Novel NFAT Sites That Mediate Activation of the Interleukin-2 Promoter in Response to T-Cell Receptor Stimulation

Rooney, John W.; Sun, Ya-Lin; Glimcher, Laurie H.; Hoey, Timothy

doi:10.1128/mcb.15.11.6299

Cited by 238 publications

(191 citation statements)

References 72 publications

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“…Moreover, we had shown that Tpl-2 activates NFAT, a complex transcription factor composed of NFAT and AP1 components, whose activation is obligatory for IL-2 induction (Jain et al, 1992;Luo et al, 1996;Northrop et al, 1993;Rooney et al, 1995). Since Tpl-2 activates NFAT as well as the MAPK pathway (Ceci et al, 1997;Tsatsanis et al, 1998), which is required for the activation of AP1 (Jain et al, 1993), we examined whether dominant negative mutants of several proteins transducing signals along these pathways inhibit the activation of the IL-2 promoter by Tpl-2.…”

Section: Resultsmentioning

confidence: 99%

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Tpl-2 induces IL-2 expression in T-cell lines by triggering multiple signaling pathways that activate NFAT and NF-κB

1998

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The Tpl-2 kinase activates the nuclear factor of activated T cells (NFAT) and induces IL-2 expression in T-cell lines. Here we show that the activation of the IL-2 promoter by Tpl-2 is inhibited by mutant signaling molecules that inhibit the mitogen-activated protein kinase (MAPK) or the calcineurin/NFAT pathways and is promoted by combinations of signaling molecules that activate these pathways. We, therefore, conclude that signals generated by the convergence of the MAPK and the calcineurin/NFAT pathway are necessary and su cient for the activation of the IL-2 promoter by Tpl-2. The activation of both the IL-2 promoter and an NFAT-driven minimal promoter were shown to depend on signals transduced by Raf1. However, it was only the IL-2 promoter whose activation by Tpl-2 was fully blocked by the dominant negative mutant MEK1S218/ 222A and the MEK1/MEK2 inhibitor PD098059. Since the activation of NFAT is MAPK-dependent these ®ndings suggested that the activation of MAPK by Tpl-2 is either independent or only partially dependent on MEK1 and MEK2. In addition, they suggested that the activation of the IL-2 promoter is under the control of not only NFAT but also a second factor whose activation is MEK-dependent. Experiments in COS-1 and EL-4 cells con®rmed both hypotheses and revealed that the second factor activated by Tpl-2 is NF-kB. While the activation of the IL-2 promoter and an NFAT-driven minimal promoter by Tpl-2 was fully blocked by the dominant negative mutant NFATD418, it was only partially blocked by the calcineurin inhibitor cyclosporin A suggesting that the Tpl-2-mediated NFAT activation is under the control of a combination of calcineurindependent and independent pathways. Both pathways were fully blocked by Bcl-2 or Bcl-X L .

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Section: Resultsmentioning

confidence: 99%

“…Activation of the IL-2 promoter relies on the simultaneous activation of the transcription factors NFAT, AP1, NF-kB and Oct (Figure 7a) (Garrity et al, 1994;Rooney et al, 1995). Of these, NFAT and NF-kB are obligatory for the activation of the IL-2 promoter.…”

Section: Tpl-2 Activates the Mapk Erk1 Via A Mek1-independent Pathwaymentioning

confidence: 99%

Tpl-2 induces IL-2 expression in T-cell lines by triggering multiple signaling pathways that activate NFAT and NF-κB

1998

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“…It has already been shown that Tat interacts with NFAT altering its transactivating capacity (20) and at present there is a controversy about the implication of NFAT in the regulation of the CD28RE/ AP1 response element (28,31). Therefore, it could be possible that the effects of Tat on this responsive element were caused by Tat-NFAT interaction, somehow altering the transactivating B-AP1 complex.…”

Section: Effect Of Tat On the Binding And Transcriptional Transactivamentioning

confidence: 99%

“…Thus, binding of NFAT proteins to B-like sites takes place on several promoters (20,(31)(32)(33). Moreover, NF-B and AP1 transcription factors are regulated not only by transcriptional and posttransductional mechanisms, but also by the qualitative composition of the dimers.…”

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confidence: 99%

HIV-1 Tat Inhibits IL-2 Gene Transcription Through Qualitative and Quantitative Alterations of the Cooperative Rel/AP1 Complex Bound to the CD28RE/AP1 Composite Element of the IL-2 Promoter

González

Punzón

González

et al. 2001

The Journal of Immunology

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Dysregulation of cytokine secretion plays an important role in AIDS pathogenesis. Here, we demonstrate that expression of HIV-1 Tat protein in Jurkat cells induces a severe impairment of IL-2 but not TNF gene transcription. Interestingly, this inhibition correlates with the effect of the viral protein on the transactivation of the CD28RE/AP1 composite element (−164/−154), but not with that observed on the NFAT/AP1 site of the IL-2 gene promoter, neither with the effect on NF-κB- nor AP1-independent binding sites. Endogenous expression of Tat induced a decrease in the amount of the specific protein complex bound to the CD28RE/AP1 probe after PMA plus calcium ionophore stimulation. This effect was accompanied by qualitative alterations of the AP1 complex. Thus, in wild-type Jurkat cells, c-jun was absent from the complex, whereas in Tat-expressing cells, c-jun was increasingly recruited overtime. By contrast, similar amounts of c-rel and a small amount of NFAT1 were detected both in wild type and in Jurkat Tat+ cells. Furthermore, Tat not only induced the participation of c-jun in the cooperative complex but also a decrease in its transactivation activity alone or in combination with c-rel. Thus, the interaction of Tat with the components of this rel/AP1 cooperative complex seems to induce quantitative and qualitative alterations of this complex as activation progresses, resulting in a decrease of IL-2 gene transcription. Altogether our results suggest the existence of tuned mechanisms that allow the viral protein to specifically affect cooperative interactions between transcription factors.

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“…1). The binding of AP-1 and NF-AT as well as Oct transcription factors controls both ARRE-1 and ARRE-2 (12)(13)(14)(15)(16)(17). Another important site within the IL-2 minimal promoter is a region that responds to CD28 costimulation, known as the CD28 response region (RR) (8,18,19) (see Fig.…”

Section: T He Generation Of T Cell-mediated Immune Responses Ismentioning

confidence: 99%

The Human IL-2 Gene Promoter Can Assemble a Positioned Nucleosome That Becomes Remodeled Upon T Cell Activation

Attema

Reeves

Murray

et al. 2002

The Journal of Immunology

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Controlled production of the cytokine IL-2 plays a key role in the mammalian immune system. Expression from the gene is tightly regulated with no detectable expression in resting T cells and a strong induction following T cell activation. The IL-2 proximal promoter (+1 to −300) contains many well-defined transcriptional activation elements that respond to T cell stimulation. To determine the role of chromatin structure in the regulation of interleukin-2 gene transcription, nucleosome assembly across the IL-2 promoter region was examined using in vitro chromatin reconstitution assays. The IL-2 promoter assembles a nucleosome that is both translationally and rotationally positioned, spanning some of the major functional control elements. The binding of transcription factors to these elements, with the exception of the architectural protein HMGA1, was occluded by the presence of the nucleosome. Analysis of the chromatin architecture of the IL-2 gene in Jurkat T cells provided evidence for the presence of a similarly positioned nucleosome in vivo. The region encompassed by this nucleosome becomes remodeled following activation of Jurkat T cells. These observations suggest that the presence of a positioned nucleosome across the IL-2 proximal promoter may play an important role in maintaining an inactive gene in resting T cells and that remodeling of this nucleosome is important for gene activation.

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Novel NFAT Sites That Mediate Activation of the Interleukin-2 Promoter in Response to T-Cell Receptor Stimulation

Cited by 238 publications

References 72 publications

Tpl-2 induces IL-2 expression in T-cell lines by triggering multiple signaling pathways that activate NFAT and NF-κB

Tpl-2 induces IL-2 expression in T-cell lines by triggering multiple signaling pathways that activate NFAT and NF-κB

HIV-1 Tat Inhibits IL-2 Gene Transcription Through Qualitative and Quantitative Alterations of the Cooperative Rel/AP1 Complex Bound to the CD28RE/AP1 Composite Element of the IL-2 Promoter

The Human IL-2 Gene Promoter Can Assemble a Positioned Nucleosome That Becomes Remodeled Upon T Cell Activation

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