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| TRANSCRIPTIONAL REPRESSION OF THE INTERLEUKIN-2 GENE BY VITAMIN-D-3 - DIRECT INHIBITION OF NFATP/AP-1 COMPLEX-FORMATION BY A NUCLEAR HORMONE-RECEPTOR |
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| Author(s): ALROY I, TOWERS TL, FREEDMAN LP |
| Source: MOLECULAR AND CELLULAR BIOLOGY Volume: 15 Issue: 10 Pages: 5789-5799 Published: OCT 1995 |
| Times Cited: 171 References: 88 |
| Abstract: T-lymphocyte proliferation is suppressed by 1,25-dihydroxyvitamin D-3 [1,25(OH)(2)D-3], the active metabolite of vitamin D-3, 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)(2)D-3-mediated repression in Jurkat cells is cycloheximide resistant, suggesting that it is a direct transcriptional repressive effect on IL-2 expression by the vitamin D-3 receptor (VDR). We therefore examined vitamin D-3-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)(2)D-3 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 fan act as potent immunosuppressive agents. |
| Document Type: Article |
| Language: English |
Addresses:
1. MEM SLOAN KETTERING CANC CTR, CELL BIOL & GENET PROGRAM, NEW YORK, NY 10021 USA
2. CORNELL UNIV, GRAD SCH MED SCI, NEW YORK, NY 10021 USA |
| Publisher: AMER SOC MICROBIOLOGY, 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 |
| Subject Category: Biochemistry & Molecular Biology; Cell Biology |
| IDS Number: RV772 |
| ISSN: 0270-7306 |
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