IRF-3 and of IFN-stimulated response elements, phosphorylation of signal transducers and activation of transcription (STAT-1), but not NF-kappaB activation. TLR3 can be functionally overexpressed in cultured human thyrocytes by dsRNA transfection or IFN-beta treatment. Immunohistochemical studies show that TLR3 protein is overexpressed in human thyrocytes surrounded by immune cells in 100% of patients with Hashimoto's thyroiditis examined, but not in normal or Graves' thyrocytes. We conclude that functional TLR3 are present on thyrocytes; TLR3 downstream signals can be overexpressed by pathogen-related stimuli; overexpression can be reversed by phenylmethimazole to a significantly greater extent than MMI by inhibiting only the IFN regulatory factor-3/IFN-beta/signal transducers and activation of transcription arm of the TLR3 signal system; and TLR3 overexpression can induce an innate immune response in thyrocytes, which may be important in the pathogenesis of Hashimoto's thyroiditis and in the immune cell infiltrates.
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PMID:Thyrocytes express a functional toll-like receptor 3: overexpression can be induced by viral infection and reversed by phenylmethimazole and is associated with Hashimoto's autoimmune thyroiditis. 1566 32

Avian influenza A virus subtype H5N1 can infect humans to cause a severe viral pneumonia with mortality rates of more than 30%. The biological basis for this unusual disease severity is not fully understood. We previously demonstrated that in contrast to human influenza A virus subtypes including H1N1 or H3N2, the H5N1 virus associated with the "bird flu" outbreak in Hong Kong in 1997 (H5N1/97) hyperinduces proinflammatory cytokines, including tumor necrosis factor alpha (TNF-alpha), in primary human macrophages in vitro. To delineate the molecular mechanisms involved, we analyzed the role of transcription factor NF-kappaB and cellular kinases in TNF-alpha dysregulation. H5N1 and H1N1 viruses did not differ in the activation of NF-kappaB or degradation of IkappaB-alpha in human macrophages. However, we demonstrated that unlike H1N1 virus, H5N1/97 strongly activates mitogen-activated protein kinase (MAPK), including p38 MAPK and extracellular signal-regulated kinases 1 and 2. Specific inhibitors of p38 MAPK significantly reduced the H5N1/97-induced TNF-alpha expression in macrophages. Taken together, our findings suggest that H5N1/97-mediated hyperinduction of cytokines involves the p38 MAPK signaling pathway. These results may provide insights into the pathogenesis of H5N1 disease and rationales for the development of novel therapeutic strategies.
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PMID:p38 mitogen-activated protein kinase-dependent hyperinduction of tumor necrosis factor alpha expression in response to avian influenza virus H5N1. 1605 7

Sphingomyelinase (SMase)-mediated release of ceramide in the plasma membrane of T-lymphocytes induced by different stimuli such as ligation of Fas/CD95, irradiation, stress, inflammation or anticancer drugs primarily involves mitochondrial apoptosis signaling, but under specific conditions non-apoptotic Fas-signaling was also reported. Here we investigated, using a quantitative simulation model with exogenous C2-ceramide (and SMase), the dependence of activation and fate of T-cells on the strength and duration of ceramide accumulation. A murine, influenza virus hemagglutinin-specific T-helper cell (IP12-7) alone or together with interacting antigen presenting B-cells (APC) was used. C2-ceramide induced apoptosis of TH cells above a 'threshold' stimulus (>25 microM in 'strength' or >30 min in duration), while below the threshold C2-ceramide was non-apoptotic, as confirmed by early and late apoptotic markers (PS-translocation, mitochondrial depolarization, caspase-3 activation, DNA-fragmentation). The modest ceramide stimuli strongly suppressed the calcium response and inhibited several downstream signal events (e.g. ERK1/2-, JNK-phosphorylation, CD69 expression or IL-2 production) in TH cells during both anti-CD3 induced and APC-triggered activation. Ceramide moderately affected the Ca2+ -release from internal stores upon antigen-specific engagement of TCR in immunological synapses, while the influx phase was remarkably reduced in both amplitude and rate, suggesting that the major target(s) of ceramide-effects are membrane-proximal. Ceramide inhibited Kv1.3 potassium channels, store operated Ca2+ -entry (SOC) and depolarized the plasma membrane to which contribution of spontaneously formed ceramide channels is possible. The impaired function of these transporters may be coupled to the quantitative, membrane raft-remodeling effect of ceramide and responsible, in a concerted action, for the suppressed activation. Our results suggest that non-apoptotic Fas stimuli, received from previously activated, FasL+ interacting lymphocytes in the lymph nodes, may negatively regulate subsequent antigen-specific T-cell activation and thus modulate the antigen-specific T-cell response.
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PMID:Death or survival: membrane ceramide controls the fate and activation of antigen-specific T-cells depending on signal strength and duration. 1609 42

Many viral oncolytic approaches against cancer are based on the ability of specific viruses to replicate in tumors expressing components of the constitutively activated Ras/mitogen-activated protein kinase (MAPK) pathways and/or inhibited or dysregulated alpha/beta interferon (IFN-alpha/beta) response pathways. A major issue when considering these approaches is their applicability to tumors that lack activated Ras. To identify the effector mechanisms activated by oncolytic viruses, we investigated inhibition of proliferation of the prostate cancer line LNCap by the recombinant TR-NS1 influenza A virus, a genetically attenuated influenza A/PR8/34 virus expressing a truncated nonstructural protein (NS1) of 126 amino acids. LNCap cells lack constitutively activated MAPK, extracellular signal-regulated kinase (ERK), and p38 and are resistant to death by IFN-alpha. Truncation of the NS1 protein of influenza viruses is known to result in viral attenuation due to a reduced ability of the NS1 to inhibit the IFN-alpha/beta response. Infection with TR-NS1 virus rapidly activated ERK-1 more than ERK-2 in LNCap cells. Importantly, TR-NS1 virus infection transiently inhibited cell proliferation and induced apoptosis in LNCap cells. Addition of peripheral blood mononuclear cells (PBMC) and interleukin 12 (IL-12) to TR-NS1 virus-infected LNCap cells (TR-NS1-LNCap) resulted in faster elimination of TR-NS1-LNCap cells compared with LNCap cells. Moreover, TR-NS1-LNCap cells induced IFN-gamma in PBMC. The levels of IFN-gamma were amplified by IL-12. TR-NS1-LNCap cells also induced tumor-lytic cytotoxic T lymphocytes (CTL). These CTL lysed noninfected LNCap cells in a CD8-dependent manner. Activation of cellular immunity to tumor cells by viruses is an intriguing effector pathway, which should be especially significant for elimination of human tumors that lack activated Ras.
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PMID:Prostate tumor cells infected with a recombinant influenza virus expressing a truncated NS1 protein activate cytolytic CD8+ cells to recognize noninfected tumor cells. 1635 63

Mice lacking CD137L (4-1BBL) show normal primary expansion and contraction of the CD8+ T cell response to influenza virus, but exhibit a defect in Ag-specific CD8+ T cell numbers at 3-6 wk postinfection. Previous results showed that the decrease in CD8+ T cell numbers in this model is not due to a programming defect during primary expansion. Thus, it appears that 4-1BB/4-1BBL interactions control the number of surviving CD8+ effector memory cells, late in the primary response. In this report, we asked how 4-1BB on T cells could play a role after Ag has apparently been cleared from the host. We show that IL-15, a cytokine involved in regulation of CD8+ memory T cell survival, induces the expression of 4-1BB on CD8+CD44(high) memory phenotype T cells, but not on CD4+ T cells. The Ag-independent induction of 4-1BB by IL-15 was dependent on MAPK p38 and ERK activation. Transfer of in vitro-generated OT-I CD8+ memory T cells into unimmunized wild-type or 4-1BBL-deficient hosts revealed a 2- to 3-fold survival advantage when 4-1BBL was present, recapitulating the effect seen in the endogenous response to influenza in mice. Decreases in the overall number of memory CD8+ T cells were also observed in the bone marrow of unmanipulated 4-1BBL-deficient mice. These data suggest a model whereby 4-1BB expression on memory CD8+ T cells, perhaps due to encounter with IL-15 in the bone marrow, allows 4-1BB/4-1BBL interactions to maintain memory CD8 T cell survival in the absence of Ag.
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PMID:IL-15-dependent induction of 4-1BB promotes antigen-independent CD8 memory T cell survival. 1649 29


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