The CD40L Promoter Contains Nuclear Factor of Activated T Cells-binding Motifs Which Require AP-1 Binding for Activation of Transcription

Tsytsykova, Alla V.; Tsitsikov, Erdyni; Geha, Raif S.

doi:10.1074/jbc.271.7.3763

Cited by 116 publications

(96 citation statements)

References 35 publications

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“…We and others have previously described and characterized the CD154 transcriptional promoter. 2,4,13,[18][19][20][21][22][23] In addition, we have identified a 3 0 CD154 transcriptional enhancer 5 located just downstream of the 3 0 UTR mRNA stability element. 24,25 In vitro, both the hCD154 transcriptional promoter and 3 0 enhancer element are relatively weak, despite the abundant and rapid generation of CD154 mRNA following CD4 T-cell activation.…”

Section: Discussionmentioning

confidence: 99%

A T-cell-specific CD154 transcriptional enhancer located just upstream of the promoter

Brunner

Genin

et al. 2008

Genes Immun

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CD154 (CD40-ligand) is a critical immune regulator. CD154 expression is tightly regulated and largely restricted to activated CD4 T cells. Using DNase I hypersensitivity site (HSS) mapping, we identified two novel HSS mapping to the human CD154 promoter element and just upstream. Both HSS were activation independent and CD4 T-cell specific. Approximately 350 bp of DNA sequence flanking the upstream HSS site was highly conserved between mouse and man, and was rich in binding sites for GATA and NFAT proteins. Gel shift and chromatin immunoprecipitation assays demonstrated both NFAT1 and the Th2 factor, GATA-3, bound this enhancer element in vitro and in vivo, respectively. A PstI/XbaI 345 bp fragment of this region acted as a transcriptional enhancer of the CD154 promoter in primary human CD4 T cells. Overexpression of repressor of GATA and a dominant negative GATA-3 protein independently inhibited transcription, whereas overexpression of wild-type GATA-3 enhanced transcriptional activity, by this element in primary CD4 T cells. Moreover, more interleukin-4-producing CD4 T cells expressed CD154 following activation than interferon-g-producing CD4 T cells. Thus, we identified a novel T-cell-specific, GATA-3 responsive, CD154 transcriptional enhancer, which may contribute to increased propensity of Th2 cells to express CD154.

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Section: Discussionmentioning

confidence: 99%

A T-cell-specific CD154 transcriptional enhancer located just upstream of the promoter

Brunner

Genin

et al. 2008

Genes Immun

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“…The transcription factor NF-AT is activated by the calcium-dependent tyrosine phosphatase calcineurin, forms a transcriptionally active complex with AP-1, and plays a critical role in the induction of CD40L expression (38,39). Baseline CD40L expression may reflect baseline NF-AT activity.…”

Section: Discussionmentioning

confidence: 99%

Glucocorticoids upregulate CD40 ligand expression and induce CD40L-dependent immunoglobulin isotype switching

Jabara¹,

Brodeur²,

Geha³

2001

J. Clin. Invest.

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“…3). Among the genes described to be regulated by NFAT in T cells are IL-2 (6, 7), IL-3 (8), IL-4 (9 -11), IL-5 (12), GM-CSF (13,14), IFN-␥ (15,16), TNF-␣ (17,18), IL-13 (19), Fas ligand (FasL) 3 (20), and CD40 ligand (21).…”

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confidence: 99%

The Duration of Nuclear Residence of NFAT Determines the Pattern of Cytokine Expression in Human SCID T Cells

Feske

Draeger

Peter

et al. 2000

The Journal of Immunology

124

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The expression of cytokine genes and other inducible genes is crucially dependent on the pattern and duration of signal transduction events that activate transcription factor binding to DNA. Two infant patients with SCID and a severe defect in T cell activation displayed an aberrant regulation of the transcription factor NFAT. Whereas the expression levels of the NFAT family members NFAT1, -2, and -4 were normal in the patients’ T cells, dephosphorylation and nuclear translocation of these NFAT proteins occurred very transiently and incompletely upon stimulation. Only after inhibition of nuclear export with leptomycin B were we able to demonstrate a modest degree of nuclear translocation in the patients’ T cells. This transient activation of NFAT was not sufficient to induce the expression of several cytokines, including IL-2, IL-3, IL-4, and IFN-γ, whereas mRNA levels for macrophage inflammatory protein-1α, GM-CSF, and IL-13 were only moderately reduced. By limiting the time of NFAT activation in normal control cells using the calcineurin inhibitor cyclosporin A, we were able to mimic the cytokine expression pattern in SCID T cells, suggesting that the expression of different cytokine genes is differentially regulated by the duration of NFAT residence in the nucleus.

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The CD40L Promoter Contains Nuclear Factor of Activated T Cells-binding Motifs Which Require AP-1 Binding for Activation of Transcription

Cited by 116 publications

References 35 publications

A T-cell-specific CD154 transcriptional enhancer located just upstream of the promoter

A T-cell-specific CD154 transcriptional enhancer located just upstream of the promoter

Glucocorticoids upregulate CD40 ligand expression and induce CD40L-dependent immunoglobulin isotype switching

The Duration of Nuclear Residence of NFAT Determines the Pattern of Cytokine Expression in Human SCID T Cells

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