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

---

Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acute myelogenous leukemia (AML) is considered to be in complete remission when fewer than 5% of the cells in bone marrow are blasts. Nevertheless, approximately two thirds of patients relapse due to persisting leukemic blasts. The persistence of these cells, below the threshold of morphological detection, is termed minimal residual disease (MRD) and various methods are used for its detection. These methods include classical cytogenetics, fluorescence in situ hybridization, qualitative and quantitative RT-PCR and multiparametric flow cytometry. Currently, less than half of the AML patients have a specific marker detectable by RT-PCR techniques. The major specific molecular markers are involvement of the MLL gene with up to 50 different partners and partial tandem duplications, the core binding factor leukemias with AML1/ETO and CBFbeta/MYH11 rearrangements, PML/RARalpha in acute promyelocytic leukemia, internal tandem duplications and mutations of FLT3 and some other rare translocations. In addition, several other genes show abnormal expression levels in AML, including the Wilms tumor gene, the PRAME gene and Ig/TCR rearrangements. Most of these genetic abnormalities can be detected by qualitative but more importantly by quantitative RT-PCR. The kinetics of disappearance of molecular markers in AML differs between the various types of leukemias, although at least a 2 log reduction of transcript after induction chemotherapy is necessary for long-term remission in all types. Conversely, the change of PCR from negativity to positivity is highly predictive of relapse. Whereas in acute lymphoblastic leukemia, multiparametric flow cytometry is an established method for MRD detection, this is less so in AML. The reason is the absence of well-characterized leukemia-specific antigens and the existence of phenotypic changes at relapse. On the other hand, this method is convenient due to its simplicity and universal applicability. In conclusion, several methods can be used for MRD detection in AML patients; each has its pros and cons. Several issues still remain to be settled including the choice of the best method and the timing for MRD monitoring and above all the practical clinical implications of MRD in the various types of AML.
...
PMID:Detection of minimal residual disease in acute myelogenous leukemia. 1517 4

One of the potential mechanisms of peripheral tolerance is the unresponsiveness of T cells to secondary antigenic stimulation as a result of the induction of anergy. It has been widely reported that antigenic unresponsiveness may be due to uncoupling of MAPK signal transduction pathways. However, such signaling defects in anergic T cell populations have been mainly identified using immortalized T cell lines or T cell clones, which do not truly represent primary Ag-specific T cells. We have therefore attempted to quantify signaling events in murine primary Ag-specific T cells on an individual cell basis, using laser-scanning cytometry. We show that there are marked differences in the amplitude and cellular localization of phosphorylated ERK p42/p44 (ERK1/2) signals when naive, primed and anergic T cells are challenged with peptide-pulsed dendritic cells. Primed T cells display more rapid kinetics of phosphorylation and activation of ERK than naive T cells, whereas anergic T cells display a reduced ability to activate ERK1/2 upon challenge. In addition, the low levels of pERK found in anergic T cells are distributed diffusely throughout the cell, whereas in primed T cells, pERK appears to be targeted to the same regions of the cell as the TCR. These data suggest that the different consequences of Ag recognition by T cells are associated with distinctive kinetics, amplitude, and localization of MAPK signaling.
...
PMID:Differences in the kinetics, amplitude, and localization of ERK activation in anergy and priming revealed at the level of individual primary T cells by laser scanning cytometry. 1526 85

Little is known about the role of the Gads (GrpL) adaptor protein in mature T cell populations. In this study we show that the effects of Gads deficiency on murine CD4(+) and CD8(+) T cells are markedly different. Gads(-/-) CD4(+) T cells were markedly deficient in the spleen and had an activated phenotype and a rapid turnover rate. When transferred into a wild-type host, Gads(-/-) CD4(+) T cells continued to proliferate at a higher rate than wild-type CD4(+) T cells, demonstrating a defect in homeostatic proliferation. Gads(-/-) CD8(+) T cells had a memory-like phenotype, produced IFN-gamma in response to ex vivo stimulation, and underwent normal homeostatic proliferation in wild-type hosts. Gads(-/-) T cells had defective TCR-mediated calcium responses, but had normal activation of ERK. Gads(-/-) CD4(+) T cells, but not CD8(+) T cells, had a severe block of TCR-mediated proliferation and a high rate of spontaneous cell death and were highly susceptible to CD95-induced apoptosis. This suggests that the rapid turnover of Gads(-/-) CD4(+) T cells is due to a defect in cell survival. The intracellular signaling pathways that regulate homeostasis in CD4(+) and CD8(+) T cells are clearly different, and the Gads adaptor protein is critical for homeostasis of CD4(+) T cells.
...
PMID:The Gads (GrpL) adaptor protein regulates T cell homeostasis. 1526

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.
...
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 role of membrane cofactor protein (MCP, CD46) on human T cell activation has been analyzed. Coligation of CD3 and CD46 in the presence of PMA or CD28 costimuli enhanced IL-2, IFN-gamma, or IL-10 secretion by CD4+ T lymphocytes. The effect of CD46 on IL-10 secretion did not require additional costimuli like anti-CD28 antibodies or phorbol esters. CD46 also enhanced IL-2 or IFN-gamma secretion by CD4+ blasts. In contrast, IL-5 secretion was inhibited upon CD46-CD3 coligation, in all the cells analyzed. These effects were independent of IL-12 and suggest that CD46 costimulation promotes a Th1-biased response in human CD4+ T lymphocytes. CD46 enhanced TCR/CD3-induced tyrosine phosphorylation of CD3zeta and ZAP-70, as well as the activation of the ERK, JNK, and p38, but did not modify intracellular calcium. The effect of specific inhibitors shows that enhanced ERK activation contributes to augmented IFN-gamma and lower IL-5 secretion and, consequently, to the Th1 bias. Cross-linking CD46 alone induced weak tyrosine phosphorylation of CD3zeta and ZAP-70. However, CD46 cross-linking by itself did not induce cell proliferation or lymphokine secretion, and pretreatment of CD4+ T lymphocytes with anti-CD46 antibodies did not significantly alter TCR/CD3 activation.
...
PMID:CD46-mediated costimulation induces a Th1-biased response and enhances early TCR/CD3 signaling in human CD4+ T lymphocytes. 1530 76

Although IL-15 is known to be a T cell growth factor, the function in T cells of IL-15Ralpha, its high affinity receptor, remains unclear. We found that murine IL-15Ralpha(-/-) CD4(+) T cells hyperproliferated in response to TCR stimulation, in vitro and in vivo, and displayed a lower TCR activation threshold than wild-type CD4(+) T cells. TCR-induced activation of Zap70 and of the phospholipase C-gamma1-NFATp, Ras-ERK-c-Fos, and Rac-JNK-c-Jun pathways was all augmented in IL-15Ralpha(-/-) CD4(+) T cells. This in turn led to earlier IL-2Ralpha induction and higher IL-2 production, which most likely contribute to the hyperproliferation of IL-15Ralpha(-/-) CD4(+) T cells. Exogenous IL-15 reduced levels of TCR-activated signals, transcription factors, IL-2, and IL-2Ralpha, and division in wild-type CD4(+) T cells. These results reveal IL-15Ralpha to be a negative regulator for CD4(+) T cell activation and demonstrate a novel layer of regulation of TCR signaling by a cytokine system.
...
PMID:IL-15Ralpha is a negative regulator of TCR-activated proliferation in CD4+ T cells. 1532 76

Stimulatory killer Ig-like receptors (KIRs) are expressed by various lymphocytes, including NK cells and subsets of T cells. In NK cells, KIRs associate with the adapter molecule KARAP/DAP12, which confers the ability to function as an independent activation unit. The function of KIRs and killer cell activating receptor-associated protein (KARAP)/DAP12 in T cells is unclear. By flow cytometry, we demonstrated that CD4+CD28null T cells heterogeneously express KIRs and/or KARAP/DAP12. In clones that lacked expression of KARAP/DAP12, the stimulatory KIR KIR2DS2 signaled through the JNK pathway, but did not activate the ERK pathway. However, in the presence of KARAP/DAP12, stimulation through KIR2DS2 led to phosphorylation of both JNK and ERK. Transfection experiments confirmed that KIR2DS2-mediated ERK phosphorylation was dependent on KARAP/DAP12. The differential signaling of KIR2DS2 through association with alternative adapter molecules resulted in differential regulation of cellular activity. In clones that lacked expression of KARAP/DAP12, stimulation of KIR2DS2 did not induce cytotoxicity. However, KIR2DS2 did augment suboptimal TCR stimulation, leading to enhanced IFN-gamma production. In clones that expressed KARAP/DAP12, KIR2DS2 directly activated both cytotoxicity and IFN-gamma production without the need for TCR-derived signals. The function of stimulatory KIRs in T cells is determined by the expression of the appropriate adapter molecule. Expression of KARAP/DAP12 is sufficient to convert a costimulatory KIR into a stimulatory molecule. These differing functions mediated by alternative signaling pathways have implications for the pathogenesis of diseases such as rheumatoid arthritis and acute coronary syndromes, in which aberrant expression of KIRs on T cells is frequently observed.
...
PMID:Stimulatory killer Ig-like receptors modulate T cell activation through DAP12-dependent and DAP12-independent mechanisms. 1535 18

A major function of NKG2D linking innate and adaptive immunity is to upregulate antigen-specific CTL-mediated cytotoxicity in tissues expressing stress-induced NKG2D ligands, such as MIC, by coactivating TCR signaling. Here, we show that, under conditions of dysregulated IL15 expression in vivo in patients with celiac disease and in vitro in healthy individuals, multiple steps of the NKG2D/DAP10 signaling pathway leading to ERK and JNK activation are coordinately primed to activate direct cytolytic function independent of TCR specificity in effector CD8 T cells. These findings may not only explain previous reports of transformation of CTL into NK-like "lymphokine-activated killers" (LAK cells) under high doses of IL2 (a substitute for IL15) but may also have significant implications for understanding and treating immunopathological diseases.
...
PMID:Coordinated induction by IL15 of a TCR-independent NKG2D signaling pathway converts CTL into lymphokine-activated killer cells in celiac disease. 1535 41

In spite of recent great advances in our understanding of both Hodgkin lymphoma (HL) and anaplastic large cell lymphoma (ALCL), occasionally there are CD30-positive large cell hematopoietic neoplasms, in which the morphologic and phenotypic features overlap to such an extent that they cannot easily be classified. We report a histologically unusual case of HL that mimicked ALCL, but had phenotypical characteristics of HL. The neoplastic cells resembling Reed-Sternberg cells or Hodgkin cells were mainly situated within sinusoidal spaces, which are characteristically seen in ALCL. However, they showed unequivocal expression of both CD30 and CD15, and no aberrant antigen expression to suggest ALCL (BSAP+, EMA-, LCA-, CD43-, CD2-, CD3-, CD4-, CD45RO-, ALK-, granzymeB-), with negative TCR gene rearrangement and no expression of EBV. HL with intrasinusoidal pattern has rarely been described, but we suggest that, although cases of HL with such a striking sinusoidal pattern are rare, nevertheless do exist. Since the identification of sinusoidal infiltration by CD30-positive neoplastic cells may lead to a mistaken view of ALCL, wide panel of antibodies should be used to confirm the diagnosis.
...
PMID:Hodgkin lymphoma with unusual intrasinusoidal pattern of infiltration. 1537 Feb 61

XLP is caused by mutations affecting SAP, an adaptor that recruits Fyn to SLAM family receptors. SAP-deficient mice recapitulate features of XLP, including increased T cell activation and decreased humoral responses post-infection. SAP-deficient T cells also show increased TCR-induced IFN-gamma and decreased T(H)2 cytokine production. We demonstrate that the defect in IL-4 secretion in SAP-deficient T cells is independent of increased IFN-gamma production. SAP-deficient cells respond normally to polarizing cytokines, yet show impaired TCR-mediated induction of GATA-3 and IL-4. Examination of TCR signaling revealed normal Ca(2+) mobilization and ERK activation in SAP-deficient cells, but decreased PKC-theta recruitment, Bcl-10 phosphorylation, IkappaB-alpha degradation, and nuclear NF-kappaB1/p50 levels. Similar defects were observed in Fyn-deficient cells. SLAM engagement amplified PKC-theta recruitment in wt but not SAP- or Fyn-deficient cells, arguing that a SAP/Fyn-mediated pathway enhances PKC-theta/NF-kappaB1 activation and suggesting a role for this pathway in T(H)2 regulation.
...
PMID:SAP regulates T(H)2 differentiation and PKC-theta-mediated activation of NF-kappaB1. 1553 55


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---