Abstract
Nuclear hormone receptors, such as the thyroid hormone receptors (T3Rs) and retinoid X receptors (RXRs), are ligand-regulated transcription factors that control key aspects of metazoan gene expression. T3Rs can bind to DNA either as receptor homodimers or as heterodimers with RXRs. Once bound to DNA, nuclear hormone receptors regulate target gene expression by recruiting auxiliary proteins, denoted corepressors and coactivators. We report here that T3R homodimers assembled on DNA exhibit particularly strong interactions with the SMRT corepressor, whereas T3R.RXR heterodimers are inefficient at binding to SMRT. Mutants of T3R that exhibit enhanced repression properties, such as the v-Erb A oncoprotein or the T3Rbeta-Delta432 mutant found in human resistance to thyroid hormone syndrome, display enhanced homodimerization properties and exhibit unusually strong interactions with the SMRT corepressor. Significantly, the topology of a DNA binding site can determine whether that site recruits primarily homodimers or heterodimers and therefore whether corepressor is efficiently or inefficiently recruited to the resulting receptor-DNA complex. We suggest that T3R homodimers, and not heterodimers, may be important mediators of transcriptional repression and that the nature of the DNA binding site, by selecting for receptor homodimers or heterodimers, can influence the ability of the receptor to recruit corepressor.
Highlights
Small, hydrophobic hormones, such as steroids, retinoids, and the thyroid hormones T3 and T4 thyronine, regulate many important aspects of metazoan differentiation, reproduction, and homeostasis
We report here that T3R homodimers assembled on DNA exhibit strong interactions with the SMRT corepressor, whereas T3R1⁄7RXR heterodimers are inefficient at binding to SMRT
We report here that T3R homodimers assembled on DNA exhibit strong interactions with the SMRT corepressor, whereas T3R1⁄7RXR heterodimers are inefficient at binding to corepressors
Summary
T3Rs can bind to DNA either as receptor homodimers or as heterodimers with RXRs. Once bound to DNA, nuclear hormone receptors regulate target gene expression by recruiting auxiliary proteins, denoted corepressors and coactivators. We suggest that T3R homodimers, and not heterodimers, may be important mediators of transcriptional repression and that the nature of the DNA binding site, by selecting for receptor homodimers or heterodimers, can influence the ability of the receptor to recruit corepressor Small, hydrophobic hormones, such as steroids, retinoids, and the thyroid hormones T3 and T4 thyronine, regulate many important aspects of metazoan differentiation, reproduction, and homeostasis. T3R Homodimers Recruit SMRT Corepressor oncoprotein or the T3R-⌬432 mutant found in human resistance to thyroid hormone (RTH) syndrome [8, 53], display enhanced homodimerization properties and exhibit unusually strong interactions with corepressor. In contrast to T3Rs, RARs efficiently recruit corepressor both as homodimers and as heterodimers with RXR, indicating that the nature of the receptor dimer may play a less decisive role in corepressor recruitment by RARs
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