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J. Biol. Chem., Vol. 276, Issue 6, 3929-3936, February 9, 2001
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From the Division of Endocrinology and Metabolism, University of
Michigan Medical Center, Ann Arbor, Michigan 48109-0678
Thyroid hormone receptors (TRs) are transcription
factors that bind to thyroid hormone response elements (TREs) in the
regulatory regions of target genes. TRs are thought to activate
transcription primarily as heterodimers with retinoid X receptors
(RXRs), with RXR binding upstream to the two directly repeated
half-sites in a typical TRE. However, given that TRs and RXRs prefer to
bind to different DNA sequences (T(A/G)AGGTCA and GGGGTCA), we
postulate that only certain TREs require RXR-TR heterodimerization,
depending on the TRE sequence. We have tested this hypothesis by
comparing in Saccharomyces cerevisiae the functional
activity of TR ± RXR on 10 naturally occurring mammalian TREs.
S. cerevisiae was used as a model system because yeast lack
endogenous nuclear receptors and thus can be manipulated to express TRs
and/or RXRs. We first studied ligand-independent reporter gene
activation, which reflects the activity of the activator function 1 (AF-1) domain. The 10 TREs formed a continuous spectrum from being
fully dependent on RXR for TR AF-1 activity to being essentially
independent of RXR. Relative independence of RXR generally was seen
when the TRE upstream half-site has a TA or TG 5' to the core hexamer.
Gel mobility shift assays revealed that functional independence of RXR
correlates with the strong binding of TR alone, whereas more RXR
dependence correlates with higher binding of RXR-TR heterodimers.
Restoration of ligand-dependent (AF-2 domain) reporter gene
activation was achieved by expression of the coactivator TIF2. This
ligand-induced stimulation was stronger in the presence of TR alone
than with RXR plus TR, suggesting a preference for TIF2 activation of
TR homodimers. Overall the data support the notion that the TRE
sequence plays an important role in determining the nuclear hormone
receptor and coactivator requirements for TR action.
Thyroid Hormone Response Element Sequence and the Recruitment of
Retinoid X Receptors for Thyroid Hormone Responsiveness*
*
This work was supported by National Institutes of Health
Grant DK44155.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Division of
Endocrinology and Metabolism, University of Michigan Medical Center, 5560 MSRB-II, 1150 West Medical Center Dr., Ann Arbor, MI 48109-0678. Tel.: 734-763-3056; Fax: 734-936-6684; E-mail:
Rkoenig@umich.edu.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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