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)

Sequences of 31 bp containing putative AP-1 and AP-4 binding sequences in the U3 region of the feline immunodeficiency virus (FIV) long terminal repeat (LTR) were deleted and the basal promoter activity of the LTR was measured by the chloramphenicol acetyltransferase (CAT) assay. The activity of the FIV LTR was reduced in Felis catus whole foetus 4 (fcwf-4) cells and Crandell feline kidney cells by this deletion. Cotransfection of murine c-Fos or c-Jun expression plasmids with the FIV LTR-CAT reporter plasmid into fcwf-4 cells revealed that FIV LTR could be activated by c-Fos but not c-Jun in the cells. The mutated LTR was introduced into an infectious molecular clone of FIV and the replication rate and the cytopathogenic activity of the mutant were compared with those of the wild-type in two feline CD4-positive T lymphoblastoid cell lines. It was found that the rate and activity of the mutant were almost the same as those of the wild-type. From these data, we conclude that the 31 bp fragment is important for achieving maximal expression of the FIV genome, but not required for the replication of FIV in feline T lymphocytes.
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PMID:The AP-1 binding site in the feline immunodeficiency virus long terminal repeat is not required for virus replication in feline T lymphocytes. 839 13

Under physiological conditions, activation of CD4+ T cells by major histocompatibility complex (MHC)antigen complexes requires engagement of both the T cell receptor and the CD4 molecule. However, CD4 ligands binding to the CD4 molecule has also been shown to inhibit T cell proliferation and interleukin (IL)-2 production in human CD4+ T cells, in an MHC-independent way. We have previously shown that this inhibition was associated with a diminished binding activity of the IL-2 transcription factors NF-AT, NF-kappaB, and AP-1. AP-1 plays a key role in the regulation of IL-2 transcription, and ERK and JNK activities are necessary for regulating AP-1 at both the transcriptional and the post-transcriptional levels. We therefore studied, in human peripheral CD4+ T cells, the regulation of the activities of extracellular signal-regulated protein kinases (ERK) and c-Jun N-terminal kinases (JNK) by two CD4 ligands, gp160 the envelope glycoprotein of human immunodeficiency virus (HIV) and an anti-CD4 monoclonal antibody (mAb). Pre-incubation of CD4+ T lymphocytes in the presence of anti-CD4 mAb or gp160 inhibits the activation of JNK in response to phorbol 12-myristate 13-acetate and ionomycin. In the same conditions, phosphorylation and activation of ERK-2 were also inhibited. Inhibition of both JNK and ERK-2 activities are specific for binding of CD4 ligands to the CD4 molecule. They were not observed in CD8+ T lymphocytes. These results suggest that a specific inhibition of JNK and ERK-2 activities contributes to defective IL-2 production in T lymphocytes pre-incubated with CD4 ligands.
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PMID:gp160 of HIV or anti-CD4 monoclonal antibody ligation of CD4 induces inhibition of JNK and ERK-2 activities in human peripheral CD4+ T lymphocytes. 904 10

IL-16 has been reported as a modulator of T cell activation and was shown to function as chemoattractant factor. The chemotactic activity of IL-16 depends on the expression of CD4 on the surface of target cells, but the intracellular signaling pathways are only now being deciphered. This report describes IL-16 as an additional activator of the stress-activated protein kinase (SAPK) pathway in CD4+ macrophages. Treatment of these cells with recombinant expressed IL-16 leads to the phosphorylation of SEK-1, resulting in activation of the SAPKs p46 and p54. IL-16 stimulation also leads to the phosphorylation of c-Jun and p38 MAPK (mitogen-activated protein kinase), without inducing MAPK-family members ERK-1 and ERK-2. Interestingly, the IL-16-mediated activation of SAPKs and p38 MAPK in macrophages alone induces no detectable apoptotic cell death. These observations suggest specific regulatory functions of IL-16 distinct from the proinflammatory cytokines TNF-alpha and IL-1beta.
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PMID:IL-16 activates the SAPK signaling pathway in CD4+ macrophages. 963 99

A number of indirect methods have been utilized in demonstrating activator protein-1 transcription factor function in IL-2 promoter activity. However, there has been no direct demonstration that activator protein-1 is involved in CD28-dependent costimulation of IL-2 gene transcription in freshly isolated naive and memory human T lymphocytes. To address this issue, the method of scrape loading was applied to purified peripheral blood T lymphocytes. Since scrape loading relies on adherent cells, peripheral blood human T (PB-T) cells were immobilized on the nonspecific cell attachment factor poly-L-lysine. Cells scraped off poly-L-lysine in the presence of Ig FITC efficiently incorporated Ig, with relatively uniform fluorescence. T cells retained their physical parameters as measured by forward and side light scatter, and functional activity as measured by costimulation of proliferation and IL-2 production after being scraped off this substrate. CD28/CD3-costimulated T cells produced intracellular IL-2 from all subsets measured (CD4+, CD4-, CD45RO+, and CD45RO-). IL-2 production and intracellular accumulation in nonscraped PB-T cells activated with CD28/CD3 coligation were skewed favoring CD45RO+ and CD4+ subsets, as was IL-2 production in scraped PB-T cells. The intracellular incorporation of Abs specific for c-Fos and c-Jun family members by scrape loading inhibited the production and intracellular accumulation of IL-2 within 6 h of costimulation with PMA/ionomycin, or costimulation by CD28 and CD3 ligation. Scrape loading thus provides an efficient mechanism for intracellular incorporation of macromolecules, and the first direct evidence that c-Fos and c-Jun are involved in transcription of the IL-2 gene within its correct chromosomal context, in resting human T lymphocyte subpopulations.
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PMID:Inhibition of CD28/CD3-mediated costimulation of naive and memory human T lymphocytes by intracellular incorporation of polyclonal antibodies specific for the activator protein-1 transcriptional complex. 967 Sep 39

CD4 ligand binding to the CD4 molecules has been shown to inhibit T cell proliferation and IL-2 transcription and synthesis. We have recently shown that this inhibition correlated with a CD4-mediated inhibition of the kinase Erk-2 and c-Jun-N-terminal kinases (JNK) which play a key role in IL-2 transcription. Moreover, we have previously reported that antigen-independent adhesion of CD45RObright/CD4+ T cells to B cells is negatively regulated by CD4 ligands, whereas that of CD45RAbright/CD4+ naive T cells is not. Other groups have described, in murine models, a differential sensitivity of memory and naive T cells to CD4-mediated inhibitory effects on T cell activation. The aim of the present report was to study the sensitivity of the naive and memory CD4+ T cell populations to the CD4-mediated inhibition of Erk-2 and JNK activation. Our data show that preincubation with anti-CD4 mAb, of the CD45RAbright/CD4+ naive and the CD45RObright/CD4+ memory human T cell populations, induces inhibition of both Erk-2 phosphorylation and Erk-2 activation by phorbol ester or anti-CD3 mAb. In contrast, CD3 mediated JNK activation was inhibited in the memory but not in the naive CD4+ T cell population, whereas JNK activation by phorbol ester or phorbol esters plus Ca2+ ionophore was inhibited by anti-CD4 mAb in both T cell populations. These data further demonstrate a differential sensitivity of naive and memory CD4+ T cell populations to the CD4-mediated negative signaling.
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PMID:Differential CD4-dependent inhibition of JNK but not Erk-2 activities in human naive and memory CD4+ T cell populations. 970 Oct 25

The extracellular signal-regulated kinase (ERK), the c-Jun NH2-terminal kinase (JNK), and p38 MAP kinase pathways are triggered upon ligation of the antigen-specific T cell receptor (TCR). During the development of T cells in the thymus, the ERK pathway is required for differentiation of CD4(-)CD8(-) into CD4(+)CD8(+) double positive (DP) thymocytes, positive selection of DP cells, and their maturation into CD4(+) cells. However, the ERK pathway is not required for negative selection. Here, we show that JNK is activated in DP thymocytes in vivo in response to signals that initiate negative selection. The activation of JNK in these cells appears to be mediated by the MAP kinase kinase MKK7 since high levels of MKK7 and low levels of Sek-1/MKK4 gene expression were detected in thymocytes. Using dominant negative JNK transgenic mice, we show that inhibition of the JNK pathway reduces the in vivo deletion of DP thymocytes. In addition, the increased resistance of DP thymocytes to cell death in these mice produces an accelerated reconstitution of normal thymic populations upon in vivo DP elimination. Together, these data indicate that the JNK pathway contributes to the deletion of DP thymocytes by apoptosis in response to TCR-derived and other thymic environment- mediated signals.
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PMID:The JNK pathway regulates the In vivo deletion of immature CD4(+)CD8(+) thymocytes. 981 59

The c-Jun NH2-terminal kinase (JNK) signaling pathway has been implicated in the immune response that is mediated by the activation and differentiation of CD4 helper T (TH) cells into TH1 and TH2 effector cells. JNK activity observed in wild-type activated TH cells was severely reduced in TH cells from Jnk1-/- mice. The Jnk1-/- T cells hyperproliferated, exhibited decreased activation-induced cell death, and preferentially differentiated to TH2 cells. The enhanced production of TH2 cytokines by Jnk1-/- cells was associated with increased nuclear accumulation of the transcription factor NFATc. Thus, the JNK1 signaling pathway plays a key role in T cell receptor-initiated TH cell proliferation, apoptosis, and differentiation.
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PMID:Defective T cell differentiation in the absence of Jnk1. 985 32

The regulation of apoptosis in mature CD4+ or CD8+ alphabeta+ T cells has been well studied. How the survival and death is regulated in peripheral CD4-CD8- (double negative, DN) alphabeta+ T cells remains unknown. Recent studies suggest that peripheral DN T cells may play an important role in the regulation of the immune responses mediated by CD4+ or CD8+ T cells. Here, we used immunosuppressive DN T cell clones to elucidate the mechanisms involved in the regulation of death and survival of alphabeta+ DN T cells. The DN T cell clones were generated from the spleen cells of 2C transgenic mice, which express the transgenic TCR specific for Ld and permanently accepted Ld+ skin allografts after pretransplant infusion of Ld+ lymphocytes. We report that 1) the mature DN T cells are highly resistant to TCR cross-linking-induced apoptosis in the presence of exogenous IL-4; 2) Fas/Fas-ligand and TNF-alpha/TNFR pathways do not play an apparent role in regulating apoptosis in DN T cells; 3) the DN T cells constitutively express a high level of Bcl-xL, but not Bcl-2; 4) both Bcl-xL and Bcl-2 are up-regulated following TCR-cross-linking; and 5) IL-4 stimulation significantly up-regulates Bcl-xL and c-Jun expression and leads to mitogen-activated protein kinase phosphorylation in DN T cells, which may contribute to the resistance to apoptosis in these T cells. Taken together, these results provide us with an insight into how mature DN T cells resist activation-induced apoptosis to provide a long-term suppressor function in vivo.
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PMID:Regulation of apoptosis in mature alphabeta+CD4-CD8- antigen-specific suppressor T cell clones. 1022 21

While Jun/Fos-containing transcription factors are known to be necessary for many TCR-mediated events in mature T cells, relatively little is known about their roles in thymocyte development. We have generated transgenic mice that express a trans-dominant-negative mutant of c-Jun (TAM-67) specifically in thymocytes. Expression of TAM-67 inhibited the up-regulation of AP-1-responsive genes such as c-jun and IL-2 in stimulated thymocytes from transgenic mice. In addition, altered thymocyte development in TAM-67-expressing mice was revealed by a decrease in thymic cellularity ( approximately 50%) which could be accounted for primarily by a reduction in the number of CD4(+)CD8(+) thymocytes, a large percentage of which retained CD25. The decrease in the number of CD4(+)CD8(+) thymocytes did not appear to be due to an enhanced rate of apoptosis but rather to a decrease in the number of CD4(-)CD8(-)CD25(-) cells in the S + G(2)/M stages of the cell cycle. These results indicate that Jun/Fos-containing transcription factors promote the proliferative burst that accompanies the transition from the CD4(-)CD8(-) to the CD4(+)CD8(+) stage of thymocyte development.
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PMID:A dominant-negative mutant of c-Jun inhibits cell cycle progression during the transition of CD4(-)CD8(-) to CD4(+)CD8(+) thymocytes. 1042 78

c-Jun N-terminal kinase (JNK) is activated when T-lymphocytes are stimulated jointly through the T-cell receptor (TCR) and CD28, and it contributes to T-cell activation and IL-2 production through phosphorylation of transcription factors, including c-Jun. We performed in vitro kinase assays on JNK in CD4(+) T-cells, from young and old mice, activated by antibodies to CD3, CD4, and CD28, and found a approximately 2-fold decline in JNK activity at the peak of activation, but no significant change in the kinetics of stimulation or in the steady-state expression of JNK. We found a similar decline in c-Jun phosphorylation in stimulated CD4(+) T-cells from old mice, suggesting that JNK activation also declined with age in intact cells. Aging does not, however, alter the level of Ras activation by anti-CD3/CD4 +/- anti-CD28 or change the level of Ras protein in CD4(+) cells, suggesting that the JNK defect is due to changes in the regulation of other upstream regulators. Our results suggest that a decline with age in JNK responses may contribute to the decline in proliferation and IL-2 production seen in CD4(+) T-cells from old mice.
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PMID:Age-related decline in activation of JNK by TCR- and CD28-mediated signals in murine T-lymphocytes. 1060 24


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