Variable RXR requirements for thyroid hormone responsiveness of endogenous genes

Diallo, Ericka M.; Wilhelm, Kenneth; Thompson, Deborah; Koenig, Ronald J.

doi:10.1016/j.mce.2006.11.004

Cited by 16 publications

(12 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…SRC-1 NR2 peptide stabilizes the DNA binding of RAR homodimer (Kd ¼ 25 AE 2 nM). These results are consistent with the observed enhanced DNA binding of TR homodimers in presence of SRC-1 (13). SAXS was used to obtain structural information on the dimers bound to SRC RID.…”

Section: Rarβ Forms Dimers In Solution In Presence Of Ligand and Coacsupporting

confidence: 86%

“…Whether RAR homodimers may play a role in the regulation of specific target genes acting as additional modulators of physiological response to retinoic acid is not fully admitted, but some results support the possibility (11)(12)31). The formation of such homodimers is contingent upon either the nature of the coactivator interacting with RAR or the promoter context of target genes (11,13). Other NR LBDs that are known to function as heterodimers with RXR such as PPAR (21), LXRα (22) or LXRβ (23) have also been crystallized as homodimers, with the same interface as RAR, in presence of coactivator peptides.…”

Section: Discussionmentioning

confidence: 99%

“…In vivo, the targeted ablation of all RXR isotypes in mouse Sertoli cells yields a phenotype distinct from that observed upon ablation of all RARs isotypes suggesting that in Sertoli cells an alternate RXR independent mechanism accounts for the RAR-mediated biological responses (12). Similarly, knockdown of RXRs by RNAi impair only a subset of T3 regulated genes (13).…”

mentioning

confidence: 98%

See 2 more Smart Citations

Structural basis for a molecular allosteric control mechanism of cofactor binding to nuclear receptors

Ősz

Brélivet

Peluso‐Iltis

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Transcription regulation by steroid hormones, vitamin derivatives, and metabolites is mediated by nuclear receptors (NRs), which play an important role in ligand-dependent gene expression and human health. NRs function as homodimers or heterodimers and are involved in a combinatorial, coordinated and sequentially orchestrated exchange between coregulators (corepressors, coactivators). The architecture of DNA-bound functional dimers positions the coregulators proteins. We previously demonstrated that retinoic acid (RAR-RXR) and vitamin D3 receptors (VDR-RXR) heterodimers recruit only one coactivator molecule asymmetrically without steric hindrance for the binding of a second cofactor. We now address the problem of homodimers for which the presence of two identical targets enhances the functional importance of the mode of binding. Using structural and biophysical methods and RAR as a model, we could dissect the molecular mechanism of coactivator recruitment to homodimers. Our study reveals an allosteric mechanism whereby binding of a coactivator promotes formation of nonsymmetrical RAR homodimers with a 2∶1 stoichiometry. Ligand conformation and the cofactor binding site of the unbound receptor are affected through the dimer interface. A similar control mechanism is observed with estrogen receptor (ER) thus validating the negative cooperativity model for an established functional homodimer. Correlation with published data on other NRs confirms the general character of this regulatory pathway.allostery | structure T he superfamily of nuclear receptors (NRs) comprises liganddependent transcription factors involved in the regulation of gene expression. They constitute key drug targets for human diseases such as cancer, osteoporosis, obesity, or type II diabetes (1-2). NRs share a common structural organization with a variable amino-terminal domain, a conserved DNA-binding domain (DBD), and a C-terminal ligand-binding domain (LBD) linked by a flexible hinge peptide. In addition to the ligand-binding pocket, the LBD comprises dimerization surfaces and the sites for coregulator interactions. In the classic mode of action, in absence of ligand, some NRs are associated with corepressors (NCoRs) that harbor histone-deacetylase activity to maintain the chromatin in a transcriptionally silent state (3-4). Upon ligand binding, DNA-bound receptors recruit coactivators like the steroid receptor coactivator 1 (SRC-1), a member of p160 CoA family (5), to enhance target gene expression. The receptor interaction domain (RID) of the coactivators is responsible for the interaction with NRs and contains several copies of the short consensus interaction motif LXXLL (6).The vast majority of NRs functions as dimers. RAR, like the vitamin D (VDR) and thyroid hormone (TR) receptors, heterodimerizes with rexinoid receptors (RXRs) (7). Their ability to form homodimers is also documented (8-10). RAR homodimers have been shown to be functional in yeast using a two-hybrid system, and their activity is further enhanced by the presence of SRC-2 c...

show abstract

Section: Rarβ Forms Dimers In Solution In Presence Of Ligand and Coacsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 98%

See 1 more Smart Citation

Structural basis for a molecular allosteric control mechanism of cofactor binding to nuclear receptors

Ősz

Brélivet

Peluso‐Iltis

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Thyroid hormone receptors mediate repression (usually in the absence of ligand) by interacting with nuclear co-repressors NCoR and/or SMRT (Eckey et al, 2003;Makowski et al, 2003;Havis et al, 2006). In fact, a growing body of evidence indicates that heterodimers of thyroid hormone and Rxr receptors adopt different configurations based on information provided by the DNA binding site with which they associate, that facilitate or block interactions with co-activators or co-repressors [ (Harvey et al, 2007) and references cited therein; (Ghosh et al, 2002;Diallo et al, 2007)]. Thus, the action of a nuclear receptor heterodimer can be influenced by each target promoter sequence to finetune interactions with ligands and cofactors.…”

Section: Trβ2 Is a Positive Regulator For M-conesmentioning

confidence: 99%

Regulation of photoreceptor gene expression by Crx-associated transcription factor network

2008

View full text Add to dashboard Cite

Rod and cone photoreceptors in the mammalian retina are special types of neurons that are responsible for phototransduction, the first step of vision. Development and maintenance of photoreceptors require precisely regulated gene expression. This regulation is mediated by a network of photoreceptor transcription factors centered on Crx, an Otx-like homeodomain transcription factor. The cell type (subtype) specificity of this network is governed by factors that are preferentially expressed by rods or cones or both, including the rod-determining factors neural retina leucine zipper protein (Nrl) and the orphan nuclear receptor Nr2e3; and cone-determining factors, mostly nuclear receptor family members. The best-documented of these include thyroid hormone receptor β2 (Trβ2), retinoid related orphan receptor Rorβ, and retinoid X receptor Rxrγ. The appropriate function of this network also depends on general transcription factors and co-factors that are ubiquitously expressed, such as the Sp zinc finger transcription factors and STAGA coactivator complexes. These cell type-specific and general transcription regulators form complex interactomes; mutations that interfere with any of the interactions can cause photoreceptor development defects or degeneration. In this manuscript, we review recent progress on the roles of various photoreceptor transcription factors and interactions in photoreceptor subtype development. We also provide evidence of auto-, para-, and feedback regulation among these factors at the transcriptional level. These protein-protein and protein-promoter interactions provide precision and specificity in controlling photoreceptor subtype-specific gene expression, development and survival. Understanding these interactions may provide insights to more effective therapeutic interventions for photoreceptor diseases.

show abstract

“…Although the fact that TR homodimers dissociate rapidly from cognate TREs and T 3 suppresses homodimer formation on DNA has been taken as an argument against a role for this species in T 3 activation (1), other studies reveal that TR-TR⅐DNA complexes are stabilized by coactivators (32) and that T 3 response at IP-6 elements is often independent of coexpressed RXR in transfections (9,33). Most strikingly, a recent study revealed that RXR expression was only required for optimal T 3 response at subsets of positively regulated genes in a mouse preneuronal cell line (34). Thus, there are several indications that alternate TR oligomers contribute to T 3 induction.…”

mentioning

confidence: 99%

Thyroid Hormone Response Element Organization Dictates the Composition of Active Receptor

Velasco

Togashi

Walfish

et al. 2007

Journal of Biological Chemistry

View full text Add to dashboard Cite

Thyroid hormone (triiodothyronine, T 3 ) is known to activate transcription by binding heterodimers of thyroid hormone receptors (TRs) and retinoid X receptors (RXRs). RXR-TRs bind to T 3 response elements (TREs) composed of direct repeats of the sequence AGGTCA spaced by four nucleotides (DR-4). In other TREs, however, the half-sites can be arranged as inverted palindromes and palindromes (Pal). Here we show that TR homodimers and monomers activate transcription from representative TREs with alternate half-site placements. TR␤ activates transcription more efficiently than TR␣ at an inverted palindrome (F2), and this correlates with preferential TR␤ homodimer formation at F2 in vitro. Furthermore, reconstruction of TR transcription complexes in yeast indicates that TR␤ homodimers are active at F2, whereas RXR-TRs are active at DR-4 and Pal. Finally, analysis of TR␤ mutations that block homodimer and/or heterodimer formation reveal TRE-selective requirements for these surfaces in mammalian cells, which suggest that TR␤ homodimers are active at F2, RXR-TRs at DR-4, and TR monomers at Pal. TR␤ requires higher levels of hormone for activation at F2 than other TREs, and this differential effect is abolished by a dimer surface mutation suggesting that it is related to composition of the TR⅐TRE complex. We propose that interactions of particular TR oligomers with different elements play unappreciated roles in TRE-selective actions of liganded TRs in vivo.

show abstract

Variable RXR requirements for thyroid hormone responsiveness of endogenous genes

Cited by 16 publications

References 19 publications

Structural basis for a molecular allosteric control mechanism of cofactor binding to nuclear receptors

Structural basis for a molecular allosteric control mechanism of cofactor binding to nuclear receptors

Regulation of photoreceptor gene expression by Crx-associated transcription factor network

Thyroid Hormone Response Element Organization Dictates the Composition of Active Receptor

Contact Info

Product

Resources

About