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

The Vav family of Rho guanine nucleotide exchange factors is thought to orchestrate signaling events downstream of lymphocyte antigen receptors. Elucidation of Vav function has been obscured thus far by the expression of three highly related family members. We generated mice lacking all Vav family proteins and show that Vav-null mice produce no functional T or B cells and completely fail to mount both T-dependent and T-independent humoral responses. Whereas T cell development is blocked at an early stage in the thymus, immature B lineage cells accumulate in the periphery but arrest at a late "transitional" stage. Mechanistically, we show that the Vav family is crucial for both TCR and B cell receptor (BCR)-induced Ca2+ signaling and, surprisingly, is only required for mitogen-activated protein kinase (MAPK) activation in developing and mature T cells but not in B cells. Thus, the abundance of immature B cells generated in Vav-null mice may be due to intact Ras/MAPK signaling in this lineage. Although the expression of Vav1 alone is sufficient for normal lymphocyte development, our data also reveal lineage-specific roles for Vav2 and Vav3, with the first demonstration that Vav3 plays a critical compensatory function in T cells. Together, we define an essential role for the entire Vav protein family in lymphocyte development and activation and establish the limits of functional redundancy both within this family and between Vav and other Rho-guanine nucleotide exchange factors.
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PMID:Vav1/2/3-null mice define an essential role for Vav family proteins in lymphocyte development and activation but a differential requirement in MAPK signaling in T and B cells. 1462 13

A series of naturally occurring isoquinoline alkaloids, besides their distribution in the environment and presence in certain food stuffs, have been detected in human tissues including particular regions of brain. An example is salsolinol (1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline) that not only induces neuronal cell death, but also causes DNA damage and genotoxicity. Tetrahydropapaveroline [THP; 6,7-dihydroxy-1-(3',4'-dihydroxybenzyl)-1,2,3,4-tetrahydroisoquinoline], a dopamine-derived tetrahydroisoquinoline alkaloid, has been reported to inhibit mitochondrial respiration and is considered to contribute to neurodegeneration implicated in Parkinson's disease. Since THP bears two catechol moieties, the compound may readily undergo redox cycling to produce reactive oxygen species (ROS) as well as toxic quinoids. In the present study, we have examined the capability of THP to cause oxidative DNA damage and cell death. Incubation of THP with phiX174 supercoiled DNA or calf thymus DNA in the presence of cupric ion caused substantial DNA damage as determined by strand scission or formation of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo), respectively. THP plus copper-induced DNA damage was ameliorated by some ROS scavengers/antioxidants and catalase. Treatment of C6 glioma cells with THP led to a concentration-dependent reduction in cell viability, which was prevented by the antioxidant N-acetyl-L-cysteine. When these cells were treated with 10microM THP, c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) were rapidly activated via phosphorylation, whereas activation of extracellular signal-regulated protein kinase (ERK) was inhibited. Furthermore, pretreatment with inhibitors of JNK and p38 MAPK rescued the glioma cells from THP-induced cytotoxicity, suggestive of the involvement of these kinases in THP-induced C6 glioma cell damage.
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PMID:Oxidative DNA damage and glioma cell death induced by tetrahydropapaveroline. 1464 15

The mechanisms governing positive selection of T cells in the thymus are still incompletely understood. Here, we describe a N-ethyl-N-nitrosourea induced recessive mouse mutant, Ms. T-less, which lacks T cells in the peripheral blood because of a complete block of thymocyte development at the CD4(+)CD8(+) stage. Single nucleotide polymorphism mapping and candidate gene sequencing revealed a nonsense mutation in the inositol (1,4,5) trisphosphate 3 kinase B (Itpkb) gene in Ms. T-less mice. Accordingly, Ms. T-less thymocytes do not show detectable expression of Itpkb protein and have drastically reduced basal inositol (1,4,5) trisphosphate kinase activity. Itpkb converts inositol (1,4,5) trisphosphate to inositol (1,3,4,5) tetrakisphosphate, soluble second messengers that have been implicated in Ca(2+) signaling. Surprisingly, Ca(2+) responses show no significant differences between wild type (WT) and mutant thymocytes. However, extracellular signal-regulated kinase (Erk) activation in response to suboptimal antigen receptor stimulation is attenuated in Ms. T-less thymocytes, suggesting a role for Itpkb in linking T cell receptor signaling to efficient and sustained Erk activation.
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PMID:Inositol (1,4,5) trisphosphate 3 kinase B controls positive selection of T cells and modulates Erk activity. 1506 1

The roles played by specific transcription factors during the regulation of early T cell development remain largely undefined. Several key genes induced during the primary checkpoint of T cell development, beta-selection, contain cAMP response element sites within their enhancer-promoter region that are regulated by CREB activation. In this study, we show that CREB is constitutively phosphorylated in the thymus, but not the spleen. We also show that CREB is activated downstream of the pre-TCR complex, and that the induction of CREB activity is regulated by protein kinase C alpha- and ERK-MAPK-mediated signals. We addressed the importance of this activation by expressing a naturally occurring inhibitor of CREB, inducible cAMP early repressor in wild-type fetal liver-derived lymphoid progenitor cells, and assessed their developmental potential. Fetal thymic organ cultures reconstituted with cells constitutively expressing inducible cAMP early repressor displayed a delay in generating CD4(+)CD8(+) thymocytes and a decrease in cellularity compared with control fetal thymic organ cultures. Taken together, our studies establish that CREB plays a central role in relaying proliferation and differentiation signals from the pre-TCR complex into the nucleus in developing thymocytes.
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PMID:Cyclic adenosine 5'-monophosphate response element binding protein plays a central role in mediating proliferation and differentiation downstream of the pre-TCR complex in developing thymocytes. 1526 11

The heterodimeric complex of aromatic hydrocarbon receptor (AHR) and Ah receptor nuclear translocator (ARNT) plays a pivotal role in controlling the expression of drug metabolism genes, such as the cytochromes p450 (Cyp) 1a1 and 1b1, believed to be responsible for most toxic effects of the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). In this study, we show that activation of Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) modulates ARNT transcription activity and potentiates the transcriptional activity of AHR/ARNT complexes. Inhibition of ERK by chemical compounds and ablation of JNK caused significant decreases in CYP1A1 induction by TCDD. Compared to wild type, JNK2 ablation significantly reduced TCDD-stimulated CYP1A1 expression in mouse thymus and testis, but not in liver. In contrast, CYP1B1 expression was unaffected in all three tissues of the knockout mice. These data suggest that JNK and ERK modulate ARNT activity and AHR/ARNT-dependent gene expression, contributing to the gene-specific and tissue-specific toxicity of environmental contaminants.
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PMID:A critical role for MAP kinases in the control of Ah receptor complex activity. 1527 35

Simultaneous exposure to lipopolysaccharide (LPS) markedly amplifies induction of proinflammatory cytokine expression as well as IL-1-driven lymphocyte apoptosis by trichothecene deoxynivalenol (DON) in the mouse. The purpose of this research was to test the hypothesis that LPS priming will sensitize a host to DON-induced proinflammatory cytokine induction and apoptosis. In mice primed with LPS (1 mg/kg bw) ip. and treated 8 h later with DON po., the minimum DON doses for inducing IL-1alpha, IL-1beta, IL-6 and TNF-alpha serum proteins and splenic mRNAs were significantly lower than the DON doses required for vehicle-primed mice. LPS priming also decreased onset time and dramatically increased magnitude and duration of cytokine responses. LPS-primed mice maintained heightened sensitivity to DON for up to 24 h. LPS priming doses as low as 50 microg/kg bw evoked sensitization. DNA fragmentation analysis and flow cytometry also revealed that mice primed with LPS (1 mg/kg) for 8 h and exposed to DON (12.5 mg/kg) exhibited massive thymocyte loss by apoptosis 12 h later compared to mice exposed to DON or LPS alone. LPS priming decreased DON-induced p38 and ERK 1/2 phosphorylation suggesting that enhanced mitogen-activated protein kinase activation was not involved in increased cytokine responses. Taken together, exposure to LPS rendered mice highly susceptible to DON induction of cytokine expression and this correlated with increased apoptosis in the thymus.
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PMID:LPS priming potentiates and prolongs proinflammatory cytokine response to the trichothecene deoxynivalenol in the mouse. 1600 89

Myasthenia gravis (MG) is an autoimmune disease of neuromuscular junctions where thymus plays a pathogenetic role. Thymectomy benefits patients, and thymic hyperplasia, a lymphoid infiltration of perivascular spaces becoming site of autoantibody production, is recurrently observed. Cytokines and chemokines, produced by thymic epithelium and supporting survival and migration of T and B cells, are likely to be of great relevance in pathogenesis of thymic hyperplasia. In thymic epithelial cell (TEC) cultures derived "in vitro" from normal or hyperplastic age-matched MG thymuses, we demonstrate by gene profiling analysis that MG-TEC basally overexpress genes coding for p38 and ERK1/2 MAPKs and for components of their signaling pathways. Immunoblotting experiments confirmed that p38 and ERK1/2 proteins were overexpressed in MG-TEC and, in addition, constitutively activated. Pharmacological blockage with specific inhibitors confirmed their role in the control of IL-6 and RANTES gene expression. According to our results, IL-6 and RANTES levels were abnormally augmented in MG-TEC, either basally or upon induction by adhesion-related stimuli. The finding that IL-6 and RANTES modulate, respectively, survival and migration of peripheral lymphocytes of myasthenic patients point to MAPK transcriptional and posttranscriptional abnormalities of MG-TEC as a key step in the pathological remodelling of myasthenic thymus.
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PMID:Constitutive activation of p38 and ERK1/2 MAPKs in epithelial cells of myasthenic thymus leads to IL-6 and RANTES overexpression: effects on survival and migration of peripheral T and B cells. 1627 63

Properly regulated mitogen-activated protein (MAP) kinase activity is critical for normal thymocyte development. MAP kinases are activated by phosphorylation of tyrosine and threonine, and dual specificity phosphatases (DUSPs) can inactivate MAP kinases by dephosphorylating both tyrosine and threonine. However, a role for DUSPs in thymocyte development has not been described. In this study, we have defined the subset of DUSP genes expressed in the murine thymus, and how their expression varies in different thymocyte subsets. Of the murine DUSP genes screened that could potentially dephosphorylate MAP kinases, we found 10 transcribed in the thymus. Seven of these 10 thymic DUSPs are true MAP kinase phosphatases based on the presence of a MAP kinase binding domain and demonstrated phosphatase activity against MAP kinases. Six of the seven thymic MAP kinase phosphatases have been shown to dephosphorylate extracellular regulated kinase (ERK). Quantitative PCR analysis of thymocyte populations isolated from different developmental stages revealed significant changes in DUSP expression as thymocytes progressed through development. Specifically, DUSPs 1, 4, and 5 significantly increase in expression as cells go from small, resting CD4/CD8 double positive cells to the CD4 single positive stage. Additionally, in vitro experiments showed that DUSPs could respond to TCR signaling, as anti-CD3 stimulation of thymocytes transiently increased transcription of six of the 10 thymic DUSP genes within 30 min. Notably, the ERK-specific phosphatase DUSP5 was upregulated 43-fold within 30 min, and returned to baseline within 24 h. Overall, we have identified a subset of DUSPs that could potentially regulate ERK activation in response to TCR signals in thymocytes.
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PMID:The dual specificity phosphatase transcriptome of the murine thymus. 1636 20

The processes of positive and negative selection in the thymus both determine the population of T cells that will enter the peripheral immune system and eliminate self-reactive T cells by apoptosis. Substantial evidence indicates that TCR signal intensity mediates this cell fate choice: low-intensity signals lead to survival and differentiation, whereas high-intensity signals generated by self-Ag lead to cell death. The molecular mechanism by which these graded signals are converted to discrete outcomes is not understood. Positive selection requires the Ca(2+)-dependent phosphatase calcineurin, whereas negative selection requires the proapoptotic Bcl-2 family member Bcl-2-interacting mediator of cell death (Bim). In this study, we investigated the regulation of Bim expression and the role of Ca(2+) in mediating negative selection. Our results show that transcription is necessary for both negative selection and Bim induction. Surprisingly, we also found that Ca(2+) is necessary for Bim induction. Induction of bim transcription appears to involve protein kinase C, but not calcineurin, JNK, p38 MAPK, or MEK. These results localize the decision point in positive vs negative selection to a step downstream of Ca(2+) signaling and suggest that negative selection signals induce Ca(2+)-dependent bim transcription through PKC.
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PMID:Thymocyte negative selection is mediated by protein kinase C- and Ca2+-dependent transcriptional induction of bim [corrected]. 1645 86

The PP2C phosphatase Wip1 dephosphorylates p38 and blocks UV-induced p53 activation in cultured human cells. Although the level of TCR-induced p38 MAPK activity is initially comparable between Wip1-/- and wild-type thymocytes, phosphatase-deficient cells failed to down-regulate p38 MAPK activity after 6 h. Analysis of young Wip1-deficient mice showed that they had fewer splenic T cells. Their thymi were smaller, contained significantly fewer cells, and failed to undergo age-dependent involution compared with wild-type animals. Analysis of thymocyte subset numbers by flow cytometry suggested that cell numbers starting at the double-negative (DN)4 stage are significantly reduced in Wip1-deficient mice, and p53 activity is elevated in cell-sorted DN4 and double-positive subpopulations. Although apoptosis and proliferation was normal in Wip1-/- DN4 cells, they appeared to be in cell cycle arrest. In contrast, a significantly higher percentage of apoptotic cells were found in the double-positive population, and down-regulation of thymocyte p38 MAPK activation by anti-CD3 was delayed. To examine the role of p38 MAPK in early thymic subpopulations, fetal thymic organ cultures cultured in the presence/absence of a p38 MAPK inhibitor did not correct the thymic phenotype. In contrast, the abnormal thymic phenotype of Wip1-deficient mice was reversed in the absence of p53. These data suggest that Wip1 down-regulates p53 activation in the thymus and is required for normal alphabeta T cell development.
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PMID:Wip1 phosphatase-deficient mice exhibit defective T cell maturation due to sustained p53 activation. 1658 76


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