Interactions that determine the assembly of a retinoid X receptor/corepressor complex

Ghosh, Jagadish C.; Yang, Xiaofang; Zhang, Aihua; Lambert, Millard H.; Li, Hui; Xu, H. Eric; Chen, J. Don

doi:10.1073/pnas.092043399

Cited by 43 publications

(54 citation statements)

References 41 publications

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“…4) as well as RXR␣/RAR␣ and RXR␣/TR␤, an observation similar to that of two previous reports (24,25). Interestingly, our FIG.…”

Section: Rar␣ Helix 12 Mutants Have Two Defects In Bothsupporting

confidence: 80%

“…Unexpectedly, we found that unliganded P408L bound weakly to ACTR (lane 9) and no further ACTR binding was induced by high concentrations of AT-RA (lanes 10 -12). Similarly, M413A also bound ACTR in the absence of ligand (lane 21), although this association was increased by AT-RA in a dose-dependent manner (lanes [22][23][24]. These data suggest that the conserved residues in the helix 12 of RAR␣ are critical for co-activator association.…”

Section: Association Of Rar␣ Helix 12 Mutants With Co-repressors-mentioning

confidence: 78%

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Retinoid X Receptor α (RXRα) Helix 12 Plays an Inhibitory Role in the Recruitment of the p160 Co-activators by Unliganded RXRα/Retinoic Acid Receptor α Heterodimers

Liu¹,

Shaw²,

Reineke

et al. 2004

Journal of Biological Chemistry

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Retinoid X receptor (RXR)/retinoic acid receptor (RAR) heterodimers control gene expression through recruitment of co-repressors or co-activators, depending on their hormone binding status. We show that the helix 12 of RXR␣ and RAR␣ is critical for recruitment of the co-regulators and transcriptional regulation by RXR␣, RAR␣, and RXR␣/RAR␣. LG268, an RXR-specific agonist, was able to promote co-activator association with the heterodimers, but was unable to dissociate corepressors. Reconstitution experiments in yeast demonstrated that LG268 was capable of activating transcription by RXR␣/RAR␣ through recruitment of the coactivator. We hypothesize that the inability to release co-repressors from RXR␣/RAR␣ is responsible for the inability of LG268 to activate RXR␣/RAR␣ heterodimers in mammalian cells. Deletion of RAR␣ helix 12 (RXR␣/ RAR␣ ⌬403) abolished both hormone-dependent dissociation from co-repressors and hormone-dependent association with co-activators. Deletion of RXR␣ helix 12 (RXR␣ ⌬443/RAR␣) resulted in a higher binding affinity for co-repressors. Unexpectedly, RXR␣ ⌬443/RAR␣ also gained hormone-independent co-activator binding activity. Moreover, LG268 became an antagonist to RXR␣ ⌬443/RAR␣ heterodimers. These data suggest that the helix 12 of RXR␣ plays an inhibitory role in the recruitment of co-activators by unliganded RXR␣/RAR␣.The nuclear hormone receptors comprise a large family of transcription factors that regulate animal development, cell proliferation, and cell differentiation through the control of a network of genes involved in these processes (1, 2). Nuclear receptors harbor two evolutionarily conserved domains, DNA binding domains (DBDs) 1 and ligand binding domains (LBDs).Whereas the DBD recognizes specific DNA sequences, the LBD dictates transcriptional activity by nuclear receptors through recruitment of co-repressors such as silencing mediator for retinoic acid and thyroid hormone receptor (SMRT) and nuclear receptor co-repressor or co-activators, including p160 family proteins (3, 4).Nuclear hormone receptors have been further subdivided into four classes based on their mode of action and DNA binding status (1). Retinoic acid receptors (RARs) and Retinoid X receptors (RXRs) are class II receptors that mediate retinoid signaling by regulating a complex gene network. RARs primarily form heterodimers with RXRs on DR5 (direct repeat spaced by 5 base pairs) or DR1-containing sequences. Conversely, RXRs are capable of forming homodimers on DR1 or heterodimers with other class II nuclear hormone receptors (1). The ability of RXRs to form homodimers or heterodimers with other receptors generates a complex mechanism by which the ligands of RXR may or may not exert effects on target genes, depending on the dimerization partner of the receptor (5). Receptors such as RARs and TRs (thyroid hormone receptors) dimerize with RXRs, generating a non-permissive complex in which RXR ligands are not capable of activating heterodimers. In such heterodimeric complexes, RXRs are referred to as silent partne...

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“…4) as well as RXR␣/RAR␣ and RXR␣/TR␤, an observation similar to that of two previous reports (24,25). Interestingly, our FIG.…”

Section: Rar␣ Helix 12 Mutants Have Two Defects In Bothsupporting

confidence: 80%

Section: Association Of Rar␣ Helix 12 Mutants With Co-repressors-mentioning

confidence: 78%

Retinoid X Receptor α (RXRα) Helix 12 Plays an Inhibitory Role in the Recruitment of the p160 Co-activators by Unliganded RXRα/Retinoic Acid Receptor α Heterodimers

Liu¹,

Shaw²,

Reineke

et al. 2004

Journal of Biological Chemistry

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“…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

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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.

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“…Co-repressors (N-CoR/SMRT) can be recruited to interacting surfaces located on the LBD surface of nuclear receptors, which partially overlaps with that used by P160 co-activators [34][35][36]. Repression of DHTactivated AR by N-CoR only requires the repressor interaction domains, and is independent of N-CoR domains that can recruit histone deacetylases [27].…”

Section: Competition Between Tif2 and N-cor Is Ligand-type-dependentmentioning

confidence: 99%

Differential modulation of androgen receptor transcriptional activity by the nuclear receptor co-repressor (N-CoR)

Berrevoets

Umar

Trapman

et al. 2004

Biochemical Journal

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Antiandrogens are widely used agents in the treatment of prostate cancer, as inhibitors of AR (androgen receptor) action. Although the precise mechanism of antiandrogen action is not yet elucidated, recent studies indicate the involvement of nuclear receptor co-repressors. In the present study, the regulation of AR transcriptional activity by N-CoR (nuclear receptor co-repressor), in the presence of different ligands, has been investigated. Increasing levels of N-CoR differentially affected the transcriptional activity of AR occupied with either agonistic or antagonistic ligands. Small amounts of co-transfected N-CoR repressed CPA (cyproterone acetate)-and mifepristone (RU486)-mediated AR activity, but did not affect agonist (R1881)-induced AR activity. Larger amounts of co-transfected N-CoR repressed AR activity for all ligands, and converted the partial agonists CPA and RU486 into strong AR antagonists. In the presence of the agonist R1881, co-expression of the p160 co-activator TIF2 (transcriptional intermediary factor 2) relieved N-CoR repression up to control levels. However, in the presence of RU486 and CPA, TIF2 did not functionally compete with N-CoR, suggesting that antagonistbound AR has a preference for N-CoR. The AR mutation T877A (Thr 877 → Ala), which is frequently found in prostate cancer and affects the ligand-induced conformational change of the AR, considerably reduced the repressive action of NCoR. The agonistic activities of CPA-and hydroxyflutamideoccupied T877A-AR were hardly affected by N-CoR, whereas TIF2 strongly enhanced their activities. These results indicate that lack of N-CoR action allows these antiandrogens to act as strong agonists on the mutant AR.

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Interactions that determine the assembly of a retinoid X receptor/corepressor complex

Cited by 43 publications

References 41 publications

Retinoid X Receptor α (RXRα) Helix 12 Plays an Inhibitory Role in the Recruitment of the p160 Co-activators by Unliganded RXRα/Retinoic Acid Receptor α Heterodimers

Retinoid X Receptor α (RXRα) Helix 12 Plays an Inhibitory Role in the Recruitment of the p160 Co-activators by Unliganded RXRα/Retinoic Acid Receptor α Heterodimers

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

Differential modulation of androgen receptor transcriptional activity by the nuclear receptor co-repressor (N-CoR)

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