Overlapping Transcriptional Programs Regulated by the Nuclear Receptors Peroxisome Proliferator-Activated Receptor α, Retinoid X Receptor, and Liver X Receptor in Mouse Liver

2004 ◽  
Vol 66 (6) ◽  
pp. 1440-1452 ◽  
Author(s):  
Steven P. Anderson ◽  
Corrie Dunn ◽  
Ashley Laughter ◽  
Lawrence Yoon ◽  
Cynthia Swanson ◽  
...  
Keyword(s):  
Nuclear Receptors ◽  
Mouse Liver ◽  
Liver X Receptor ◽  
Retinoid X Receptor ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor

scholarly journals A Novel Role for Helix 12 of Retinoid X Receptor in Regulating Repression

1999 ◽  
Vol 19 (9) ◽  
pp. 6448-6457 ◽  
Author(s):  
Jinsong Zhang ◽  
Xiao Hu ◽  
Mitchell A. Lazar
Keyword(s):  
Binding Site ◽  
Nuclear Receptors ◽  
Thyroid Hormone Receptor ◽  
Specific Interaction ◽  
Retinoid X Receptor ◽  
Peroxisome Proliferator ◽  
Specific Sequence ◽  
Peroxisome Proliferator Activated Receptor ◽  
Binding Surface ◽  
Helix 12

ABSTRACT Nutrients, drugs, and hormones influence transcription during differentiation and metabolism by binding to high-affinity nuclear receptors. In the absence of ligand, some but not all nuclear receptors repress transcription as a heterodimer with retinoid X receptor (RXR). Here we define a novel role for helix 12 (H12) in sterically masking the corepressor (CoR) binding site in apo-RXR. Removing H12 converts RXR to a potent transcriptional repressor. The length but not the specific sequence of H12 is critical for masking RXR’s intrinsic repression function. This contrasts with the amphipathic character required for mediating ligand-dependent activation and coactivator recruitment. Physiologically, we show that heterodimerization of RXR with apo-thyroid hormone receptor (TR) unmasks the CoR binding site in RXR and allows the TR-RXR heterodimer to repress. A molecular mechanism that involves sequence-specific interaction between RXR H12 and the coactivator-binding surface of the nuclear receptor is proposed for this heterodimerization-mediated unmasking. Peroxisome proliferator-activated receptor γ does not interact as well with RXR H12, thus explaining its inability to repress transcription as an RXR heterodimer. The requirement to unmask RXR’s latent repression function explains why only certain RXR partners repress transcription.

scholarly journals Agonist binding directs dynamic competition among nuclear receptors for heterodimerization with retinoid X receptor

2020 ◽  
Vol 295 (29) ◽  
pp. 10045-10061
Author(s):  
Lina Fadel ◽  
Bálint Rehó ◽  
Julianna Volkó ◽  
Dóra Bojcsuk ◽  
Zsuzsanna Kolostyák ◽  
...  
Keyword(s):  
Nuclear Receptors ◽  
Cellular Response ◽  
Nuclear Translocation ◽  
Retinoic Acid Receptor ◽  
Retinoid X Receptor ◽  
Peroxisome Proliferator ◽  
Dynamic Competition ◽  
Peroxisome Proliferator Activated Receptor ◽  
Imaging Model ◽  
Translocation Assay

Retinoid X receptor (RXR) plays a pivotal role as a transcriptional regulator and serves as an obligatory heterodimerization partner for at least 20 other nuclear receptors (NRs). Given a potentially limiting/sequestered pool of RXR and simultaneous expression of several RXR partners, we hypothesized that NRs compete for binding to RXR and that this competition is directed by specific agonist treatment. Here, we tested this hypothesis on three NRs: peroxisome proliferator-activated receptor gamma (PPARγ), vitamin D receptor (VDR), and retinoic acid receptor alpha (RARα). The evaluation of competition relied on a nuclear translocation assay applied in a three-color imaging model system by detecting changes in heterodimerization between RXRα and one of its partners (NR1) in the presence of another competing partner (NR2). Our results indicated dynamic competition between the NRs governed by two mechanisms. First, in the absence of agonist treatment, there is a hierarchy of affinities between RXRα and its partners in the following order: RARα > PPARγ > VDR. Second, upon agonist treatment, RXRα favors the liganded partner. We conclude that recruiting RXRα by the liganded NR not only facilitates a stimulus-specific cellular response but also might impede other NR pathways involving RXRα.

scholarly journals Peroxisome proliferator-activated receptor α-retinoid X receptor agonists induce beta-cell protection against palmitate toxicity

FEBS Journal ◽  
2007 ◽  
Vol 274 (23) ◽  
pp. 6094-6105 ◽  
Author(s):  
Karine Hellemans ◽  
Karen Kerckhofs ◽  
Jean-Claude Hannaert ◽  
Geert Martens ◽  
Paul Van Veldhoven ◽  
...  
Keyword(s):  
Beta Cell ◽  
Retinoid X Receptor ◽  
Peroxisome Proliferator ◽  
Cell Protection ◽  
Peroxisome Proliferator Activated Receptor ◽  
Receptor Agonists ◽  
Beta Cell Protection

scholarly journals Post-Translational Modifications of Nuclear Receptors and Human Disease

2012 ◽  
Vol 10 (1) ◽  
pp. nrs.10001 ◽  
Author(s):  
Muralidharan Anbalagan ◽  
Brandy Huderson ◽  
Leigh Murphy ◽  
Brian G. Rowan
Keyword(s):  
Breast Cancer ◽  
Prostate Cancer ◽  
Clinical Outcome ◽  
Nuclear Receptors ◽  
Inflammatory Diseases ◽  
Peroxisome Proliferator ◽  
Additional Measure ◽  
Peroxisome Proliferator Activated Receptor ◽  
Post Translational Modifications ◽  
Pparγ Phosphorylation

Nuclear receptors (NR) impact a myriad of physiological processes including homeostasis, reproduction, development, and metabolism. NRs are regulated by post-translational modifications (PTM) that markedly impact receptor function. Recent studies have identified NR PTMs that are involved in the onset and progression of human diseases, including cancer. The majority of evidence linking NR PTMs with disease has been demonstrated for phosphorylation, acetylation and sumoylation of androgen receptor (AR), estrogen receptor α (ERα), glucocorticoid receptor (GR) and peroxisome proliferator activated receptor γ (PPARΓ). Phosphorylation of AR has been associated with hormone refractory prostate cancer and decreased disease-specific survival. AR acetylation and sumoylation increased growth of prostate cancer tumor models. AR phosphorylation reduced the toxicity of the expanded polyglutamine AR in Kennedy's Disease as a consequence of reduced ligand binding. A comprehensive evaluation of ERα phosphorylation in breast cancer revealed several sites associated with better clinical outcome to tamoxifen therapy, whereas other phosphorylation sites were associated with poorer clinical outcome. ERα acetylation and sumoylation may also have predictive value for breast cancer. GR phosphorylation and acetylation impact GR responsiveness to glucocorticoids that are used as anti-inflammatory drugs. PPARγ phosphorylation can regulate the balance between growth and differentiation in adipose tissue that is linked to obesity and insulin resistance. Sumoylation of PPARγ is linked to repression of inflammatory genes important in patients with inflammatory diseases. NR PTMs provide an additional measure of NR function that can be used as both biomarkers of disease progression, and predictive markers for patient response to NR-directed treatments.

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