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J. Biol. Chem., Vol. 276, Issue 20, 16857-16867, May 18, 2001
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From the Section of Microbiology, Division of Biological Sciences,
University of California, Davis, California 95616
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
-
432 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.
To whom correspondence should be addressed. Tel.: 530-752-3013;
Fax: 530-752-9014; E-mail: mlprivalsky{at}ucdavis.edu.
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