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| DOWN-MODULATION OF INTERLEUKIN-6 GENE-EXPRESSION BY 17-BETA-ESTRADIOL IN THE ABSENCE OF HIGH-AFFINITY DNA-BINDING BY THE ESTROGEN-RECEPTOR |
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| Author(s): RAY A, PREFONTAINE KE, RAY P |
| Source: JOURNAL OF BIOLOGICAL CHEMISTRY Volume: 269 Issue: 17 Pages: 12940-12946 Published: APR 29 1994 |
| Times Cited: 209 References: 59 |
| Abstract: The mechanism of repression of the interleukin-6 (IL-6) promoter by 17 beta-estradiol (E(2)) was investigated in cells transfected with wild-type (wt) or mutant estrogen receptor (ER) expression vectors. In transient transfection experiments, IL-1-induced activation of the IL-6 promoter was efficiently inhibited by wt ER. However, estrogen receptors carrying mutations within or overlapping with the DNA binding domain did not repress IL-6 promoter activity. A mutant receptor lacking the N-terminal transactivator function-1 but retaining the C-terminal transactivator function-2 also repressed activation of the IL-6 promoter. Our recent experiments indicate the requirement for both the nuclear factor (NF)-IL6 and the NF-kappa B sites in the IL-6 promoter for activation by IL-1. We now show that activation of the IL-6 promoter, elicited by a combination of NF-IL6 and the p65 subunit of NF-kappa B, can be inhibited by the wt receptor but not by a receptor containing a mutation in its DNA binding domain. Although a deletion within the DNA binding domain of ER abolished the repressor function of the receptor, a chimeric receptor ER-GR CAS1, in which the DNA binding domain of ER was swapped with the complementary region from the glucocorticoid receptor, retained the inhibitory effects on the IL-6 promoter. This was in contrast to the absolute dependence of ER on its own DNA binding domain for activation of typical estrogen response element-containing promoters, as reported previously by other investigators. Furthermore, the repression of the IL-6 promoter by a combination of ER and E(2), unlike activation of estrogen response elements by the same combination, did not appear to be mediated via high affinity binding of the receptor to the promoter. In functional experiments, the transactivator function of ER was totally inhibited by overexpression of p65 and to a lesser extent by that of NF-IL6. These results indicate that ER may repress gene expression in the absence of high affinity DNA binding. |
| Document Type: Article |
| Language: English |
| Reprint Address: RAY, A (reprint author), YALE UNIV, SCH MED, DEPT INTERNAL MED, PULM & CRIT CARE MED SECT, 333 CEDAR ST, POB 208057, NEW HAVEN, CT 06520 USA |
| Publisher: AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 |
| Subject Category: Biochemistry & Molecular Biology |
| IDS Number: NH716 |
| ISSN: 0021-9258 |
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