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Query: UNIPROT:P05412 (c-Jun)
 11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Costimulation of TCR/CD3 and CD28 receptors leads to activation of the Jun kinase (JNK) cascade, which plays a key role in T cell activation, including activation of the IL-2 promoter. We demonstrate that the JNK cascade plays a central role in the activation of the CD28 response element (CD28RE) in the IL-2 promoter. This response element is linked to an activating protein-1 (AP-1) site, which functions synergistically with the CD28RE. The role of the JNK cascade in the activation of this composite element is twofold: 1) activation of the AP-1 site through transcriptional activation of c-Jun, and 2) activation of the CD28RE through selective cross-talk with I kappa B kinase-beta (IKK beta). Dominant-negative versions of JNK kinase, c-Jun, and IKK beta interfered In CD3- plus CD28-induced CD28RE/AP-1 luciferase activity in Jurkat cells. In contrast, the dominant-active JNK kinase kinase, MEKK1, induced CD28RE/AP-1 luciferase activity, in parallel with induction of c-Jun and c-Rel binding to this combined promoter site. Dominant-active MEKK1 also induced transfected IKK beta, but not IKK alpha, activity. In contrast to the JNK cascade, the extracellular signal-regulated kinase (ERK) cascade did not exert an affect on the CD28RE/AP-1 site, but did contribute to activation of the distal NF-AT/AP-1 site.
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PMID:The Jun kinase cascade is responsible for activating the CD28 response element of the IL-2 promoter: proof of cross-talk with the I kappa B kinase cascade. 1009 68

Optimal T cell activation requires two signals, one generated by TCR and another by the CD28 costimulatory receptor. In this study, we investigated the regulation of costimulation-induced mitogen-activated protein kinase (MAPK) activation in primary mouse T cells. In contrast to that reported for human Jurkat T cells, we found that p38 MAPK, but not Jun NH2-terminal kinase (JNK), is weakly activated upon stimulation with either anti-CD3 or anti-CD28 in murine thymocytes and splenic T cells. However, p38 MAPK is activated strongly and synergistically by either CD3/CD28 coligation or PMA/Ca2+ ionophore stimulation, which mimics TCR-CD3/CD28-mediated signaling. Activation of p38 MAPK correlates closely with the stimulation of T cell proliferation. In contrast, PMA-induced JNK activation is inhibited by Ca2+ ionophore. T cell proliferation and production of IL-2, IL-4, and IFN-gamma induced by both CD3 and CD3/CD28 ligation and the nuclear expression of the c-Jun and ATF-2 proteins are each blocked by the p38 MAPK inhibitor SB203580. Our findings demonstrate that p38 MAPK 1) plays an important role in signal integration during costimulation of primary mouse T cells, 2) may be involved in the induction of c-Jun activation and augmentation of AP-1 transcriptional activity, and 3) regulates whether T cells enter a state of functional unresponsiveness.
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PMID:p38 mitogen-activated protein kinase mediates signal integration of TCR/CD28 costimulation in primary murine T cells. 1020 99

The CD5 lymphocyte surface glycoprotein is a coreceptor involved in the modulation of Ag-specific receptor-mediated activation and differentiation signals. The molecular basis for its modulatory properties is not yet well understood. In the present study we describe early biochemical events triggered by CD5 stimulation, which include the phosphatidylcholine-specific phospholipase C (PC-PLC)-dependent activation of acidic sphingomyelinase (A-SMase) in normal and lymphoblastoid T and B cells. The functional coupling of PC-PLC and A-SMase is demonstrated by the abrogation of A-SMase activation by 1) xanthogenate tricyclodecan-9-yl (D609), a selective inhibitor of PC-PLC, and 2) replacement of several C-terminal serine residues (S458, S459, and S461) present in the cytoplasmic tail of CD5 that are known to be critical for PC-PLC activation. Additionally, we demonstrate that activation of protein kinase C-zeta (PKC-zeta) and members of the mitogen-activated protein kinase (MAPK) cascade (MAPK kinase and c-Jun NH2-terminal kinase), but not the NF-kappaB, are downstream events of the CD5 signaling pathway. A-SMase, PKC-zeta, and MAPK family members are key mediators of cell responses as diverse as proliferation, differentiation, and growth arrest and may contribute to CD5-mediated modulation of TCR or BCR signaling.
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PMID:Signaling through CD5 involves acidic sphingomyelinase, protein kinase C-zeta, mitogen-activated protein kinase kinase, and c-Jun NH2-terminal kinase. 1022 86

LFA-1 binding to ICAM-1 can enhance TCR-dependent proliferation of T cells, but it has been difficult to distinguish contributions from increased adhesion, and thus TCR occupancy, versus costimulatory signaling. Whether LFA-1 ligation results in generation of a unique costimulatory signal(s) distinct from those activated by the TCR has been unclear. Using purified ligands, it is shown that ICAM-1 and B7. 1 provide comparable costimulation for proliferation of CD8+ T cells, and that both ligands up-regulate the activities of phosphatidylinositol 3-kinase, sphingomyelinase, and c-Jun NH2-terminal kinase (JNK). These pathways are distinct from those activated by the TCR, and have previously been implicated in up-regulating IL-2 production in response to CD28-B7 interaction. Thus, under conditions in which ICAM-1 provides costimulation of proliferation, LFA-1 ligation activates some of the same signaling pathways as does CD28 ligation. LFA-1 and CD28 do not act identically, however, as indicated by differential sensitivity to inhibitors of phosphatidylinositol 3-kinase; LFA-1-dependent costimulation of proliferation is inhibited, while CD28-dependent costimulation is not. Given the broad distribution of class I and ICAMs on many cell types, the ability of LFA-1 to provide costimulatory signals has implications for where and how CD8+CTL may become activated in response to an antigenic challenge.
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PMID:Signaling pathways activated by leukocyte function-associated Ag-1-dependent costimulation. 1022 91

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

The biological function of CD30 in the thymus has been only partially elucidated, although recent data indicate that it may be involved in negative selection. Because CD30 is expressed only by a small subpopulation of medullary thymocytes, we generated transgenic (Tg) mice overexpressing CD30 in T lymphocytes to further address its role in T cell development. CD30 Tg mice have normal thymic size with a normal number and subset distribution of thymocytes. In vitro, in the absence of CD30 ligation, thymocytes of CD30 Tg mice have normal survival and responses to apoptotic stimuli such as radiation, dexamethasone, and Fas. However, in contrast to controls, CD30 Tg thymocytes are induced to undergo programmed cell death (PCD) upon cross-linking of CD30, and the simultaneous engagement of TCR and CD30 results in a synergistic increase in thymic PCD. CD30-mediated PCD requires caspase 1 and caspase 3, is not associated with the activation of NF-kappaB or c-Jun, but is totally prevented by Bcl-2. Furthermore, CD30 overexpression enhances the deletion of CD4+/CD8+ thymocytes induced by staphylococcal enterotoxin B superantigen and specific peptide. These findings suggest that CD30 may act as a costimulatory molecule in thymic negative selection.
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PMID:CD30 overexpression enhances negative selection in the thymus and mediates programmed cell death via a Bcl-2-sensitive pathway. 1038 16

IFN-gamma is a key regulatory cytokine of the immune system. Reporter transgenic mice expressing the luciferase gene under the control of separate TCR-response elements (TCR-RE) from the IFN-gamma promoter or expressing the green fluorescent protein gene under the control of an IFN-gamma "minigene" were employed to explore the basis for IL-12 regulation of IFN-gamma gene transcription. In the absence of TCR stimulation, IL-12 did not activate the TCR-REs but did induce green fluorescent protein expression. TCR plus IL-12R stimulation of effector Th cells resulted in: 1) enhanced activation of the proximal, but not the distal, TCR-RE, and 2) increased induction of cJun-proximal TCR-RE complexes and c-Jun protein expression. Overexpression of cJun, but not cFos, increased activity of the proximal TCR-RE in T cells. These results suggest that IL-12R signaling affects IFN-gamma gene transcription by at least two separate mechanisms; IL-12R signaling without TCR signaling targets promoter regions outside of the approximately 100-bp IFN-gamma TCR-RE, and IL-12R signaling also stimulates TCR-induced activity of the proximal TCR-RE.
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PMID:TCR and IL-12 receptor signals cooperate to activate an individual response element in the IFN-gamma promoter in effector Th cells. 1039 64

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

Anergic T cells display a marked decrease in their ability to produce IL-2 even in the presence of optimal TCR and costimulatory signals. Using IL-2 enhancer/promoter-driven reporter constructs, we have previously identified a region that appears to be a target for cis transcriptional repression in anergy. This region of the promoter, which shares partial homology with a consensus AP-1-binding sequence, is located about -180 bp from the transcriptional start site. In the present study, we demonstrate that cAMP response element-binding protein/cAMP response element modulator (CREB/CREM), activating transcription factor-2/c-Jun, and Jun-Jun/Oct complexes bind to this site. However, the induction of anergy by prolonged stimulation through the TCR led to an increase in binding of only the CREB/CREM complex. Furthermore, the level of binding of this complex appeared to be up-regulated in both resting and restimulated anergic T cells. Finally, an IL-2 promoter-driven reporter construct that contained a mutation that specifically reduced the binding of the CREB/CREM complex displayed a decreased ability to be affected by anergy, while a construct that contained a mutation that decreased the binding of the Jun-Jun/Oct complex was still susceptible to anergy. These findings suggest that the -180 region of the IL-2 promoter is the target of a CREB/CREM transcriptional inhibitor that contributes to the repression of IL-2 production in T cell anergy.
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PMID:The -180 site of the IL-2 promoter is the target of CREB/CREM binding in T cell anergy. 1058 58

The proline-, glutamic acid-, serine- and threonine-enriched protein tyrosine phosphatase PEP, which is expressed primarily in hematopoietic cells, was recently discovered to be physically associated with the 50-kDa cytosolic protein tyrosine kinase (PTK) Csk, an important suppressor of Src family PTK, including Lck and Fyn in T cells. We report that this phosphatase has an inhibitory effect on TCR-induced transcriptional activation of the c-fos proto-oncogene and elements from the IL-2 gene promoter. Catalytically inactive mutants of PEP had no effects in these assays. Expression of PEP also reduced activation of the N-terminal c-Jun kinase Jnk2 in response to receptor ligation, but not in response to UV light. In agreement with a more receptor-proximal site of action, we found that PEP reduced the TCR-induced increase in tyrosine phosphorylation of an Lck mutant, Lck-Y505F, which is only phosphorylated on tyrosine 394, the positive regulatory site. Finally, we observed that PEP reduced c-fos activation in a synergistic manner with Csk, supporting the notion that these two enzymes form a functional team acting on Src family kinases involved in TCR signaling.
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PMID:Characterization of TCR-induced receptor-proximal signaling events negatively regulated by the protein tyrosine phosphatase PEP. 1060 92


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