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Papers In Press, published online ahead of print November 17, 2000
J. Biol. Chem, 10.1074/jbc.M006743200
Submitted on July 27, 2000
Revised on November 16, 2000
Accepted on November 17, 2000
Endocrinology Division, University of Michigan Medical Center, Ann Arbor, MI 48109-0678
Corresponding Author: rkoenig{at}umich.edu
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 to the upstream of the two directly repeated half-sites in a typical TRE. However, given that TRs and RXRs prefer to bind to different DNA sequences (TA/GAGGTCA 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 S. cerevisiae the functional activity of TR ± RXR on ten 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 ten 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.
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