The DOI matches its Crossref record; 82 of the 82 references it cites were found in a registry or an index.
Transcriptional Repression of the Interleukin-2 Gene by Vitamin D 3 : Direct Inhibition of NFATp/AP-1 Complex Formation by a Nuclear Hormone Receptor
Open accessAbstract
T-lymphocyte proliferation is suppressed by 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], the active metabolite of vitamin D3, and is associated with a decrease in interleukin 2 (IL-2), gamma interferon, and granulocyte-macrophage colony-stimulating factor mRNA levels. We report here that 1,25(OH)2D3-mediated repression in Jurkat cells is cycloheximide resistant, suggesting that it is a direct transcriptional repressive effect on IL-2 expression by the vitamin D3 receptor (VDR). We therefore examined vitamin D3-mediated repression of activated IL-2 expression by cotransfecting Jurkat cells with IL-2 promoter/reporter constructs and a VDR overexpression vector and by DNA binding. We delineated an element conferring both DNA binding by the receptor in vitro and 1,25(OH)2D3-mediated repression in vivo to a short 40-bp region encompassing an important positive regulatory element, NF-AT-1, which is bound by a T-cell-specific transcription factor, NFATp, as well as by AP-1. VDR DNA-binding mutants were unable to either bind to this element in vitro or repress in vivo; the VDR DNA-binding domain alone, however, bound the element but also could not repress IL-2 expression. These results indicate that DNA binding by VDR is necessary but not sufficient to mediate IL-2 repression. By combining partially purified proteins in vitro, we observed the loss of the bound NFATp/AP-1-DNA complex upon inclusion of VDR or VDR-retinoid X receptor. Order of addition and off-rate experiments indicate that the VDR-retinoid X receptor heterodimer blocks NFATp/AP-1 complex formation and then stably associates with the NF-AT-1 element. This direct inhibition by a nuclear hormone receptor of transcriptional activators of the IL-2 gene may provide a mechanistic explanation of how vitamin derivatives can act as potent immunosuppressive agents.
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“DNA binding alone, however, is apparently not sufficient, because the VDR DBD bound the element but nevertheless could not repress activated IL-2 transcription.”
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Metadata
- Authors
- Alroy, I., Towers, T. L., & Freedman, L. P.
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 1995-10
- Volume
- 15
- Issue
- 10
- Pages
- 5789-5799
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- OpenAlex
- W2151176594
- Cited by
- 398
- References
- 82
- FWCI
- 10.32
- Type
- journal article
- Language
- en
- Open access
- green
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- Alroy, I., Towers, T. L., & Freedman, L. P. (1995). Transcriptional Repression of the Interleukin-2 Gene by Vitamin D 3 : Direct Inhibition of NFATp/AP-1 Complex Formation by a Nuclear Hormone Receptor. Molecular and Cellular Biology. https://doi.org/10.1128/mcb.15.10.5789
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
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