Thyroid hormone alters the DNA binding properties of chicken thyroid hormone receptors α and β

Andersson, Monika L.; Nordström, Kristina; Demczuk, Stephen; Harbers, Matthias; Vennström, Björn

doi:10.1093/nar/20.18.4803

Cited by 85 publications

(55 citation statements)

References 38 publications

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“…Although it remains to test a possible involvement of CAF-1, a component of the CCR4 transcriptional complex (Rouault et al, 1998), one major observation is that BTG1 induces TRa1 transcriptional activity in the absence of RXR through a DR4 T3RE. As T3 is known to dissociate TR homodimers from this particular responsive element (Andersson et al, 1992), this result indicates that BTG1 induces stabilization of the receptor's homodimeric binding to DNA in the presence of T3, in agreement with the possible formation of a stable transcriptional complex.…”

Section: Btg1 Is a Coactivator Of Positive Regulators Of Myoblast Difmentioning

confidence: 54%

Coactivation of nuclear receptors and myogenic factors induces the major BTG1 influence on muscle differentiation

et al. 2005

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The btg1 (B-cell translocation gene 1) gene coding sequence was isolated from a translocation break point in a case of B-cell chronic lymphocytic leukaemia. We have already shown that BTG1, considered as an antiproliferative protein, strongly stimulates myoblast differentiation. However, the mechanisms involved in this influence remained unknown. In cultured myoblasts, we found that BTG1 stimulates the transcriptional activity of nuclear receptors (T3 and all-trans retinoic acid receptors but not RXRa and PPARc), c-Jun and myogenic factors (CMD1, Myf5, myogenin). Immunoprecipitation experiments performed in cells or using in vitro-synthesized proteins and GST pull-down assays established that BTG1 directly interacts with T3 and all-trans retinoic acid receptors and with avian MyoD (CMD1). These interactions are mediated by the transactivation domain of each transcription factor and the A box and C-terminal part of BTG1. NCoR presence induces the ligand dependency of the interaction with nuclear receptors. Lastly, deletion of BTG1 interacting domains abrogates its ability to stimulate nuclear receptors and CMD1 activity, and its myogenic influence. In conclusion, BTG1 is a novel important coactivator involved in the regulation of myoblast differentiation. It not only stimulates the activity of myogenic factors, but also of nuclear receptors already known as positive myogenic regulators.

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Section: Btg1 Is a Coactivator Of Positive Regulators Of Myoblast Difmentioning

confidence: 54%

Coactivation of nuclear receptors and myogenic factors induces the major BTG1 influence on muscle differentiation

et al. 2005

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“…This notion is supported by the observation that "homodimers" on TREpal are formed very weakly as compared with those on DR-4 and F2 (6,7). Another indication that TR "dimers" on TREpal are really two monomers is based on the fact that T 3 increases TR binding as monomers with several TREs and as "homodimers" on TREpal (6, 7), whereas T 3 decreases TR binding as homodimers with DR-4 or F2 elements (6,7,43,44). The data indicate that at least part of the TR surface that mediates both dimerization on DR-4 and F2 and heterodimerization on GST⅐RXR also mediates TR-RXR heterodimerization on DR-4, F2, and TREpal elements.…”

Section: Discussionmentioning

confidence: 92%

Definition of the Surface in the Thyroid Hormone Receptor Ligand Binding Domain for Association as Homodimers and Heterodimers with Retinoid X Receptor

Ribeiro

Feng²,

Wagner

et al. 2001

Journal of Biological Chemistry

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Thyroid hormone receptors (TRs) bind as homodimers or heterodimers with retinoid X receptors (RXRs) to DNA elements with diverse orientations of AGGTCA half-sites. We performed a comprehensive x-ray crystal structure-guided mutation analysis of the TR ligand binding domain (TR LBD) surface to map the functional interface for TR homodimers and heterodimers with RXR in the absence and/or in the presence of DNA. We also identified the molecular contacts in TR LBDs crystallized as dimers. The results show that crystal dimer contacts differ from those found in the functional studies. We found that identical TR LBD residues found in helices 10 and 11 are involved in TR homodimerization and heterodimerization with RXR. Moreover, the same TR LBD surface is operative for dimerization with direct repeats spaced by 4 base pairs (DR-4) and with the inverted palindrome spaced by 6 base pairs (F2), but not with TREpal (unspaced palindrome), where homodimers appear to be simply two monomers binding independently to DNA. We also demonstrate that interactions between the TR and RXR DNA binding domains stabilize TR-RXR heterodimers on DR-4. The dimer interface can be functional in the cell, because disruption of key residues impairs transcriptional activity of TRs mediated through association with RXR LBD linked to GAL4 DNA-binding domain.Thyroid hormone receptors (TRs) 1 are members of the nuclear receptor superfamily, which includes receptors for steroid hormones, vitamins, retinoids, prostaglandins, fatty acids, and orphan receptors for which no ligands are known (1-4). These receptors are modular transcription factors that bind to specific sequences in promoters of target genes. They bind DNA as monomers, homodimers, or heterodimers through the DNA binding domain (DBD) (1, 5). Steroid receptors bind as homodimers to two half-sites of a DNA palindrome. In contrast, TRs, retinoic acid receptors (RARs), vitamin D receptors (VDRs), peroxisome proliferator-activated receptors (PPARs), and several orphan receptors bind as heterodimers with retinoid X receptors (RXRs) to direct repeats (DRs) of the AGGTCA half-site (1) but also bind to elements oriented as palindromes or inverted palindromes (1). Binding specificity of these receptors is determined by spacing between the half-sites, because PPARs, VDRs, TRs, and RARs bind preferentially to DRs spaced by 1, 3, 4, or 5 nucleotides, respectively (1). Unlike PPARs, VDRs, and RARs, TRs also bind DNA as monomers and as homodimers to DRs and to inverted palindromes spaced by 4 -6 nucleotides (F2) (1, 6, 7). Current concepts of the dimerization and heterodimerization interfaces for nuclear receptors are based on mutational and x-ray crystal structural data. The mutation data for LBDs are mostly limited to TR, RAR, VDR, and RXR. Little is known from mutation studies with the steroid receptors, because only few studies report single mutations in the LBDs that disrupt dimerization (8). This is due in part to the fact that the DBDs and amino-terminal fragments of these receptors contribute su...

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“…Studies using circular dichroism spectroscopic analysis have provided evidence for a ligand-induced conformational change in TR, while gel shift experiments have shown that the mobility of DNA-bound complexes is increased with T 3 (9,11,50). Crystallographic studies of the LBD of the ␣ isoform of TR, which is highly homologous to TR␤ (51), also suggest an influence of ligand binding on dimerization.…”

Section: Discussionmentioning

confidence: 99%

Thyroid Hormone-mediated Enhancement of Heterodimer Formation between Thyroid Hormone Receptor β and Retinoid X Receptor

Collingwood

Butler

Tone

et al. 1997

Journal of Biological Chemistry

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A subset of nuclear receptors, including those for thyroid hormone (TR), retinoic acid, vitamin D 3 , and eicosanoids, can form heterodimers with the retinoid X receptor (RXR) on DNA regulatory elements in the absence of their cognate ligands. In a mammalian twohybrid assay, we have found that recruitment of a VP16-RXR chimera by a Gal4-TR␤ ligand-binding domain fusion is enhanced up to 50-fold by thyroid hormone (T 3 ). This was also observed with a mutant fusion, Gal4-TR(L454A), lacking ligand-inducible activation function (AF-2) and unable to interact with putative coactivators, suggesting that the AF-2 activity of TR or intermediary cofactors is not involved in this effect. The wild-type and mutant Gal4-TR fusions also exhibited hormonedependent recruitment of RXR in yeast. Hormone-dependent recruitment of RXR was also evident with another Gal4-TR mutant, AHTm, which does not interact with the nuclear receptor corepressor N-CoR, suggesting that ligand-enhanced dimerization is not a result of T 3 -induced corepressor release. Finally, we have shown that the interaction between RXR and TR is augmented by T 3 in vitro, arguing against altered expression of either partner in vivo mediating this effect. We propose that ligand-dependent heterodimerization of TR and RXR in solution may provide a further level of control in nuclear receptor signaling.The thyroid hormone receptor (TR) 1 is a member of the nuclear receptor superfamily of ligand-inducible transcription factors. A subset of receptors, including those for estrogen and glucocorticoid, bind to regulatory sequences in target gene promoters as homodimers, with cooperative DNA binding and dimerization mediated by regions within their DNA-and ligand-binding domains (1-7). The thyroid hormone receptor is also capable of binding to thyroid hormone response elements (TREs) as a monomer or homodimer, but the latter complex is known to dissociate in the presence of thyroid hormone (T 3 ) (8 -11). More recently, it has been shown that TR as well as receptors for vitamin D 3 , retinoic acid (RAR), and eicosanoids form heterodimeric complexes with an auxiliary factor, the retinoid X receptor (RXR) (12-22). The TR⅐RXR heterodimer binds TREs with higher affinity than TR alone and remains stable in the presence of T 3 (8 -11), suggesting that this complex mediates ligand-dependent transcriptional activation.The isolated DNA-binding domains (DBDs) of TR and RXR are capable of both cooperative binding to and discrimination of direct repeat TREs (23). The dimerization interface between DBDs was mapped initially by mutational analyses (24) and then elucidated from the crystal structure of TR⅐RXR DBDs bound to a DR4 TRE (25). A separate dimerization interface in the carboxyl-terminal domains of nuclear receptors was first delineated as a series of nine conserved hydrophobic heptad repeats (26) predicted to form ␣-helices with the potential to mediate a coiled-coil protein interaction. A 40-amino acid region encompassing the ninth heptad has been shown to be critical for heter...

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Thyroid hormone alters the DNA binding properties of chicken thyroid hormone receptors α and β

Cited by 85 publications

References 38 publications

Coactivation of nuclear receptors and myogenic factors induces the major BTG1 influence on muscle differentiation

Coactivation of nuclear receptors and myogenic factors induces the major BTG1 influence on muscle differentiation

Definition of the Surface in the Thyroid Hormone Receptor Ligand Binding Domain for Association as Homodimers and Heterodimers with Retinoid X Receptor

Thyroid Hormone-mediated Enhancement of Heterodimer Formation between Thyroid Hormone Receptor β and Retinoid X Receptor

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