Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P05412 (c-Jun)
 11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To delineate the molecular mechanisms regulating Th2 cell differentiation, CD28-mediated generation of Th2 effectors was analyzed. In the absence of TCR ligation CD28 stimulation induced Th2 differentiation of memory but not of naive CD4(+) T cells, whereas costimulation via CD28 and the TCR enhanced Th2 differentiation from naive T cells but suppressed it from memory T cells. Stimulation of T cells via the CD28 pathway, therefore, provided critical signals facilitating Th2 cell differentiation. By comparing the responses to CD28 stimulation in memory and naive T cells and by using specific inhibitors, signaling pathways were defined that contributed to Th2 differentiation. CD28-induced Th2 differentiation required IL-4 stimulation and the activation of the mitogen-activated protein kinases p38 and extracellular signal-regulated kinases 1/2. CD28 engagement directly initiated IL-4 gene transcription in memory T cells and induced activation of phosphatidylinositol 3-kinase, p38, and c-Jun NH(2)-terminal kinase/stress-activated protein kinase pathways. Extracellular signal-regulated kinase phosphorylation that was necessary for Th2 differentiation, however, required stimulation by IL-2. These results indicate that optimal TCR-independent generation of Th2 effectors requires coordinate signaling via the CD28 and IL-2 pathways. TCR-independent generation of Th2 effectors might provide a mechanism to control Th1-dominated cellular inflammation.
 ...
PMID:Antigen-independent Th2 cell differentiation by stimulation of CD28: regulation via IL-4 gene expression and mitogen-activated protein kinase activation. 1125 80

Immune cell-specific adaptor proteins create various combinations of multiprotein complexes and integrate signals from cell surface receptors to the nucleus, modulating the specificity and selectivity of intracellular signal transduction. Grap2 is a newly identified adaptor protein specifically expressed in lymphoid tissues. This protein shares 40--50% sequence homology in the SH3 and the SH2 domain with Grb2 and Grap. However, the Grap2 protein has a unique 120-amino acid glutamine- and proline-rich domain between the SH2 and C-terminal SH3 domains. The expression of Grap2 is highly restricted to lymphoid organs and T lymphocytes. In order to understand the role of this specific adaptor protein in immune cell signaling and activation, we searched for the Grap2 interacting protein in T lymphocytes. We found that Grap2 interacted with the hematopoietic progenitor kinase 1 (HPK1) in vitro and in Jurkat T cells. The interaction was mediated by the carboxyl-terminal SH3 domain of Grap2 with the second proline-rich motif of HPK1. Coexpression of Grap2 with HPK1 not only increased the kinase activity of HPK1 in the cell, but also had an additive effect on HPK1 mediated JNK activation. Furthermore, over expression of Grap2 and HPK1 induced significant transcriptional activation of c-Jun in the JNK signaling pathway and IL-2 gene reporter activity in stimulated Jurkat T cells. Therefore, our data suggest that the hematopoietic specific proteins Grap2 and HPK1 form a signaling complex to mediate the c-Jun NH(2)-terminal kinase (JNK) signaling pathway in T cells.
 ...
PMID:Leukocyte-specific adaptor protein Grap2 interacts with hematopoietic progenitor kinase 1 (HPK1) to activate JNK signaling pathway in T lymphocytes. 1131 18

In HIV-infected individuals dysregulation of the immune system is characterized by severe disorders of the cytokine network. Increase secretion of IL-2, the major T cell growth and differentiation cytokine, may play a decisive role in sensitization of T cells for activation induced apoptosis and indirect death of activated T cells through augmented virus replication. We investigated the cause of enhanced IL-2 secretion and found that the HIV Tat induces this effect. We demonstrate that increased IL-2 secretion is due to Tat-enhanced IL-2 promoter activation. Tat derepresses and activates the distal AP-1 site (position -185 to -177) in the IL-2 promoter. In nonstimulated T cells a repressor complex containing NF-IL6, JunB, c-Fos and Fra-1 is formed on the AP-1(IL-2/d) site and represses IL-2 promoter activity. After T cell activation, a heterodimeric activator containing p65 and c-Jun binds to the AP-1(IL-2/d) site. HIV Tat enhances activation of NF-kappaB and consequently, activates the AP-1(IL-2/d) site. Our data provide evidence for a novel mechanism by which HIV Tat dysregulates IL-2 production and therefore may contribute to the HIV-1 infection in a way yet to be clarified.
 ...
PMID:The effect of HIV-1 regulatory proteins on cellular genes: derepression of the IL-2 promoter by Tat. 1138 24

The immunosuppressive effects of glucocorticoids arise largely by inhibition of cytokine gene expression, which has been ascribed to interference between the glucocorticoid receptor and transcription factors such as AP-1 and NF-kappa B as well as by competition for common coactivators. Here we show that glucocorticoid-induced inhibition of interleukin-2 mRNA expression in activated normal T cells required new protein synthesis, suggesting that this phenomenon is secondary to expression of glucocorticoid-regulated genes. One of the most prominent glucocorticoid-induced genes is glucocorticoid-induced leucine zipper (GILZ), which has been reported to inhibit activation-induced up-regulation of Fas ligand (FasL) mRNA. Indeed, transient expression of GILZ in Jurkat T cells blocked induction of a reporter construct driven by the FasL promoter. This could be accounted for by GILZ-mediated inhibition of Egr-2 and Egr-3, NFAT/AP-1-inducible transcription factors that bind a regulatory element in the FasL promoter and up-regulate FasL expression. GILZ also potently inhibited AP-1-driven and IL-2 promoter-driven reporter constructs, and recombinant GILZ specifically interacted with c-Fos and c-Jun in vitro and inhibited the binding of active AP-1 to its target DNA. Whereas homodimerization of GILZ required the presence of its leucine zipper, the interaction with c-Fos and c-Jun occurred through the N-terminal 60-amino acid region of GILZ. Thus, GILZ represents a glucocorticoid-induced gene product that can inhibit a variety of activation-induced events, at least in part by direct interference with AP-1, and is therefore a candidate for a mediator of glucocorticoid-induced immunosuppression.
 ...
PMID:Inhibition of AP-1 by the glucocorticoid-inducible protein GILZ. 1139 94

The molecular basis of X-linked lymphoproliferative (XLP) disease has been attributed to mutations in the signaling lymphocytic activation molecule-associated protein (SAP), an src homology 2 domain-containing intracellular signaling molecule known to interact with the lymphocyte-activating surface receptors signaling lymphocytic activation molecule and 2B4. To investigate the effect of SAP defects on TCR signal transduction, herpesvirus saimiri-immortalized CD4 Th cells from XLP patients and normal healthy individuals were examined for their response to TCR stimulation. CD4 T cells of XLP patients displayed elevated levels of tyrosine phosphorylation compared with CD4 T cells from healthy individuals. In addition, downstream serine/threonine kinases are constitutively active in CD4 T cells of XLP patients. In contrast, TCR-mediated activation of Akt, c-Jun-NH(2)-terminal kinases, and extracellular signal-regulated kinases in XLP CD4 T cells was transient and rapidly diminished when compared with that in control CD4 T cells. Consequently, XLP CD4 T cells exhibited severe defects in up-regulation of IL-2 and IFN-gamma cytokine production upon TCR stimulation and in MLRs. Finally, SAP specifically interacted with a 75-kDa tyrosine-phosphorylated protein upon TCR stimulation. These results demonstrate that CD4 T cells from XLP patients exhibit aberrant TCR signal transduction and that the defect in SAP function is likely responsible for this phenotype.
 ...
PMID:Abnormal T cell receptor signal transduction of CD4 Th cells in X-linked lymphoproliferative syndrome. 1150 8

A novel polyunsaturated fatty acid (PUFA), beta-oxa 21:3n-3, containing an oxygen atom in the beta position, was chemically synthesized, and found to have more selective biological activity than the n-3 PUFA, docosahexaenoic acid (22:6n-3) on cells of the immune system. Although beta-oxa 21:3n-3 was very poor compared with 22:6n-3 at stimulating oxygen radical production in neutrophils, it was more effective at inhibiting human T lymphocyte proliferation (IC(50) of 1.9 vs 5.2 microM, respectively). beta-Oxa 21:3n-3 also inhibited the production of TNF-beta, IFN-gamma, and IL-2 by purified human T lymphocytes stimulated with PHA plus PMA, anti-CD3 plus anti-CD28 mAbs, or PMA plus A23187. Metabolism of beta-oxa 21:3n-3 via the cyclooxygenase and lipoxygenase pathways was not required for its inhibitory effects. Consistent with its ability to suppress T lymphocyte function, beta-oxa 21:3n-3 significantly inhibited the delayed-type hypersensitivity response and carrageenan-induced paw edema in mice. In T lymphocytes, beta-oxa 21:3n-3 inhibited the agonist-stimulated translocation of protein kinase C-betaI and -epsilon, but not -alpha, -betaII, or -theta to a particulate fraction, and also inhibited the activation of the extracellular signal-regulated protein kinase, but not c-Jun NH(2)-terminal kinase and p38. In contrast, 22:6n-3 had no effects on these protein kinase C isozymes. The increase in antiinflammatory activity and loss of unwanted bioaction through the generation of a novel synthetic 22:6n-3 analogue provides evidence for a novel strategy in the development of anti-inflammatory agents by chemically engineering PUFA.
 ...
PMID:A novel long chain polyunsaturated fatty acid, beta-Oxa 21:3n-3, inhibits T lymphocyte proliferation, cytokine production, delayed-type hypersensitivity, and carrageenan-induced paw reaction and selectively targets intracellular signals. 1156 17

Jun N-terminal kinase (JNK) is a stress-activated protein kinase that can be induced by inflammatory cytokines, bacterial endotoxin, osmotic shock, UV radiation, and hypoxia. We report the identification of an anthrapyrazolone series with significant inhibition of JNK1, -2, and -3 (K(i) = 0.19 microM). SP600125 is a reversible ATP-competitive inhibitor with >20-fold selectivity vs. a range of kinases and enzymes tested. In cells, SP600125 dose dependently inhibited the phosphorylation of c-Jun, the expression of inflammatory genes COX-2, IL-2, IFN-gamma, TNF-alpha, and prevented the activation and differentiation of primary human CD4 cell cultures. In animal studies, SP600125 blocked (bacterial) lipopolysaccharide-induced expression of tumor necrosis factor-alpha and inhibited anti-CD3-induced apoptosis of CD4(+) CD8(+) thymocytes. Our study supports targeting JNK as an important strategy in inflammatory disease, apoptotic cell death, and cancer.
 ...
PMID:SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase. 1171 29

The c-Jun NH(2)-terminal kinase (JNK) signaling pathway is induced by cytokines and stress stimuli and is implicated in cell death and differentiation, but the specific function of this pathway depends on the cell type. Here we examined the role of JNK1 and JNK2 in CD8(+) T cells. Unlike CD4(+) T cells, the absence of JNK2 causes increased interleukin (IL)-2 production and proliferation of CD8(+) T cells. In contrast, JNK1-deficient CD8(+) T cells are unable to undergo antigen-stimulated expansion in vitro, even in the presence of exogenous IL-2. The hypoproliferation of these cells is associated with impaired IL-2 receptor alpha chain (CD25) gene and cell surface expression. The reduced level of nuclear activating protein 1 (AP-1) complexes in activated JNK1-deficient CD8(+) T cells can account for the impaired IL-2 receptor alpha chain gene expression. Thus, JNK1 and JNK2 play different roles during CD8(+) T cell activation and these roles differ from those in CD4(+) T cells.
 ...
PMID:c-Jun NH(2)-terminal kinase (JNK)1 and JNK2 have distinct roles in CD8(+) T cell activation. 1192 26

CARMA1 is a lymphocyte-specific member of the membrane-associated guanylate kinase (MAGUK) family of scaffolding proteins, which coordinate signaling pathways emanating from the plasma membrane. CARMA1 interacts with Bcl10 via its caspase-recruitment domain (CARD). Here we investigated the role of CARMA1 in T cell activation and found that T cell receptor (TCR) stimulation induced a physical association of CARMA1 with the TCR and Bcl10. We found that CARMA1 was constitutively associated with lipid rafts, whereas cytoplasmic Bcl10 translocated into lipid rafts upon TCR engagement. A CARMA1 mutant, defective for Bcl10 binding, had a dominant-negative (DN) effect on TCR-induced NF-kappa B activation and IL-2 production and on the c-Jun NH(2)-terminal kinase (Jnk) pathway when the TCR was coengaged with CD28. Together, our data show that CARMA1 is a critical lipid raft-associated regulator of TCR-induced NF-kappa B activation and CD28 costimulation-dependent Jnk activation.
 ...
PMID:CARMA1 is a critical lipid raft-associated regulator of TCR-induced NF-kappa B activation. 1220 67

CC-4047 (Actimid) and CC-5013 (Revimid) belong to a class of thalidomide analogs collectively known as the immunomodulatory drugs (IMiDs), which are currently being assessed in the treatment of patients with multiple myeloma and other cancers. IMiDs potently enhance T cell and natural killer cell responses and inhibit tumor necrosis factor-alpha, interleukin (IL)-1 beta, and IL-12 production from LPS-stimulated peripheral blood mononuclear cells. However, the molecular mechanism of action for these compounds is unknown. Herein, we report on the ability of the IMiDs to up-regulate production of IL-2 from activated human CD4+ and CD8+ peripheral blood T cells, production of IL-2 and IFN-gamma from T helper (Th)1-type cells, and production of IL-5 and IL-10 from Th2-type cells. Elevation of IL-2 production from Jurkat T cells was observed as early as 6 h poststimulation and correlated with an increase in IL-2 promoter activity that was dependent upon the proximal but not the distal AP-1 binding site. The IMiDs enhanced AP-1-driven transcriptional activity 2- to 4-fold after 6 h of T cell stimulation, and their relative potencies for AP-1 activation correlated with their potencies for increased IL-2 production in Jurkat T cells and in CD4+ or CD8+ human peripheral blood T cells. The most potent of these IMiDs, CC-4047, had no effect on nuclear factor of activated T cells transcriptional activity, calcium signaling, or phosphorylation of extracellular signal-regulated kinase 1/2, c-Jun NH2-terminal kinase 1/2, p38 mitogen-activated protein kinase, or c-Jun/Jun D in Jurkat T cells. These data suggest that IMiDs increase T cell cytokine production by potentiating AP-1 transcriptional activity.
 ...
PMID:Enhancement of cytokine production and AP-1 transcriptional activity in T cells by thalidomide-related immunomodulatory drugs. 1264 1


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