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

Collingwood, Trevor N.; Butler, Alison Jane; Tone, Yukiko; Clifton‐Bligh, Roderick; Parker, Malcolm G.; Chatterjee, Krishna

doi:10.1074/jbc.272.20.13060

Cited by 42 publications

(31 citation statements)

References 56 publications

(62 reference statements)

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“…A similar observation that confirms these results was reported while this paper was under review (11). Thus, we propose that RXR differentially interacts with the unliganded and liganded conformations of TR.…”

Section: Discussionsupporting

confidence: 79%

Differential Recognition of Liganded and Unliganded Thyroid Hormone Receptor by Retinoid X Receptor Regulates Transcriptional Repression

Zhang

Zamir

Lazar

1997

Molecular and Cellular Biology

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Thyroid hormone receptor (TR) functions as part of multiprotein complexes that also include retinoid X receptor (RXR) and transcriptional coregulators. We have found that both the TR CoR box and ninth heptad are required for RXR interaction and in turn for interaction with corepressor proteins N-CoR and SMRT. Remarkably, the recruitment of RXR to repression-defective CoR box and ninth-heptad mutants via a heterologous dimerization interface restores both corepressor interaction and repression. The addition of thyroid hormone obviates the CoR box requirement for RXR interaction, provided that the AF2 activation helix at the C terminus of TR is intact. These results indicate that RXR differentially recognizes the unliganded and liganded conformations of TR and that these differences appear to play a major role in the recruitment of corepressors to TR-RXR heterodimers.Thyroid hormone receptor (TR) is a multifunctional protein. It is a transcriptional repressor in the absence of ligand and a transcriptional activator in the presence of thyroid hormone (T3). Repression is mediated by interaction with a family of corepressor proteins, including N-CoR and SMRT (10,17,34,45). A ligand-induced conformational change causes dissociation of the corepressor and recruitment of a transcriptional coactivator to the DNA-bound TR. TR binds DNA most effectively as a heterodimer with retinoid X receptor (RXR) (6,19,22,23,25,44,47). Although RXR itself is a retinoid receptor (24), its main function in TR action does not appear to require retinoid binding (14). The TR-RXR interaction is stable in solution in both the presence and absence of ligand, and it has previously been suggested that the primary role of RXR is to increase the affinity and specificity of TR for T3 response elements, which often consist of two TR half-sites separated by 4 bp (39).The primary region of importance for the TR-RXR interaction in solution is the region which is generally known as the ninth heptad, corresponding to helices 10 and 11 of the crystal structure of the TR ligand binding domain (LBD) (40). The importance of this domain explains why C-terminal deletions of TR and the C-terminal variant TR␣2 do not interact with RXR in solution (31, 42). Interestingly, although the interaction between TR and RXR is ligand independent, two groups have previously described TR ninth-heptad point mutants which interact with RXR only in the presence of T3 (1, 28). Although the TR LBD structure has been solved only in the presence of ligand, a comparison with the unliganded RXR suggests that one of the effects of ligand binding is conformational change in the region between helices 10 and 11 in addition to the turning back of the amphipathic AF2 helix (helix 12) towards the core of the TR (5, 40).In contrast to the importance of C-terminal domains for RXR interaction, previous studies of TR interaction with NCoR and SMRT have focused on the CoR box within the hinge region of TR (10, 17). Like the ninth heptad, the CoR box is highly conserved among receptors that int...

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Section: Discussionsupporting

confidence: 79%

Differential Recognition of Liganded and Unliganded Thyroid Hormone Receptor by Retinoid X Receptor Regulates Transcriptional Repression

Zhang

Zamir

Lazar

1997

Molecular and Cellular Biology

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“…2, B and C). These results are consistent with recent reports in which basal interactions of RXR-RAR and RXR-TR were shown to be further stimulated by ligand (22,23). Given these results, we wanted to make certain that the differential interaction profiles of these RXR mutants are not the result of different protein expression levels.…”

Section: Specific Dimerization Defects Of Rxr-a416d and Rxr-a416k-quasupporting

confidence: 80%

“…Next, these interactions were further confirmed in the GST pull-down assays. Consistent with recent reports (22,23), radiolabeled wild type RXR interacted with GST fusions to TR and RAR in a ligand-dependent manner but not with GST alone, whereas radiolabeled luciferase interacted with none of these GST proteins (Fig. 3B).…”

Section: Specific Dimerization Defects Of Rxr-a416d and Rxr-a416k-quasupporting

confidence: 79%

Mutations in Retinoid X Receptor That Impair Heterodimerization with Specific Nuclear Hormone Receptor

Lee

2000

Journal of Biological Chemistry

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Retinoid X receptor (RXR) serves as a promiscuous heterodimerization partner for many nuclear receptors through the identity box, a 40-amino acid subregion within the ligand binding domain. In this study, we randomly mutated two specific residues within the human RXR␣ identity box region previously identified as important determinants in heterodimerization (i.e. Ala 416 and Arg 421 ). Interestingly, most of these mutants still retained wild type interactions with thyroid hormone receptor (TR), retinoic acid receptor, peroxisome proliferator-activated receptor ␣, small heterodimer partner, and constitutive androstane receptor. However, RXR-A416D and R421L were specifically impaired for interactions with TR, whereas RXR-A416K lost both TR and retinoic acid receptor interactions. Accordingly, RXR-A416D did not support T3 transactivation in mammalian cells, whereas RXR-A416K was not supportive of transactivation by retinoids or T3. These results provide a basis upon which to further design mutant RXRs highly selective in heterodimerization, potentially useful tools to probe nuclear receptor function in vivo.

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“…3C). A similar degree of interference of PPARG point mutants has been attributed to a dominant negative mode of action (35)(36)(37). Indeed, we assayed one of these dominant negative mutants in our cell system, obtaining results similar to those reported here with the new isoform (data not shown).…”

Section: Identification and Analysis Of The ␥Orf4 Transcript-usingsupporting

confidence: 72%

A Novel Peroxisome Proliferator-activated Receptor γ Isoform with Dominant Negative Activity Generated by Alternative Splicing

Sabatino

Casamassimi

Peluso

et al. 2005

Journal of Biological Chemistry

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We examined the peroxisome proliferator-activated receptor ␥ (PPARG) locus in an attempt to identify expressed sequence tags and/or conserved non-coding sequences in the intron sequences containing open reading frames and potentially able to encode new proteins. We identified a new PPARG transcript, defined ␥ORF4, which harbors a readthrough in intron 4. The expected translated protein lacks the ligand-binding domain encoded by exons 5 and 6. We identified the transcript in human tumor cell lines and tissues, synthesized the cDNA, and cloned it in expression vectors. Using transient transfections, we found that ␥ORF4 cDNA is translated into a predominantly nuclear protein that does not transactivate a reporter gene. Moreover, the isoform is dominant negative versus PPAR␥. Interestingly, ␥ORF4 was expressed in vivo in a series of sporadic colorectal cancers. In some cases, it was expressed, albeit at lower levels, also in the mucosa adjacent to the tumors, suggesting that it may be related to tumorigenesis. A tumorigenic effect of ␥ORF4 is in line with our finding that ␥ORF4 has not only lost the capacity to restrain cell growth but has acquired the potential to stimulate it. In conclusion, this study demonstrates that ␥ORF4 is expressed in vivo, that it has lost some PPAR␥ properties, and that it affects PPAR␥ functioning. The ability to counteract PPAR␥ suggests that ␥ORF4 plays a role in the pathogenesis of colorectal cancers.

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

Cited by 42 publications

References 56 publications

Differential Recognition of Liganded and Unliganded Thyroid Hormone Receptor by Retinoid X Receptor Regulates Transcriptional Repression

Differential Recognition of Liganded and Unliganded Thyroid Hormone Receptor by Retinoid X Receptor Regulates Transcriptional Repression

Mutations in Retinoid X Receptor That Impair Heterodimerization with Specific Nuclear Hormone Receptor

A Novel Peroxisome Proliferator-activated Receptor γ Isoform with Dominant Negative Activity Generated by Alternative Splicing

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