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Papers In Press, published online ahead of print February 21, 2001
Section of Microbiology, University of California at Davis, Davis, CA 95616
Corresponding Author: mlprivalsky{at}ucdavis.edu
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 T3R-beta deletion-432 mutant found in human Resistance to Thyroid Hormone Syndrome, display enhanced homodimerization properties and exhibit unusually strong interactions with 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.
J. Biol. Chem, 10.1074/jbc.M010022200
Submitted on November 3, 2000
Revised on January 17, 2001
Accepted on February 21, 2001
Transcriptional repression by thyroid hormone receptors: a role for receptor homodimers in the recruitment of SMRT corepressor
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