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J. Biol. Chem., Vol. 277, Issue 51, 49517-49522, December 20, 2002
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from a Negative Hormone Response Element*
§,,§,,§
From the Nuclear receptors are ligand-modulated
transcription factors that transduce the presence of lipophilic ligands
into changes in gene expression. Nuclear receptor activity is regulated
by ligand-induced interactions with coactivator or corepressor
molecules. From a positive hormone response element (pHRE) and in the
absence of hormone, corepressors SMRT and N-CoR are bound to some
nuclear receptors such as the thyroid hormone (T3Rs) and
retinoic acid receptors and mediate inhibition of basal levels of
transcription. Ligand binding results in dissociation of corepressors
and association of coactivators, resulting in the reversal of
inhibition and a net activation of transcription. However, the role of
cofactors on the activity of nuclear receptors from negative HREs
(nHREs) is poorly understood. Here we show that corepressor SMRT can
act as a potent coactivator for T3R Biotechnology Centre of Oslo and the
§ Department of Biology, University of Oslo, Postboks 1050 Blindern, Oslo 0316, Norway and the ¶ Metabolic Research Unit,
University of California, San Francisco, California, 94143-0540
from a nHRE; N-CoR has a similar but significantly attenuated activity. Mutagenesis of residues in the
hinge region of T3R that block binding of SMRT and N-CoR inhibits
ligand-independent transcriptional activation by T3R from a nHRE.
These mutations also abrogate SMRT-mediated increase in transcriptional
activity by T3R at a nHRE without significantly affecting
ligand-dependent activation at a pHRE. Partial protease digestion coupled to the mobility shift assay indicate differences in
the conformation of T3R-SMRT complexes bound to a pHRE
versus a nHRE. These results suggest that allosteric
changes resulting from binding of T3R to different response
elements, i.e. pHREs versus nHREs, dictate
whether a cofactor will function as a coactivator or a corepressor.
This, in turn, greatly expands the repertoire of mechanisms used
in modulating transcription without the need for expression of new
regulatory molecules.
To whom correspondence should be addressed. Tel.: 47-22854569;
Fax: 47-22854601; E-mail: fahris@bio.uio.no.
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