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

Tolerance in vivo and its in vitro counterpart, anergy, are defined as the state in which helper T lymphocytes are alive but incapable of producing IL-2 and expanding in response to optimal antigenic stimulation. Anergy is induced when the T cell receptor (TCR) is engaged by antigen in the absence of costimulation or IL-2. This leads to unique intracellular signaling events that stand in contrast to those triggered by coligation of the TCR and costimulatory receptors. Specifically, anergy is characterized by lack of activation of lck, ZAP 70, Ras, ERK, JNK, AP-1, and NF-AT. In contrast, anergizing stimuli appear to activate the protein tyrosine kinase fyn, increase intracellular calcium levels, and activate Rap1. Moreover, anergizing TCR signals result in increased intracellular concentrations of the second messenger cAMP. This second messenger upregulates the cyclin-dependent kinase (cdk) inhibitor p27kip1, sequestering cyclin D2-cdk4, and cyclin E/cdk2 complexes and preventing progression of T cells through the G1 restriction point of the cell cycle. In contrast, costimulation through CD28 prevents p27kip1 accumulation by decreasing the levels of intracellular cAMP and promotes p27kip1 down-regulation due to direct degradation of the protein via the ubiquitin-proteasome pathway. Subsequent autocrine action of IL-2 leads to further degradation of p27kip1 and entry into S phase. Understanding the biochemical and molecular basis of T cell anergy will allow the development of new assays to evaluate the immune status of patients in a variety of clinical settings in which tolerance has an important role, including cancer, autoimmune diseases, and organ transplantation. Precise understanding of these biochemical and molecular events is necessary in order to develop novel treatment strategies against cancer. One of the mechanisms by which tumors down-regulate the immune system is through the anergizing inactivation of helper T lymphocytes, resulting in the absence of T cell help to tumor-specific CTLs. Although T-cells specific for tumor associated antigens are detected in cancer patients they often are unresponsive. Reversal of the defects that block the cell cycle progression is mandatory for clonal expansion of tumor specific T cells during the administration of tumor vaccines. Reversal of the anergic state of tumor specific T cells is also critical for the sufficient expansion of such T cells ex vivo for adoptive immunotherapy. On the other hand, understanding the molecular mechanisms of anergy will greatly improve our ability to design novel clinical therapeutic approaches to induce antigen-specific tolerance and prevent graft rejection and graft-versus-host disease. Such treatment approaches will allow transplantation of bone marrow and solid organs between individuals with increasing HLA disparity and therefore expand the donor pool, enable reduction in the need for nonspecific immunosuppression, minimize the toxicity of chemotherapy, and reduce the risk of opportunistic infections.
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PMID:Helper T cell anergy: from biochemistry to cancer pathophysiology and therapeutics. 1143 20

Untransformed CD4(+) Th1 cells stimulated with Ag and APC demonstrated a dependence on B7- and CD28-mediated costimulatory signals for the expression and function of AP-1 proteins. The induction of transactivation by the c-fos gene regulator Elk-1 mirrored this requirement for TCR and CD28 signal integration. c-Jun N-terminal kinase (JNK) (but not extracellular signal-regulated kinase or p38) protein kinase activity was similarly inhibited by neutralizing anti-B7 mAbs. Blockade of JNK protein kinase activity with SB 202190 prevented both Elk-1 transactivation and c-Fos induction. These results identify a unique role for B7 costimulatory molecules and CD28 in the activation of JNK during Ag stimulation in Th1 cells, and suggest that JNK regulates Elk-1 transactivation at the c-fos gene to promote the formation of AP-1 complexes important to IL-2 gene expression.
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PMID:CD28 signaling augments Elk-1-dependent transcription at the c-fos gene during antigen stimulation. 1144 Oct 89

The hematopoietic-specific Rho-family GTP exchange factor Vav-1 is a regulator of lymphocyte antigen receptor signaling and mediates normal maturation and activation of B and T cells. Recent findings suggest that Vav-1 also forms part of signaling pathways required for natural and antibody dependent cellular cytotoxicity (ADCC) of human NK cells. In this study, we show that Vav-1 is also expressed in murine NK cells. Vav-1(-/-) mice had normal numbers of splenic NK cells, and these displayed a similar expression profile of NK cell receptors as wild-type mice. Unexpectedly, IL-2-activated Vav-1(-/-) NK cells retained normal ADCC. Fc-receptor mediated activation of ERK, JNK, and p38 was also normal. In contrast, Vav-1(-/-) NK cells exhibited reduced natural cytotoxicity against EL4, C4.4.25, RMA and RMA/S. Together, the results demonstrate that Vav-1 is dispensable for mainstream NK cell development, but is required for NK natural cytotoxicity. Unlike the findings for NK cells, NK T cells were dramatically diminished in Vav-1(-/-) mice and splenocytes from Vav-1 mutant mice failed to produce IL-4 in response to in vivo CD3 stimulation. These data highlight the important role of Vav-1 in NK T cell development and NK cell function.
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PMID:Vav-1 regulates NK T cell development and NK cell cytotoxicity. 1150 Aug 24

Previously, we have demonstrated age-associated alterations in transmembrane signaling. One of the most reproducible alterations found in the immune response with aging is the decrease of lymphocyte proliferation on stimulation with various different mitogens. Here, we confirm that proliferative responses to stimulation with phytohaemagglutin (PHA), recombinant human IL-2, or anti-CD3 monoclonal antibody are all greater in the young (20-25 years) than old (60-87 years) population. We attempted to modulate the proliferative response using various agents acting at different levels of transmembrane signaling (pertussis toxin, cholera toxin, isoproterenol, PMA, Ca ionophore A23187), as well as at the level of the lymphocyte plasma membrane (methyl-beta-cyclodextrin, MBCD), or by using antioxidant vitamins (Vitamin E or C). None of these agents was able to restore effectively the proliferative response of lymphocytes from the aged to the level of young subjects. Even the combination of A23187 and PMA acting directly on calcium metabolism and protein kinase C activity was insufficient to restore the decreased mitogenic capacity of T cells from elderly subjects. Cyclodextrin, which decreases the cholesterol content of the membrane, increased the proliferative response of lymphocytes of elderly subjects, but not to the level of the young. Vitamin E had a very strong inhibitory effect on lymphocyte stimulation in both the age groups, except in combination with MBCD in T cells of the elderly, while Vitamin C had no significant modulatory effect. MAPK ERK and p38 activation was found to be decreased with aging in T cells after anti-CD3 mAb stimulation. Vitamin E but not Vitamin C strongly inhibited MAPK ERK or p38 activation. The direct activation of certain molecules or the modulation of the cholesterol content of the membrane seems to be effective immunomodulatory interventions with aging.
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PMID:Modulation of human lymphocyte proliferative response with aging. 1177 24

Expression profiling of cellular genes was performed using a 10,000 cDNA human gene array in order to identify expression changes following chronic infection of human hematopoietic cells with Kaposi's Sarcoma-associated Virus (KSHV) also known as Human Herpesvirus 8 (HHV8) and Human T cell leukemia virus-1 (HTLV-1). We performed cell-free in vitro infection of primary bone marrow derived CD34+ cells using semi-purified HHV8 and a mature IL-2 dependent T cell line, KIT 225, using highly concentrated viral stocks prepared from an infectious molecular clone of HTLV-1. Thirty days post infection, mRNA was isolated from infected cultures and uninfected controls and submitted for microarray analysis. More than 400 genes were differentially expressed more than two-fold following HHV8 infection of primary bone marrow derived CD34+ cells. Of these 400, interferon regulatory factor 4 (IRF4), cyclin B2, TBP-associated factor, eukaryotic elongation factor and pim 2 were up-regulated more than 3.5 fold. In contrast, less than 100 genes were differentially expressed more than two-fold following chronic infection of a mature T cell line with HTLV-1. Of these, only cdc7 was up-regulated more than 3.5 fold. These data may provide insight into cellular signatures of infection useful for diagnosis of infection as well as potential targets for therapeutic intervention.
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PMID:Potential cellular signatures of viral infections in human hematopoietic cells. 1179 Aug 84

Recent studies have demonstrated that neural cell adhesion molecule (NCAM) is involved in multiple adhesive interactions with several different classes of ligands on the cell surface and in the extracellular matrix. One of these ligands is fibroblast growth factor receptor (FGFR) that is expressed on neural cells. While it is known that CD56 is a molecular isoform of NCAM expressed on human NK cells and a subset of T cells, it remains poorly characterized, with its ligand unidentified. Therefore, we were prompted to examine if CD56 molecules on NK cells interact with FGFR expressed on T cells. We demonstrate that ligation of FGFR1 beta on J.C2-14 Jurkat T cells by CD56 on fixed NK-92 cells costimulates TCR/CD3-triggered IL-2 production. CD56-binding mAbs inhibited the costimulatory effect of NK-92 cells in 50-75%. Flow cytometric analysis and cell adhesion assays showed that FGFR1 beta/Fc and FGFR2 beta/Fc chimeric proteins bind to NK-92 cells. The binding of FGFR1 beta/Fc protein to CD56 molecules was verified by immunoprecipitation of CD56 with anti-CD56 mAb followed by Western blotting with FGFR1 beta/Fc. These findings suggest that ligation of FGFR1 by CD56 may contribute to the interaction between NK cells and T cells that we have postulated in our previous studies.
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PMID:Costimulation of T cell receptor-triggered IL-2 production by Jurkat T cells via fibroblast growth factor receptor 1 upon its engagement by CD56. 1212 Dec 26

Chronic engagement of the T cell receptor mediates the induction of T lymphocyte unresponsiveness called clonal anergy. The development of such unresponsiveness has been suggested as one of the mechanisms that regulate peripheral tolerance to self-antigens and hamper the capacity of tumor antigen-specific T cells to eliminate cancerous cells. In the attempt to enhance the effector function of CD4(+) T lymphocytes and their resistance to clonal anergy induction, we have transduced primary T cells with a retroviral vector encoding active p21(ras) (Ras(Leu61)). Here we show that Ras(Leu61) elicited TCR-independent activation of the Ras-Raf-ERK pathway and conferred primary T cells with the ability to secrete IL-2 in response to stimulation with a Ca(2+) ionophore alone, without altering antigen-, CD3/CD28- and PMA/ionomycin-driven IL-2 secretion and T cell proliferation in vitro. However, chronic engagement of the TCR onthe surface of Ras(Leu61) T cells still led to an inability of the cells to produce IL-2 upon restimulation. These results indicate that enforced p21(ras) functionality enhances primary T cells responses to calcium-generated signals, but is insufficient to prevent TCR-driven T cell unresponsiveness and suggest that additional biochemical mechanisms, independent of p21(ras), negatively regulate IL-2 production in unresponsive T cells.
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PMID:Constitutive active p21ras enhances primary T cell responsiveness to Ca2+ signals without interfering with the induction of clonal anergy. 1220 34

The Rac/Rho-specific guanine nucleotide exchange factor, Vav-1, is a key component of the T-cell antigen receptor (TCR)-linked signaling machinery. Here we have used somatic cell gene-targeting technology to generate a Vav-1-deficient Jurkat T-cell line. The J.Vav1 cell line exhibits dramatic defects in TCR-dependent interleukin (IL)-2 promoter activation, accompanied by significant reductions in the activities of the NFAT(IL-2), NFkappaB, AP-1 and REAP transcription factors that bind to the IL-2 promoter region. In contrast, loss of Vav-1 had variable effects on early TCR-stimulated signaling events. J.Vav1 cells display a selective defect in sustained Ca(2+) signaling during TCR stimulation, and complementation of this abnormality by exogenously introduced Vav-1 is dependent on the Vav-1 calponin homology domain. While JNK activation was severely impaired, the stimulation of Ras, ERK and protein kinase C-theta activities, as well as the mobilization of lipid rafts, appeared normal in the J.Vav1 cells. Finally, evidence is presented to suggest that the alternative Vav family members, Vav-2 and Vav-3, are activated during TCR ligation, and partially compensate for the loss of Vav-1 in Jurkat T cells.
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PMID:Pleiotropic defects in TCR signaling in a Vav-1-null Jurkat T-cell line. 1223 21

Granuloma modulation induced by antigen is an attractive model for vaccination studies of experimental schistosomiasis to test the effect of anti-pathology vaccine. We describe here an immunization procedure with culture derived macrophages-pulsed PIII, a known anionic antigen purified from S. mansoni adult worm, involved in the inhibition of granulomatous response to eggs. For our studies, peritoneal or spleen macrophages cultured over 15 days were loaded with PIII. Both macrophage sub-populations were capable to efficiently take up and subsequently present PIII to lymphocytes as evidenced by immunofluorescence assay. The vaccination of mice with intravenous injection of PIII-loaded macrophages potently induced antigen-specific immune response to S. mansoni antigens as determined by cell proliferation assay. This immunization procedure of mice caused significant decrease in hepatic granuloma formation and in vitro granuloma reaction to S. mansoni antigens coupled to polyacrylamide beads (PB-SEA, PB-SWAP or PB-PIII). Assessment of in vitro granuloma supernatant of spleen cells from PIII-loaded macrophages vaccinated mice revealed significant amounts of Th1-cytokines IFN-gamma and IL-2 compared to control cells. Collectively, our results indicate that culture derived-macrophages provided a valuable research tool to investigate aspects of immune response that promote modulation of granulomatous hypersensitivity to S. mansoni eggs in mice.
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PMID:Modulation of granulomatous hypersensitivity against Schistosoma mansoni eggs in mice vaccinated with culture-derived macrophages loaded with PIII. 1224 80

Previously protein vaccines consisting of the extracellular domain of HER2/neu (ECD(HER2)) were shown to elicit an immune response that does not provide protection against transplantable tumors expressing HER2/neu. Here, we showed that when mice were vaccinated with a mixture of human ECD(HER2) and anti-human HER2/neu IL-12, IL-2 or GM-CSF fusion proteins, significant retardation of the growth of a syngeneic carcinoma expressing rat HER2/neu, and long-term survivors were observed. Immune sera inhibited the in vitro growth of SK-BR-3, a human breast cancer overexpressing HER2/neu. Transfer of immune sera into mice challenged with TUBO also led to partial inhibition of tumor growth. Splenocytes from mice vaccinated with ECD(HER2) plus IgG3-(GM-CSF) incubated with ECD(HER2) demonstrated significant proliferation and IFN-gamma secretion. Taken together these results suggest that vaccines including ECD(HER2) and Ab-cytokine fusion proteins may be used to elicit both humoral and cell-mediated responses against HER2/neu.
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PMID:Protein vaccination with the HER2/neu extracellular domain plus anti-HER2/neu antibody-cytokine fusion proteins induces a protective anti-HER2/neu immune response in mice. 1261 26


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